2005 Research Highlights
Below are highlights of research reported by grantees supported by the Epidemiology and Genetics Research Program (EGRP). We can't begin to capture all the research contributions of our grantees and apologize for this. The names of the first authors and of the EGRP-supported Principal Investigators whose grants are credited in the published papers appear in boldface print.
- Oophorectomy Confirmed As Protecting Against Breast Cancer in BRCA1 Mutation Carriers
- SHBG Gene Variant Associated With Decreased Risk of Breast Cancer
- DNA Repair Deficiency Associated With Breast Cancer Risk in Sister Pairs
- Oral Contraceptive Use in BRCA1 and BRCA2 Gene Mutation Carriers
- Exercise and Weight Control Associated With Decreased Breast Cancer Risk
- Folate Intake Associated With Decreased ER-Breast Cancer Risk
- Physical Activity, Obesity, and Weight Gain Associated With Breast Cancer Survival
- Improved Method Demonstrated To Detect HNPCC Mutations
- New, More Accurate Information Available on Risk of Hereditary Colorectal Cancer
- Vitamin B6 Inversely Associated With Risk of Colorectal Cancer
- Pooled Analysis Shows Dietary Fiber Not Associated With Decreased Colorectal Cancer Risk
- NSAIDs May Protect Against Colon Cancer in African Americans
- Statins May Reduce Risk of Colorectal Cancer
Head and Neck Cancer
- InterLymph Consortium Investigates Alcohol Consumption and Non-Hodgkin's Lymphoma
- Western Diet Associated With Increased Risk of Non-Hodgkin's Lymphoma
- Predictors of Natural Immunity to Ovarian Cancer Identified
- Pooled Analysis Indicates Fruits and Vegetables Not Associated With Decreased Ovarian Cancer Risk
- P450 Polymorphism Associated With Risk of Prostate Cancer in African-American Men
- International Consortium Conducts Large, Genomewide Linkage Scan for Prostate Cancer-Susceptibility Genes
- Statins Associated With Decreased Risk of Advanced Prostate Cancer
Insulin-Like Growth Factors
- 1st Leadership Workshop Identifies Barriers, Gaps, and Opportunities in Tobacco, Diet/Energy Balance, and Genetic Research
- 2nd Epidemiology Leadership Workshop Focuses on Understudied Rare Cancers
- Report on Cancer Risk Prediction Models Identifies Priorities and Resources
Perspectives: Nature Reviews Cancer
- Consortium Hunts Low-Penetrance Breast and Prostate Cancer Genes
- Long Island Breast Cancer Study Project: Research on Environmental Exposures and Breast Cancer
Molecular Features of Adult Glioma Detailed
Malignant gliomas in adults represent a highly heterogeneous group of tumors with unknown etiology. Mutations in the TP53 gene, most likely arising from DNA alkylation, are common in these brain cancers and are associated with various demographic risk factors including age and ethnicity. Inactivation of the DNA repair protein O6-methylguanine- DNA-methyltransferase (MGMT), which repairs alkylation damage, is associated with TP53 mutations in human cancers, and several heritable polymorphisms in MGMT have been defined. John Wiencke, Ph.D., of the University of California at San Francisco (UCSF), and colleagues conducted molecular analyses of 556 glioma tumors (astrocytic) and collected information on TP53 status, epidermal growth factor receptor (EGFR) gene and murine double minute-2 (MDM2) gene amplification, and MGMT germline genotype data.
Patients with tumors bearing TP53 mutations tended to be younger than those whose tumors did not have this mutation, and they were more likely to be nonwhite (African American and Asian) than Latino and non-Latino white. In addition, EGFR gene amplification was associated with an older age of onset (68 years vs. 48 years); carriers of the MGMT variant 84Phe allele were less likely to have tumors with TP53 overexpression; and EGFR gene amplification and protein overexpression were inversely associated with the variant MGMT allele. An inverse relationship between TP53 mutation and MDM2 or EGFR amplification was observed. The findings indicate that age, race/ethnicity, and inherited genetic factors are linked to molecular features of glioma, and it seems likely, say the researchers, "that applying these markers in molecular epidemiology studies holds promise in searching out the underlying causes of these cancers." The study was supported in part by EGRP grants to Dr. Wiencke and Margaret Wrensch, Ph.D., also of UCSF.
Wiencke JK, Aldape K, McMillan A, Wiemels J, Moghadassi M, Miike R, Kelsey KT, Patoka J, Long J, Wrensch M. Molecular features of adult glioma associated with patient race/ethnicity, age, and a polymorphism in O6-methylguanine-DNA-methyltransferase. Cancer Epidemiol Biomarkers Prev. 2005 Jul;14(7):1774-83.
Chickenpox Virus May Protect Against Adult Brain Cancer
In past research, Margaret Wrensch, Ph.D., of the University of California at San Francisco, and colleagues unexpectedly found that adults with gliomas were less likely than controls to have a history of chickenpox and shingles and to have immunglobulin G antibodies for varicella-zoster virus, the cause of these conditions. In new research with a different study population, she and her research team investigated whether history of varicella-zoster virus infections, or immunity to the virus or to other herpesviruses, is associated with risk for glioma. They found that patients with glioma, particularly those with glioblastoma multiforme, were less likely to report a history of chicken pox and had significantly lower levels of immunoglobulin G for varicella-zoster virus than controls. Glioblastoma multiforma is the most common and aggressive type of primary brain tumor. No significant differences were noted between cases and controls for positivity to three other herpesviruses, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus. The studied included 229 adults with glioma and 289 controls participating in the San Francisco Bay Area Adult Glioma Study. The researchers recommend that cohort studies be conducted to clarify the nature of the association between immunity to and/or clinical manifestations of varicella-zoster virus and glioblastoma. The study was partly funded by an EGRP grant to Dr. Wrensch.
Wrensch M, Weinberg A, Wiencke J, Miike R, Sison J, Wiemels J, Barger G, DeLorenze G, Aldape K, Kelsey K. History of chickenpox and shingles and prevalence of antibodies to varicella-zoster virus and three other herpesviruses among adults with glioma and controls. Am J Epidemiol. 2005 May 15;161(10):929-38.
Oophorectomy Confirmed As Protecting Against Breast Cancer in BRCA1 Mutation Carriers
Findings from a large study by Andrea Eisen, M.D., of Toronto Sunnybrook Regional Cancer Centre, and colleagues demonstrate that bilateral oophorectomy is an effective means of reducing risk for breast cancer in BRCA1 gene mutation carriers, and may be effective for BRCA2 mutation carriers as well. Oophorectomy was found to be associated with a 56 percent reduction in breast cancer in BRCA1 carriers. A similar but nonsignificant reduction in breast cancer risk was found for BRCA2 carriers (Odds Ratio (OR): 0.57). The strongest effects were observed with oophorectomies performed in BRCA1 carriers before 40 years of age (OR: 0.36) and for breast cancers that were diagnosed before 40 years of age (OR: 0.53). The protective effect for carriers of both the BRCA1 and BRCA2 mutations may be limited to a period of 15 years following surgery (OR: 0.39). Data were analyzed on 1,439 patients with breast cancer and 1,866 controls from a registry of BRCA1 and BRCA2 carriers. These results confirm previously reported findings from smaller studies of women with hereditary susceptibility to breast and ovarian cancer, but go further. Earlier studies were not sufficiently large to estimate the magnitude of risk reduction by age of oophorectomy or by BRCA1/BRCA2 mutation status, or to measure the duration of the effect. This research was supported in part by an EGRP grant to Susan Neuhausen, Ph.D., of the University of California at Irvine.
Eisen A, Lubinski J, Klijn J, Moller P, Lynch HT, Offit K, Weber B, Rebbeck T, Neuhausen SL, Ghadirian P, Foulkes WD, Gershoni-Baruch R, Friedman E, Rennert G, Wagner T, Isaacs C, Kim-Sing C, Ainsworth P, Sun P, Narod SA. Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: an international case-control study. J Clin Oncol. 2005 Oct 20;23(30):7491-6.
SHBG Gene Variant Associated With Decreased Risk of Breast Cancer
Sex hormone-binding globulin (SHBG) modulates the bioavailability of circulating sex hormones, regulating their effects on target tissues. The SHBG gene in breast cancer cells inhibits estradiol-induced cell proliferation and thus may influence breast cancer risk. Yong Cui, M.D., of Vanderbilt University School of Medicine, and colleagues examined the association between a common functional polymorphism of the SHBG gene (Asp327Asn) and risk of breast cancer in a large population-based case-control study in Shanghai, China. They found the variant Asn allele associated with elevated plasma SHBG levels and decreased risk of breast cancer in postmenopausal women (27% reduction in risk). Furthermore, the allele's protective effect was much stronger among postmenopausal women with low adiposity (more than 50% reduction in risk). The inverse association between the allele and breast cancer risk also was stronger for estrogen receptor-positive cancer than for estrogen receptor-negative cancer. The study included 1,106 cases and 1,180 controls. It was funded by EGRP grants to Wei Zheng, Ph.D., of the same institution.
Cui Y, Shu XO, Cai Q, Jin F, Cheng JR, Cai H, Gao YT, Zheng W. Association of breast cancer risk with a common functional polymorphism (Asp327Asn) in the sex hormone-binding globulin gene. Cancer Epidemiol Biomarkers Prev 2005 May;14(5):1096-101.
DNA Repair Deficiency Associated With Breast Cancer Risk in Sister Pairs
Deficient DNA repair capacity may influence risk for breast cancer and may be a valuable in vitro biomarker to identify high-risk individuals, especially in breast cancer families, according to a study by David Kennedy, Ph.D., of Columbia University, and colleagues. The researchers analyzed DNA repair capacity in lymphoblastoid cells from sister pairs, comparing women diagnosed with breast cancer to their unaffected sisters. The cells were treated with a DNA-damaging carcinogen (benzo[a]pyrene diolepoxide), and those cells of sisters with breast cancer were 8.6 percent less effective than their sisters' cells in responding to the assault. Women who had the lowest levels of DNA repair capability had double the risk for breast cancer compared with women who had the highest capability. The largest differences were found between patients and controls younger than age 40. In addition, the relative risk of breast cancer was nearly 3 times greater between the groups with the most and the least DNA repair capabilities. The study population (158 case patients and 154 controls) was from the EGRP-funded Metropolitan New York Registry of Breast Cancer Families, for which Rubie Senie, Ph.D., of the same institution, is principal investigator.
Kennedy DO, Agrawal M, Shen J, Terry MB, Zhang FF, Senie RT, Motykiewicz G, Santella RM. DNA repair capacity of lymphoblastoid cell lines from sisters discordant for breast cancer. J Natl Cancer Inst. 2005 Jan 19;97(2):84-5.
Oral Contraceptive Use in BRCA1 and BRCA2 Gene Mutation Carriers
Through the EGRP-funded Breast Cancer Family Registry (CFR), researchers have conducted the first, large, population-based study focusing on the relationship between oral contraceptive use and risk for breast cancer in women with BRCA1 and BRCA2 gene mutations. Past studies have suggested that oral contraceptive use is associated with a small increased risk for breast cancer, but the risks for mutation carriers were unclear. This new study found no evidence of an association between use of current low-dose formulations of oral contraceptives and early-onset breast cancer risk (diagnosed before age 40) for either BRCA1 or BRCA2 gene mutation carriers. In fact, the risk for early-onset breast cancer may be reduced for BRCA1 gene mutation carriers. In light of these findings and given that other research suggests that current formulations of contraceptives may reduce risk for ovarian cancer among mutation carriers, their use by women with BRCA1 and BRCA2 gene mutations does not appear to be harmful. The study was conducted by Roger Milne, Ph.D., of The University of Melbourne, and colleagues. It was funded in part through EGRP grants for the Breast Cancer Family Registry to John Hopper, Ph.D., of The University of Melbourne; Irene Andrulis, Ph.D., of Cancer Care Ontario; and Dee West, Ph.D., of Northern California Cancer Center; and a grant to Alice Whittemore, Ph.D., of Stanford University.
Milne RL, Knight JA, John EM, Dite GS, Balbuena R, Ziogas A, Andrulis IL, West DW, Li FP, Southey MC, Giles GG, McCredie MR, Hopper JL, Whittemore AS. Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev 2005 Feb;14(2):350-6.
Exercise and Weight Control Associated With Decreased Breast Cancer Risk
Women who exercise more and control their weight may significantly reduce their risk of developing breast cancer, according to research by Alecia Malin, Ph.D., of Meharry Medical College, and colleagues. In their study, the researchers found a strong link between "energy balance"—the difference between energy intake (eating) and energy expenditure (physical activity)—and breast cancer risk. This association was stronger in postmenopausal women than in premenopausal women, and postmenopausal women with higher body mass index measurements who did not exercise were found to be at substantially increased risk of breast cancer (Odds Ratio (OR): 4.74). The findings support current breast cancer prevention efforts that encourage increased physical activity levels and discourage age-related weight gain. The population-based study included 1,459 breast cancer cases and 1,556 controls participating in the Shanghai Breast Cancer Study. The research was supported in part by an EGRP grant to Wei Zheng, M.D., Ph.D., M.P.H., of Vanderbilt University. The Shanghai Breast Cancer Study is a cohort that has been funded by EGRP since 1996.
Malin A, Matthews CE, Shu XO, Cai H, Dai Q, Jin F, Gao YT, Zheng W. Energy balance and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2005 Jun;14(6):1496-501.
Folate Intake Associated With Decreased ER- Breast Cancer Risk
Folate plays an important role in DNA methylation, and aberrant methylation of the estrogen receptor (ER) gene may be related to the loss of ER gene expression in breast tumors. Deficiency in folate has been hypothesized to be associated with ER- breast cancer, but data have been sparse. In new research, Shumin Zhang, M.D., Sc.D., of Harvard School of Public Health, and colleagues found that higher total folate intake was associated with a lower risk of developing ER- but not ER+ breast cancer. Women in the highest quintile of total folate intake had a 20 percent reduction in risk for ER- breast cancer compared to women in the lowest quintile of intake. The inverse association between total folate intake and ER- breast cancer was particularly strong in women who regularly consumed alcohol (15 grams per day [0.5 oz.] or more). Ensuring adequate folate intake seems especially important for women at higher risk of breast cancer because of alcohol consumption, the researchers say. The analysis is from the Nurses' Health Study I. During 20 years of followup, 2,812 ER+ and 985 ER- breast cancer cases were documented among the cohort of 88,744 women. The research was supported in part by an EGRP grant to Graham Colditz, M.D., Dr.P.H., of the same institution. NHS I has been funded by EGRP since 1973.
Zhang SM, Hankinson SE, Hunter DJ, Giovannucci EL, Colditz GA, Willett WC. Folate intake and risk of breast cancer characterized by hormone receptor status. Cancer Epidemiol Biomarkers Prev 2005 Aug;14(8):2004-8.
Physical Activity, Obesity, and Weight Gain Associated With Breast Cancer Survival
Two recent studies provide new information on physical activity, obesity, and weight gain in relation to breast cancer survival. Michelle Holmes, M.D., Dr.P.H., of Brigham and Women's Hospital and Harvard Medical School, and colleagues analyzed data from nearly 3,000 women participating in the Nurses' Health Study (NHS) who were diagnosed with stages I, II, and III breast cancer. Women with breast cancer who engaged in physical activity equivalent to walking 1 or more hours per week had better survival than those who exercised less than that or not at all. The benefit was particularly apparent for women with hormone-responsive tumors. Physical activity has been linked to lower levels of circulating ovarian hormones, which may explain the relationship between physical activity and breast cancer. The researchers concluded that women who follow the U.S. government's recommendations to exercise at moderate intensity for 30 or more minutes per day for 5 or more days per week may survive longer.
In other NHS research, Candyce Kroenke, Sc.D., also of Brigham and Women's Hospital and Harvard Medical School, and colleagues found that women who are overweight prior to breast cancer diagnosis, or who are lean but gain weight following diagnosis, are more likely to have their disease return or to die from it. This effect was particularly pronounced among women who had never smoked. This is the first study of obesity and breast cancer to separate smokers from nonsmokers. Maintaining a healthy weight is important to reduce the risk of breast cancer recurrence and death, reported the researchers. The study was based on data on 5,204 breast cancer patients collected over 24 years.
The two studies were supported by EGRP grants to Graham Colditz, M.D., Dr.P.H. EGRP has supported the NHS since its establishment in 1973.
Holmes MD, Chen WY , Feskanich D, Kroenke CH, Colditz GA. Physical activity and survival after breast cancer diagnosis. JAMA 2005 May 25;293(20):2479-86.
Kroenke CH, Chen WY, Rosner B, Holmes MD. Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol 2005 Mar 1;23(7):1370-8. Epub 2005 Jan 31.
HPV Reactivated in HIV-Positive Women
For the first time, researchers have found strong evidence that the virus that causes cervical cancer, human papillomavirus (HPV), can be reactivated after being undetectable, which is especially likely in women with impaired immunity due to HIV infection as well as other causes. These findings have major implications for HIV-positive women and others with poor immune status, report Howard Strickler, Ph.D., of Albert Einstein College of Medicine of Yeshiva University, and colleagues. The study is based on data from the Women's Interagency HIV Study (WIHS), a prospective cohort of more than 2,500 HIVpositive and HIV-negative women. Their data suggest that undetectable HPV infections become active much more frequently in HIV-positive women, which may help explain the high rates of HPV infection in these women. For HIV-positive women, the researchers found that CD4+ cell count in combination with HIV RNA levels appeared to have a significant association with incident detection of HPV, some of the association possibly reflecting HPV reactivation in sexually inactive women. Although weakened immune status due to HIV had a major effect on allowing HPV infections to develop, HIV had a relatively modest effect on HPV persistence, a necessity for cervical cancer to occur. This finding may help explain why cervical cancer rates have not reached more epidemic proportions in HIV-positive women. The research was partly funded by an EGRP grant to Dr. Strickler.
Strickler HD, Burk RD, Fazzari M, Anastos K, Minkoff H, Massad LS, Hall C, Bacon M, Levine AM, Watts DH, Silverberg MJ, Xue X, Schlecht NF, Melnick S, Palefsky JM. Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J Natl Cancer Inst 2005 Apr 20;97(8):577-86.
Improved Method Demonstrated To Detect HNPCC Mutations
Several genes involved in DNA mismatch repair have been implicated in hereditary nonpolyposis colorectal cancer (HNPCC). Detection of mutations in these genes is crucial for recommending appropriate genetic counseling, screening, and surveillance. Graham Casey, Ph.D., of The Cleveland Clinic, and other investigators of the Colon Cancer Family Registry (CFR), compared the ability of conversion analysis with conventional DNA sequencing to detect heterogeneous germline mutations in mismatch repair genes MHL1 and MSH2 in HNPCC patients. Using conventional sequencing, normal copies of genes can sometimes mask mutations in the other allele. Conversion analysis overcomes this weakness by separating pairs of chromosomes prior to analysis, through generation of human/mouse somatic cell hybrids. Results of this study demonstrated that conversion analysis provided a 33 percent improvement in detection of mismatch repair mutations in 89 colorectal cancer cases and a 56 percent increase in the diagnostic yield of genetic testing, compared with conventional sequencing. The Colon CFR is an EGRP-funded research resource.
Casey G, Lindor NM, Papadopoulos N, Thibodeau SN, Moskow J, Steelman S, Buzin CH, Sommer SS, Collins CE, Butz M, Aronson M, Gallinger S, Barker MA, Young JP, Jass JR, Hopper JL, Diep A, Bapat B, Salem M, Seminara D, Haile R; Colon Cancer Family Registry. Conversion analysis for mutation detection in MHL1 and MSH2 in patients with colorectal cancer. JAMA. 2005 Feb 16;293(7):799-809.
New, More Accurate Information Available on Risk of Hereditary Colorectal Cancer
Noralane Lindor, M.D., of the Mayo Foundation, and colleagues studied individuals with a family pedigree suggestive of hereditary nonpolyposis colorectal cancer (HNPCC) but who lacked the characteristic DNA mismatch repair gene defect (MMR). They found that families without the DNA defect had a lower risk of colorectal cancer, were diagnosed at a later age, and had a lower incidence of other cancers associated with HNPCC than did families with the defect. About 60 percent of families that meet criteria for a certain type of HNPCC, Amsterdam-I (AC-I), have an abnormality in a DNA MMR gene. Cancer incidence in AC-I families with MMR gene mutations is high, but the incidence for individuals in AC-I families without evidence of an MMR defect has been unknown. In counseling families with AC-I, clinicians now can provide more accurate and lower risk information using these new data in combination with the specific family history, report the researchers. The study included 161 families who met the AC-I criteria; most of the families were from the EGRP-funded Colon Cancer Family Registry (CFR). The research was funded by EGRP grants supporting the Registry, for which Dr. Lindor is one of the principal investigators.
Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, Gallinger S, Bapat B, Aronson M, Hopper J, Jass J, LeMarchand L, Grove J, Potter J, Newcomb P, Terdiman JP, Conrad P, Moslein G, Goldberg R, Ziogas A, Anton-Culver H, de Andrade M, Siegmund K, Thibodeau SN, Boardman LA, Seminara D. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA. 2005 Apr 27; 293(16):1979-85.
Vitamin B6 Inversely Associated With Risk of Colorectal Cancer
Vitamin B6 may be inversely associated with risk of colorectal cancer, according to findings by Esther Wei, Sc.D., of Brigham and Women's Hospital and Harvard School of Public Health, and colleagues. The main circulating form of vitamin B6, pyridoxal 5'-phosphate (PLP), is critical to DNA synthesis and methylation, processes potentially involved in carcinogenesis. The researchers conducted a prospective, nested case-control study of 32,826 women participating in the Nurses' Health Study (NHS) to evaluate the association of PLP levels with colorectal cancer risk. Women in the highest quartile of plasma PLP concentration had a 44 percent lower risk of colorectal cancer compared with women in the lowest quartile. The association between PLP concentration and colon cancer was statistically significant (58% decreased risk). Moreover, both associations were statistically significant and stronger after controlling for folate, multivitamin, and methionine intake. The research was funded partly by EGRP grants to Graham Colditz, M.D., Ph. D., Susan Hankinson, Sc.D., and Meir Stampfer, M.D., Dr.P.H., of Harvard School of Public Health.
Wei EK, Giovannucci E, Selhub J, Fuchs CS, Hankinson SE, Ma J. Plasma vitamin B6 and the risk of colorectal cancer and adenoma in women. J Natl Cancer Inst. 2005 May 4;97(9):684-92.
Pooled Analysis Shows Dietary Fiber Not Associated With Decreased Colorectal Cancer Risk
Although several mechanisms have been proposed for the ability of dietary fiber to reduce colorectal cancer risk, observational and epidemiologic studies and randomized controlled trials of dietary fiber supplements have failed to show a strong effect. To clarify the relationship, Yikyung Park, Sc.D., while at Harvard School of Public Health, and colleagues conducted a pooled analysis of 13 prospective cohort studies included in the Pooling Project of Prospective Studies of Diet and Cancer. Data from each cohort were re-analyzed using a standard approach. An age-adjusted model showed a significant inverse association between dietary fiber intake and colorectal cancer risk (16% reduction in risk). This association was slightly weakened after adjustment for nondietary risk factors, multivitamin use, and total energy intake. In the final model, however, which adjusted for other colorectal cancer risk factors, such as red meat and total milk and alcohol intake, only a nonsignificant, weak inverse association was observed. The researchers concluded that "although high dietary fiber intake may not have a major effect on the risk of colorectal cancer, a diet high in dietary fiber from whole plant foods can be advised because this has been related to lower risks of other chronic conditions such as heart disease and diabetes."
The analysis encompassed 725,628 men and women, follow up times of 6 to 20 years, and 8,081 colorectal cancer cases. Several of the cohort studies included in this analysis are funded by EGRP: Health Professionals Follow-up Study, with Walter Willett, M.D., M.P.H., Dr.P.H., Harvard School of Public Health; Iowa Women's Health Study, with Aaron Folsom, M.D., M.P.H., University of Minnesota; and Nurses' Health Study I and II, with Graham Colditz, M.D., Dr.P.H., of Harvard School of Public Health, and Dr. Willett, respectively.
Dr. Park is now a visiting research fellow in NCI's Division of Cancer Epidemiology and Genetics (DCEG), the intramural epidemiology research component of the Institute.
Park Y, Hunter DJ, Spiegelman D, Bergkvist L, Berrino F, van den Brandt PA, Buring JE, Colditz GA, Freudenheim JL, Fuchs CS, Giovannucci E, Goldbohm RA, Graham S, Harnack L, Hartman AM, Jacobs DR Jr, Kato I, Krogh V, Leitzmann MF, McCullough ML, Miller AB, Pietinen P, Rohan TE, Schatzkin A, Willett WC, Wolk A, Zeleniuch-Jacquotte A, Zhang SM, Smith-Warner SA. Dietary fiber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies. JAMA. 2005 Dec 14;294(22):2849-57.
Statins May Reduce Risk of Colorectal Cancer
Use of statins for 5 or more years has been found to be associated with a 51 percent reduction in risk of colorectal cancer in a study by Stephen Gruber, M.D., Ph.D., of the University of Michigan Comprehensive Cancer Center (pictured elsewhere on the page), and colleagues. After controlling for potential confounding factors, such as use of aspirin or nonsteroidal anti-inflammatory drugs, the risk associated with use of cholesterol-lowering statins was decreased by 46 percent. The population-based case-control study compared 1,814 colorectal cancer patients and 1,959 controls. The findings were specific to statins and not other types of cholesterol-lowering drugs.
Gruber SB. American Association for Cancer Research annual meeting, June 7, 2004 (oral presentation).
Update - Findings published: Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK, Rennert G. Statins and the risk of colorectal cancer. N Engl J Med. 2005 May 26;352(21):2184-92.
Read about in the NCI Cancer Bulletin
NSAIDs May Protect Against Colon Cancer in African Americans
African Americans have the highest rates of colon cancer incidence and mortality among all U.S. ethnic groups, and this discrepancy is not accounted for by differences in screening rates. Epidemiologic studies have shown that nonsteroidal anti-inflammatory drug (NSAID) use can reduce the risk of colon cancer, but no studies have specifically examined NSAID use and colon cancer risk in African Americans. Leah Sansbury, Ph.D., of NCI's Center for Cancer Research, and researchers at the University of North Carolina at Chapel Hill conducted a population-based case-control study to determine whether the protective effects of NSAIDs on colon cancer risk are comparable for African Americans and white Americans. They found a similar degree of protection for both groups, with Odds Ratios for regular NSAID use of 0.41 for African Americans and 0.48 for white Americans. The protective effect was stronger for women than for men. The study enrolled 731 African Americans (294 cases and 437 controls) and 960 white Americans (349 cases and 611 controls). The research was funded by EGRP grants to Robert Sandler, M.D., M.P.H., of the University of North Carolina at Chapel Hill.
Dr. Sansbury is at NCI as a Cancer Prevention Fellow, a program providing postdoctoral training opportunities in cancer prevention and control. Information on research training opportunities at NCI (intramural) and sponsored by NCI (extramural) is located at: http://www.cancer.gov/researchandfunding/training.
Sansbury LB, Millikan RC, Schroeder JC, Moorman PG, North KE, Sandler RS. Use of nonsteroidal antiinflammatory drugs and risk of colon cancer in a population-based, case-control study of African Americans and Whites. Am J Epidemiol. 2005 Sep 15;162(6):548-58.
NSAIDs May Protect Barrett's Esophagus Patients From Esophageal Cancer
Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) may significantly reduce risk of esophageal cancer in people with Barrett's esophagus, a precancerous condition that affects 1 million to 2 million Americans, according to findings by Thomas Vaughan, M.D., M.P.H., of Fred Hutchinson Cancer Research Center, and colleagues. In the largest and longest observational study of its kind, the researchers examined the relationship between duration, frequency, and recency of NSAID use and risk of esophageal cancer. They found that people with Barrett's esophagus who regularly took NSAIDs had a substantially reduced risk of developing esophageal cancer and did not develop the cancer as soon as people who did not take them regularly. Current NSAIDs users had one-third the risk of developing esophageal cancer compared to those who had never used them. The protective effect of NSAID use disappeared rapidly after usage stopped, however. This prospective, longitudinal observational study involved a cohort of 350 people with Barrett's esophagus. The findings lend support to previous observational studies and animal studies that have shown that NSAIDs might protect against cancer in people with Barrett's esophagus. The research was supported in part by an EGRP grant to Brian Reid, M.D., Ph.D., of the same institution.
Vaughan TL, Dong LM, Blount PL, Ayub K, Odze RD, Sanchez CA, Rabinovitch PS, Reid BJ. Non-steroidal anti-inflammatory drugs and risk of neoplastic progression in Barrett's oesophagus: a prospective study. Lancet Oncol. 2005 Dec;6(12):945-52.
New Microarray Assay Used to Search for Markers of Cancer Susceptibility
In earlier research, Qingyi Wei, M.D., Ph.D., of The University of Texas M.D. Anderson Cancer Center, and colleagues showed that increased risk of squamous cell carcinomas of the head and neck (SCCHN) is associated with reduced DNA repair capacity and reduced levels of nucleotide excision repair (NER) mRNA in lymphocytes. In a pilot case-control study, he and his team investigated expression of six core NER proteins in relation to risk of SCCHN. They developed a reverse-protein microarray assay to measure NER protein expression in lymphocytes from 57 SCCHN patients and 63 controls. In a model that included all covariates and NER proteins, only low expression of the NER protein XPF remained a significant risk factor. They concluded that XPF may be a crucial rate-limiting factor in DNA repair and that the microarray assay may be a useful tool for measuring protein markers of susceptibility to cancer. The study was partly funded by an EGRP grant to Dr. Wei.
Wei Q, Wang LE, Sturgis EM, Mao L. Expression of nucleotide excision repair proteins in lymphocytes as a marker of susceptibility to squamous cell carcinomas of the head and neck. Cancer Epidemiol Biomarkers Prev. 2005 Aug;14(8):1961-6.
Vitamin D and Surgery Season Associated With Improved Survival in Early Lung Cancer
Vitamin D has anti-proliferative and anti-invasive properties in vitro and in animal studies and may induce apoptosis of cancer cells. In humans, dietary vitamin D intake, regional ultraviolet light B levels, and sunlight exposure all contribute to vitamin D levels. Wei Zhou, M.D., Ph.D., of Harvard School of Public Health, and colleagues examined the association of surgery season, as a marker for sunlight exposure, and vitamin D intake with recurrence-free and overall survival in 456 patients with early-stage non-small cell lung cancer. Patients undergoing surgery in the summer had a higher recurrence-free survival rate than patients undergoing surgery in the winter (Hazard Ratio (HR): 0.75). No association between vitamin D intake and survival was found. However, analysis of the joint effects of vitamin D and surgery season showed that patients with the highest vitamin D intake who had surgery in the summer had a 5-year recurrence-free survival rate of 56 percent, compared to 23 percent for patients with low intake who had surgery in the winter. These findings should be confirmed in a prospective study to assess the serum vitamin D levels at time of surgery, say the researchers; if confirmed, dietary vitamin D supplementation may be advisable for early-stage lung cancer patients, particularly during the winter and in groups that tend to be deficient in vitamin D. This research was supported in part by an EGRP grant to David Christiani, M.D., M.P.H., M.S., of the same institution.
Zhou W, Suk R, Liu G, Park S, Neuberg DS, Wain JC, Lynch TJ, Giovannucci E, Christiani DC. Vitamin D is associated with improved survival in early-stage non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev. 2005 Oct;14(10):2303-9.
InterLymph Consortium Investigates Alcohol Consumption and Non-Hodgkin's Lymphoma
InterLymph, short for the International Consortium of Investigators Working on Non-Hodgkin's Lymphoma Epidemiologic Studies, is an open scientific forum for epidemiologic research in non-Hodgkin's lymphoma (NHL) comprised of international researchers who have completed or ongoing case-control studies. The investigators discuss and undertake research projects that pool data across studies or otherwise undertake collaborative research.
For a recent pooled analysis, InterLymph researchers obtained original data from nine case-control studies totaling 15,175 individuals (6,492 cases and 8,693 controls) from the United States, United Kingdom, Sweden, and Italy to study the association between alcohol consumption and risk for NHL. They found that individuals who drank alcohol had a lower risk of NHL than nondrinkers. Risk estimates were lower for current drinkers than former drinkers compared to nondrinkers. Risk did not decrease with increasing alcohol consumption, nor did the protective effect vary by type of alcohol consumed, although it did change by subtype of NHL. The lowest risk estimates were for Burkitt's lymphoma. Other studies on alcohol consumption and risk for NHL have yielded inconsistent results, as have studies that have investigated type of alcoholic beverage or subtype of NHL. Further study is warranted to confirm their findings and to determine the biological mechanism for the association, suggest the researchers.
The study's lead author is Lindsay Morton, Ph.D., of NCI's Division of Cancer Epidemiology and Genetics (DCEG), which is the intramural epidemiology research component of the Institute. Some of the case-control studies included in the analysis are supported through EGRP grants to Elizabeth Holly, Ph.D., M.P.H., of the University of California, San Francisco; Alexandra Levine, M.D., of the University of Southern California; Mads Melby, M.D., Ph.D., of Statens Serum Institute, Denmark; and Tongzhang Zheng, M.D., Sc.D., of Yale University.
Support for InterLymph's logistical needs is provided by EGRP and DCEG; the International Agency for Research on Cancer (IARC), Lyon, France; and the Leukaemia Research Fund, London, England.
Lymphoma researchers without case-control data to pool may participate in InterLymph's annual meetings and working groups. The next conference is Friday, March 31, 2006, in Washington, D.C., with NCI investigators as hosts. Contact Geoffrey Tobias, DCEG: firstname.lastname@example.org. The InterLymph website is: epi.grants.cancer.gov/InterLymph.
Morton LM, Zheng T, Holford TR, Holly EA, Chiu BC, Costantini AS, Stagnaro E, Willett EV, Dal Maso L, Serraino D, Chang ET, Cozen W, Davis S, Severson RK, Bernstein L, Mayne ST, Dee FR, Cerhan JR, Hartge P; InterLymph Consortium. Alcohol consumption and risk of non-Hodgkin lymphoma: a pooled analysis. Lancet Oncol. 2005 Jul;6(7):469-76.
Western Diet Associated With Increased Risk of Non-Hodgkin's Lymphoma
The incidence of non-Hodgkin's lymphoma (NHL) has increased rapidly worldwide in recent decades for reasons that are largely unknown. Ellen Chang, Sc.D., of the Karolinska Institutet, and colleagues examined the role of diet in the development of NHL in a population-based case control study in Sweden. Higher intakes of dairy products and fried meat, especially red meat, were associated with increased risk of some NHL subtypes in both men and women. The odds ratio (OR) of NHL for individuals in the highest quartile of intake of dairy products to the lowest quartile was 1.5. The OR for the highest quartile of intake of fried red meat was 1.5. Higher intakes of fruits and vegetables were associated with decreased risk of NHL, particularly follicular lymphoma, among women (OR=0.3). The researchers concluded that spread of the Western diet, with its high intake of dairy products and cooked and processed meats and low intake of fruits and vegetables, could account for a moderate proportion of the worldwide increase in NHL incidence, and that dietary modifications could help prevent some of the more common subtypes of NHL. The study included 597 cases and 467 controls. The research was partly funded by an EGRP grant to Dr. Chang.
Chang ET, Smedby KE, Zhang SM, Hjalgrim H, Melbye M, Ost A, Glimelius B, Wolk A, Adami HO. Dietary factors and risk of non-Hodgkin lymphoma in men and women. Cancer Epidemiol Biomarkers Prev 2005 Feb;14(2):512-20.
Predictors of Natural Immunity to Ovarian Cancer Identified
MUC1 is a high molecular weight protein that is expressed in different forms by both healthy and cancerous cells. When expressed by cancerous cells, MUC1 stimulates the production of antibodies. In a case-control study of ovarian cancer, Daniel Cramer, M.D., Sc.D., of Brigham and Women's Hospital, and colleagues measured anti-MUC1 antibodies in 705 women who did not have ovarian cancer, identified events that predicted antibody production, and estimated risk for the cancer by comparing profiles of the events that generated antibodies in the women with similar events in 668 women with ovarian cancer. Factors that predicted antibody production included use of oral contraceptives and intrauterine devices, breast mastitis, bone fracture or osteoporosis, pelvic surgeries, nonuse of talc in genital hygiene, and being a current smoker. Women who had two factors leading to elevated MUC1 antibody levels were about 30 percent less likely to develop ovarian cancer than women with none or only one MUC1 antibody-promoting event. Women with five of the factors had about a 70 percent reduction in risk compared with women with none or one of them. Besides presenting a new model to explain risk factors for ovarian cancer, the researchers speculated that the findings could lead to development of preventive vaccines for ovarian and perhaps other cancers that express MUC1. The study was partly funded by an EGRP grant to Dr. Cramer.
Cramer DW, Titus-Ernstoff L, McKolanis JR, Welch WR, Vitonis AF, Berkowitz RS, Finn OJ. Conditions associated with antibodies against the tumor-associated antigen MUC1 and their relationship to risk for ovarian cancer. Cancer Epidemiol Biomarkers Prev 2005 May; 4(5):1125-31.
Pooled Analysis Indicates Fruits and Vegetables Not Associated With Decreased Ovarian Cancer Risk
Anita Koushik, Ph.D., of Harvard School of Public Health, and colleagues conducted a pooled analysis of 12 prospective studies in North America and Europe to learn if increased fruit and vegetable consumption decreased risk for ovarian cancer. They found that neither total fruit or vegetable intake in adulthood, intake of specific fruit or vegetable groups, nor intake of individual fruits or vegetables were associated with risk for the cancer. This large study of more than 2,000 ovarian cancer cases also enabled the researchers to conduct analyses by main histologic type and levels of risk factors for the cancer. The researchers point out that the findings may not generalize to fruit and vegetable intake at an earlier time in life, and regardless of their findings, fruit and vegetable consumption remain important components of a healthy diet. A previous evaluation by the International Agency for Research on Cancer (IARC) of eight published case-control and cohort studies conducted through early 2003 had concluded that vegetable intake might reduce risk for ovarian cancer, but inconsistent results precluded drawing a firm conclusion. This new pooled analysis included data from several cohorts supported by grants from EGRP: Iowa Women's Health Study, with Aaron Folsom, M.D., M.P.H., of the University of Minnesota; and Nurses' Health Study I and II, with Graham Colditz, M.D., Dr.P.H., and Walter Willett, M.D., M.P.H., Dr.P.H., respectively, of Harvard School of Public Health.
Koushik A, Hunter DJ, Spiegelman D, Anderson KE, Arslan AA, Beeson WL, van den Brandt PA, Buring JE, Cerhan JR, Colditz GA, Fraser GE, Freudenheim JL, Genkinger JM, Goldbohm RA, Hankinson SE, Koenig KL, Larsson SC, Leitzmann M, McCullough ML, Miller AB, Patel A, Rohan TE, Schatzkin A, Smit E, Willett WC, Wolk A, Zhang SM, Smith-Warner SA. Fruits and vegetables and ovarian cancer risk in a pooled analysis of 12 cohort studies. Cancer Epidemiol Biomarkers Prev 2005 Sep;14(9):2160-2167.
Red and Processed Meat Associated With Increased Pancreatic Cancer Risk
Consumption of meat has been associated with risk of pancreatic cancer, but previous findings were inconsistent. An analysis of pancreatic cancer cases in a multiethnic population by Ute Nöthlings, Dr.P.H., of the University of Hawaii, Manoa, and colleagues found that red and processed meat are strong risk factors for the disease. Red and processed meats were associated with 50 percent and 70 percent increases in risk, respectively, across quintiles, independent of energy intake. Data from the Multiethnic Cohort Study (MEC) were analyzed for associations between intake of meat, other animal products, fat, and cholesterol and pancreatic cancer risk. No link was found between the disease and consumption of poultry, fish, dairy products, or eggs. Fat and saturated fat were found to be unlikely contributors to the underlying carcinogenic mechanism. Carcinogenic substances related to meat preparation methods might be responsible for the risk, say the researchers, and they suggest that future research focus on meat preparation methods and related carcinogens. The analysis was based on data on 482 cases of pancreatic cancer diagnosed over a 7-year period. The research was supported in part by an EGRP grant for the MEC to Laurence Kolonel, M.D., Ph.D., of the same institution. EGRP has funded the MEC since 1993.
Nöthlings U, Wilkens LR, Murphy SP, Hankin JH, Henderson BE, Kolonel LN. Meat and fat intake as risk factors for pancreatic cancer: the multiethnic cohort study. J Natl Cancer Inst. 2005 Oct 5;97(19):1458-65.
P450 Polymorphism Associated With Risk of Prostate Cancer
Members of the cytochrome P450 3A subfamily of enzymes are involved in steroid hormone metabolism. A study by Angie Stone, B.S., of the National Center for Toxicological Research, and colleagues investigated the association between the CYP3A43*3 genotype and risk of prostate cancer in African Americans and Caucasians. Their findings suggest that the CYP3A43 Pro340 Ala polymorphism contributes to prostate cancer risk in African Americans. They found a 3-fold increased risk of prostate cancer among men with the CYP3A43-Ala/Ala genotype compared with men with the CYP3A43-Pro/Pro genotype when analyzing data on all study participants. The CYP3A43-Ala/Ala genotype polymorphism was more frequently found in African Americans than in Caucasians (45% versus 13%), and African Americans with the CYP3A43-Ala/Ala genotype had a 2.6-fold increased risk of prostate cancer. The study is one of the first case-control studies to associate polymorphisms in the CYP3A43 gene with prostate cancer susceptibility. It included 124 African Americans and 358 Caucasians with prostate cancer and 167 African-American and 319 Caucasian controls. The research was partly supported by an EGRP grant to Nicholas Lang, M.D., of the Central Arkansas Veteran's Health Care System and Arkansas Cancer Research Center.
Stone A, Ratnasinghe LD, Emerson GL, Modali R, Lehman T, Runnells G, Carroll A, Carter W, Barnhart S, Rasheed AA, Greene G, Johnson DE, Ambrosone CB, Kadlubar FF, Lang NP. CYP343 Pro340 Ala polymorphism and prostate cancer risk in African Americans and Caucasians. Cancer Epidemiol Biomarkers Prev 2005 May;14(5):1257-61.
International Consortium Conducts Large-Scale, Combined Genomewide Linkage Scan for Prostate Cancer-Susceptibility Genes
Genomewide screens have been performed in more than a dozen independent studies, but few chromosomal regions have been consistently identified as regions of interest. A major difficulty is genetic heterogeneity, possibly due to multiple, incompletely penetrant prostate cancer-susceptibility genes.
Jianfeng Xu, M.D., Dr.P.H., of Wake Forest University, and other members of the International Consortium for Prostate Cancer Genetics (ICPCG) explored two approaches to overcome this difficulty. The Consortium combined linkage data from 1,233 families to increase the statistical power for detecting linkage, and identified five regions with "suggestive" linkage. It also focused on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis.
Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with an LOD score of 3.57 and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. Additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of 65 years. A conservative interpretation of these results would be that if major prostate cancer-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study, report the researchers. An EGRP grant for the ICPCG, with William Isaacs, Ph.D., of Johns Hopkins University, as principal investigator, supported the research.
Xu J, Dimitrov L, Chang BL, Adams TS, Turner AR, Meyers DA, Eeles RA, Easton DF, Foulkes WD, Simard J, Giles GG, Hopper JL, Mahle L, Moller P, Bishop T, Evans C, Edwards S, Meitz J, Bullock S, Hope Q, Hsieh CL, Halpern J, Balise RN, Oakley- Girvan I, Whittemore AS, Ewing CM, Gielzak M, Isaacs SD, Walsh PC, Wiley KE, Isaacs WB, Thibodeau SN, McDonnell SK, Cunningham JM, Zarfas KE, Hebbring S, Schaid DJ, Friedrichsen DM, Deutsch K, Kolb S, Badzioch M, Jarvik GP, Janer M, Hood L, Ostrander EA, Stanford JL, Lange EM, Beebe-Dimmer JL, Mohai CE, Cooney KA, Ikonen T, Baffoe-Bonnie A, Fredriksson H, Matikainen MP, Tammela TL, Bailey-Wilson J, Schleutker J, Maier C, Herkommer K, Hoegel JJ, Vogel W, Paiss T, Wiklund F, Emanuelsson M, Stenman E, Jonsson BA, Gronberg H, Camp NJ, Farnham J, Cannon-Albright LA, Seminara D; ACTANE Consortium. A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics. Am J Hum Genet. 2005 Aug;77(2):219-29. Epub 2005 June 29.
Statins Associated With Decreased Risk of Advanced Prostate Cancer
The longer men take cholesterol-lowering drugs such as statins, the far less likely they are to develop advanced prostate cancer, according to findings by Elizabeth Platz, Sc.D., M.P.H., of Johns Hopkins University, and colleagues. The researchers tracked use of cholesterol-lowering drugs and diagnosis of prostate cancer among 34,428 men participating in the Health Professionals Follow-up Study (HPFS) and followed them for more than a decade. Men who used these medications had one-half the risk of advanced prostate cancer and one-third of the risk of metastatic or fatal prostate cancer, compared with men who did not use cholesterol lowering drugs. Risk of advanced prostate cancer fell with increasing duration of use of the drugs. Use of cholesterol-lowering drugs did not have any influence on prostate cancer confined within the organ. The researchers believe that most of the protective effect comes from statins, because by 2000 more than 90 percent of the men who reported using cholesterol-lowering drugs said that they were using statins. It is not known whether the apparent benefit of statins is due to their cholesterol-lowering effect or their other properties, such as anti-inflammatory activity or effects on post-translational modification of proteins. The research was partly funded by an EGRP grant to Edward Giovannuci, M.D., Sc.D., of Harvard School of Public Health. EGRP has supported the HPFS since its establishment in the early 1980s.
American Association for Cancer Research Annual Meeting, 2005;46:4374.
Insulin-Like Growth Factor Polymorphisms Associated With Body Size
Insulin-like growth factor (IGF) regulatory molecules mediate growth hormone signaling and affect cell proliferation and apoptosis, influencing weight gain, body fat distribution, and risk of obesity-related diseases, including cancer. Carol Sweeney, Ph.D., of the University of Utah, and colleagues examined associations of polymorphisms affecting IGF, IGF binding proteins (IGFBP), insulin receptor substrates, and the vitamin D receptor (VDR) with body size and fat distribution in Hispanic and non-Hispanic white women. Two associations were observed in both groups of women: IGF1 CA repeat alleles greater than 19 repeats in length were associated with higher waist-to-hip ratios, and women with an IGFBP3 A allele more often reported higher birth weights. In Hispanic women only, the IGFBP3 A allele was associated with taller height, the IRS1R allele was associated with smaller waist-to-hip ratio, and the VDR FokI ff genotype was associated with larger waist-to-hip ratio. The researchers say that the findings support the thinking that genetic variation in IGF pathway molecules has functional consequences for growth and central obesity, and that genotype-phenotype relationships are ethnic specific. The study included 462 Hispanic women and 1,702 non-Hispanic white women. It was funded in part by an EGRP grant to Martha Slattery, Ph.D., of the same institution.
Sweeney C, Murtaugh MA, Baumgartner KB, Byers T, Giuliano AR, Herrick JS, Wolff R, Caan BJ, Slattery ML. Insulin-like growth factor pathway polymorphisms associated with body size in Hispanic and non-Hispanic white women. Cancer Epidemiol Biomarkers Prev. 2005 Jul;14(7):1802-9.
1st Leadership Workshop Identifies Barriers, Gaps, and Opportunities in Tobacco, Diet/Energy Balance, and Genetic Research
The meeting summary for The 1st NCI Epidemiology Leadership Workshop: Tobacco, Diet/Energy Balance, and Genetic Research, sponsored by EGRP, is now available. Seasoned principal investigators funded through EGRP were asked to this by-invitation-only-meeting in September 2004 to identify barriers and gaps in cancer epidemiology and to advance solutions to the study of tobacco diet/energy balance, and genes.
The summary includes presentations on the state-of-the science in these areas and on opportunities to explore new collaborations and reports from the four working groups: (1) Challenges to Diet/Energy Balance Epidemiology Research, (2) Haplotypes Versus Genotypes, (3) Design Issues and Strategies in the Study of Rare Cancer, and (4) Susceptibility in Tobacco Carcinogenesis: Genotypes Versus Phenotypes. The Web site also includes the speakers' presentations (PDF format).
2nd Epidemiology Leadership Workshop Focuses on Understudied Rare Cancers
The summary from The 2nd NCI Epidemiology Leadership Workshop: Understudied Rare Cancers is available now on EGRP's Web site along with the slides of the presenters (PDF format). Last fall in Boston, investigators funded by EGRP to conduct research on understudied rare cancers were invited to meet and identify gaps in epidemiologic and genetic research on the cancers, and to discuss ways to foster collaborations and partnerships among basic, clinical, and population scientists within the extramural and intramural communities. The workshop was sponsored by EGRP and NIH's Office of Rare Diseases.
"The four major cancers, lung, breast, prostate, and colorectal cancer, comprise the lion's share of our portfolio, but there are other cancers—some of them highly lethal—that need more study," said Ed Trapido, Sc.D., EGRP Associate Director. "We sought the help of our investigators to identify the gaps and stumbling blocks and suggest new approaches to move forward epidemiologic research on these diseases."
The workshop focused on cancers of the brain, eye, oral cavity, pharynx, head, neck, endometrium, ovary, testis, digestive and urinary systems, larynx, bones, joints, soft tissues, thyroid and other cancers of the endocrine systems, non-Hodgkin's lymphoma, Hodgkin's disease, leukemia, myeloma, and Kaposi's sarcoma. Pancreatic cancer was excluded because it is addressed in a trans-NCI PA that EGRP is cosponsoring (PA for Pilot Studies on Pancreatic Cancer [PA 05-116]).
Four major themes emerged from the workshop discussions. The investigators expressed the need for: (1) improvements to the review process for rare cancer proposals, (2) targeted funding for rare cancers, (3) suggestions for promoting formation of consortia, and (4) exploration of the potential usefulness of greater involvement of cancer registries in research. EGRP plans to use the information gathered from the workshop to prioritize funding mechanisms, develop new initiatives, and to discuss review issues with appropriate NIH staff.
Report Published on Cancer Risk Prediction Models
Cancer researchers, clinicians, and the public are increasingly interested in statistical models designed to predict the occurrence of cancer. As the number and sophistication of cancer risk prediction models have grown, so too, has interest in ensuring that they are appropriately applied, correctly developed, and rigorously evaluated. A report on an NCI-sponsored workshop, held in May 2004 and cosponsored by EGRP, focusing on statistical models for predicting a person's risk of developing cancer is now published in the Journal of the National Cancer Institute. Research priorities and resources are identified in the areas of (1) revising existing breast cancer risk assessment models and developing new models, (2) encouraging the development of new risk models, (3) obtaining data to develop more accurate risk models, (4) supporting validation mechanisms and resources, (5) strengthening model development efforts and encouraging coordination, and (6) promoting effective cancer risk communication and decision-making.
Workshop planning committee members, left to right: Ruth Pfeiffer, Ph.D., Division of Cancer Epidemiology and Genetics (DCEG); Mitchell Gail, M.D., Ph.D., DCEG; Daniela Seminara, Ph.D., M.P.H., Epidemiology and Genomics Research Program (EGRP), Division of Cancer Control and Population Sciences (DCCPS); Andrew Freedman, Ph.D., Applied Research Program (ARP), DCCPS; and RAchel Ballard-Barbash, M.D., M.P.H., ARP, DCCPS. Not pictured: Patricia Hartge, Sc.D., DCEG, and Hraham Colditz, M.D., Dr.P.H., Harvard Medical School.
Freedman AN, Seminara D, Gail MH, Hartge P, Colditz GA, Ballard-Barbash R, Pfeiffer RM. Cancer risk prediction models: a workshop on development, evaluation, and application. J Natl Cancer Inst. 2005 May 18;97(10):715-23.
Consortium Hunts Low-Penetrance Breast and Prostate Cancer Genes
The research team testing the principle that pooling data and biospecimens across large-scale studies through consortial arrangements is an effective approach to research on genes and the environment describes its approach to searching for low-penetrance breast and prostate cancer genes of the hormone-regulated pathway in the December 2005 issue of Nature Reviews Cancer.
The Breast and Prostate Cancer Cohort Consortium, also known as the BPC3, is characterizing variations in about 50 genes that mediate two pathways associated with these cancers—the steroid-hormone metabolism pathway and the insulin-like growth factor signaling pathway—and are associating these variations with cancer risk. The BPC3 combines the resources of 10 large prospective cohorts; three genomic facilities; and epidemiologists, population geneticists, and biostatisticians from multiple institutions. Data and biospecimens are being pooled on more than 8,000 cases of prostate cancer and 5,000 cases of breast cancer.
Participation of eight of the cohorts is funded through four EGRP grants to: David Hunter, M.D., Sc.D., of Harvard School of Public Health, for the participation of the Physicians' Health Study I and II, Nurses' Health Study, Health Professionals Follow-up Study, and Women's Health Study; Michael Thun, M.D., of the American Cancer Society (ACS), for the ACS Cancer Prevention Study II; Elio Riboli, M.D., M.Sc., of the Imperial College, London, for the European Prospective Investigation into Cancer and Nutrition (EPIC); and Brian Henderson, M.D., of the University of Southern California/Norris Comprehensive Cancer Center,for the Multiethnic Cohort Study. The four investigators are pictured above, in order, left to right. Two cohorts from NCI's Division of Cancer Epidemiology and Genetics (DCEG), the intramural epidemiology research component of the Institute, also participate: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, directed by Richard Hayes, D.D.S., Ph.D., and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, directed by Demetrius Albanes, M.D.
The BPC3 is the first research project initiated by the Consortium of Cohorts, a group formed by NCI to address the need for large-scale collaborations in the genetic and molecular epidemiology of cancer. The Consortium is a joint initiative of NCI's Division of Cancer Control and Population Sciences (DCCPS), of which EGRP is a part, and DCEG. The Consortium and BPC3 Web site is: epi.grants.cancer.gov/Consortia/cohort.html.
Hunter DJ, Riboli E, Haiman CA, Albanes D, Altshuler D, Chanock SJ, Haynes RB, Henderson BE, Kaaks R, Stram DO, Thomas G, Thun MJ, Blanche H, Buring JE, Burtt NP, Calle EE, Cann H, Canzian F, Chen YC, Colditz GA, Cox DG, Dunning AM, Feigelson HS, Freedman ML, Gaziano JM, Giovannucci E, Hankinson SE, Hirschhorn JN, Hoover RN, Key T, Kolonel LN, Kraft P, Le Marchand L, Liu S, Ma J, Melnick S, Pharaoh P, Pike MC, Rodriguez C, Setiawan VW, Stampfer MJ, Trapido E, Travis R, Virtamo J, Wacholder S, Willett WC; National Cancer Institute Breast and Prostate Cancer Cohort Consortium. A candidate gene approach to searching for low-penetrance breast and prostate cancer genes. Nat Rev Cancer. 2005 Dec;5(12):977-85
Long Island Breast Cancer Study Project: Research on Environmental Exposures and Breast Cancer
The Long Island Breast Cancer Study Project (LIBCSP) was initiated in the early 1990s in response to a congressional mandate to investigate possible environmental factors that may be responsible for high rates of breast cancer in Nassau and Suffolk counties (Long Island) and two other counties. More than 10 studies were conducted through grants to investigators, and a geographic information system (LI GIS) was developed under contract that presently is available to researchers to explore relationships between environmental exposures and breast cancer risk.
The LIBCSP has played an important role in efforts to understand the high rates of breast cancer in some regions of the United States. In the December 2005 issue of Nature Reviews Cancer, EGRP's Debbie Winn, Ph.D., reviews its accomplishments and provides a broad overview of NCI's extramural epidemiologic research initiatives on the environment and breast cancer that have been supported since the early 1990s, including the presently funded Breast Cancer and Environment Research Centers (BCERCs). EGRP manages NCI's extramural research program in epidemiology. Funding for the LIBCSP and BCERCs has been in collaboration with the National Institute of Environmental Health Sciences (NIEHS).
Winn DM. Science and society: the Long Island Breast Cancer Study Project. Nat Rev Cancer. 2005 Dec;5(12):986-94.