2006 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.

Breast Cancer

Cervical Cancer

Colorectal Cancer

Gynecological Cancers

Gastrointestinal Cancers

Liver Cancer

Lung Cancer

Melanoma

Non-Hodgkin's Lymphoma

Pancreatic Cancer

Prostate Cancer

HIV

Methods

General


BPC3 Consortium Finds Polymorphisms in the Androgen Receptor Are Not Linked to Breast Cancer Risk

Androgens may influence breast cancer risk through mechanisms including conversion to estradiol or by binding to the estrogen receptor and/or the androgen receptor (AR) in the breast. The AR is expressed in the normal breast as well as in breast cancer tumors, and both the expression and protein levels have been correlated with tumor invasiveness.

Michael Thun Elio Riboli David Hunter Brian Henderson

To analyze whether polymorphisms in the AR gene are associated with breast cancer risk, Brian Henderson, M.D., of the University of Southern California/Norris Comprehensive Cancer Center, David Hunter, M.D., Sc.D., of the Harvard School of Public Health, Elio Riboli, M.D., M.Sc., of the Imperial College, London, Michael Thun, M.D., of the American Cancer Society, and colleagues participating in the EGRP-sponsored Breast and Prostate Cancer Cohort Consortium (BPC3) Study first determined the underlying genetic variation in the AR coding regions in a panel of 95 advanced breast cancer cases and genotyped markers in a panel of 349 healthy women.

They identified linkage disequilibrium relationships across the gene and selected haplotype-tagged single nucleotide polymorphisms (htSNPs) that captured the common genetic variants across the locus. The htSNPs then were genotyped in nested breast cancer cases (5,603) and controls (7,480) from the Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study, and Women's Health Study cohorts.

The authors found no association between any genetic variation in the AR gene and breast cancer risk. They concluded that, in postmenopausal Caucasian women, common polymorphisms in AR are not associated with breast cancer risk.

Cox DG, Blanche H, Pearce CL, Calle EE, Colditz GA, Pike MC, Albanes D, Allen NE, Amiano P, Berglund G, Boeing H, Buring J, Burtt N, Canzian F, Chanock S, Clavel-Chapelon F, Feigelson HS, Freedman M, Haiman CA, Hankinson SE, Henderson BE, Hoover R, Hunter DJ, Kaaks R, Kolonel L, Kraft P, LeMarchand L, Lund E, Palli D, Peeters PH, Riboli E, Stram DO, Thun M, Tjonneland A, Trichopoulos D, Yeager M; Breast and Prostate Cancer Cohort Consortium. A comprehensive analysis of the androgen receptor gene and risk of breast cancer: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3)External Web Site Policy. Breast Cancer Res. 2006;8(5):R54.

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BRCA1 and BRCA2 Mutation Frequencies and Their Association With Cancer

Harvey Risch

The presence of BRCA1 and BRCA2 mutations in the general population and the link between these mutations and various types of cancers have not been well documented. A study by Harvey A. Risch, M.D., Ph.D., of the Yale University School of Medicine, and colleagues investigated the presence of BRCA1 and BRCA2 mutations in 1,171 unselected patients with newly diagnosed incident ovarian cancer in Ontario, Canada, with respect to cancers reported among their relatives. The patients were screened for germline mutations throughout the BRCA1 and BRCA2 genes.

Higher risks for various cancers, including ovarian, female breast, and testicular cancer in the general Ontario population, were associated with carrying BRCA1 mutations versus not carrying mutations (ovarian cancer relative risk (RR) = 21, 95% confidence interval (CI) = 12 to 36; female breast cancer RR = 11, 95% CI = 7.5 to 15; and testicular cancer RR = 17, 95% CI = 1.3 to 230). Similarly, higher risks were associated with carrying BRCA2 mutations versus not carrying mutations, particularly for ovarian (RR = 7.0, 95% CI = 3.1 to 16), female and male breast (RR = 4.6, 95% CI = 2.7 to 7.8; and RR = 102, 95% CI = 9.9 to 1,050; respectively), and pancreatic (RR = 6.6, 95% CI = 1.9 to 23) cancers.

Cancer risks differed according to a mutation's position on the gene. Estimated cumulative incidence to age 80 years among women carrying BRCA1 mutations was 24% for ovarian cancer and 90% for breast cancer; in women carrying BRCA2 mutations, the estimated cumulative incidence was 8.4% for ovarian cancer and 41% for breast cancer. For the general Ontario population, estimated carrier frequencies of BRCA1 and BRCA2 mutations were, respectively, 0.32% (95% CI = 0.23% to 0.45%) and 0.69% (95% CI = 0.43% to 1.10%).

The researchers concluded that BRCA1 and BRCA2 mutations may be more frequent in general populations than previously thought and may be associated with various types of cancers. This research was supported by EGRP grants to Dr. Risch and Steven Narod, M.D., Ph.D., University of Toronto.

Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, Tang J, Li S, Zhang S, Shaw PA, Narod SA. Population BRCAl and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada.External Web Site Policy J Natl Cancer Inst. 2006 Dec 6;98(23):1694-706.

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Human Papillomavirus Type 16 and 18 Variants Show Race-Related Distribution and Persistence

Persistent human papillomavirus (HPV) infection, particularly with HPV types 16 or 18, places women at increased risk for cervical cancer. HPV variants, which are viral isolates for any HPV type that differ by less than 2% in the L1 gene sequence, appear to segregate geographically. The persistence of these variants in certain geographic populations of infected individuals may be related to the racial composition of that population.

Long Fu Xi

Long Fu Xi, M.D., Ph.D., of the University of Washington, and colleagues studied 1,114 women in the United States participating in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study who were positive for HPV16 and/or HPV18 at enrollment and classified the HPV variants based on established HPV lineages.

They found that 63.9% of women infected with HPV18 who self-reported as African American were infected with the HPV18 African variant (95% confidence interval (CI) = 53.5% to 73.4%); 54.2% of white women infected with HPV18 were infected with the European variant (95% CI = 46.3% to 61.9%). The likelihood of staying HPV18 positive was statistically significant and higher for African-American women if infected with the African variant compared to the European variant, and statistically significant and higher for white women if infected with the European variant compared to the African variant. The same pattern was found for HPV16 infection.

This work suggests that HPV infection persists longer in a host whose race indicates an ancestral geographic distribution that once was shared with that of the infecting HPV variant. This study was funded by an EGRP grant to Dr. Xi.

Xi LF, Kiviat NB, Hildesheim A, Galloway DA, Wheeler CM, Ho J, Koutsky LA. Human papillomavirus type 16 and 18 variants: race-related distribution and persistenceExternal Web Site Policy. J Natl Cancer Inst. 2006 Aug 2;98(15):1045-52.

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Multiple-Type Human Papillomavirus Infection Increases Risk of Cervical Cancer

Human papillomavirus (HPV) infection is one of the most common sexually transmitted diseases and plays the main causal role in cervical carcinogenesis. Certain HPV genotypes, such as HPV16, are associated with a high risk of cervical cancer, but little is known about the effects of infection with multiple HPV genotypes on cervical cancer.

Eduardo Franco Helen Trottier

Helen Trottier, Ph.D., and Eduardo Franco, Dr.P.H., of McGill University, and colleagues used PCR to type HPV present in cervical specimens from 2,462 Brazilian women and assessed the relationship between infection with multiple HPV types and any-grade squamous intraepithelial lesions (SIL) and high-grade SIL (HSIL). Infection with multiple HPV types was associated positively with HSIL risk. Relative to women consistently negative for HPV infection, after a 1-year followup for HSIL, women infected with a single type of HPV had an odds ratio (OR) of 41.5, 95% confidence interval (CI) = 5.3 to 323.2; women infected with two to three types of HPV had an OR of 91.7, 95% CI = 11.6 to 728.1; and women infected with four to six types had an OR of 424.0, 95% CI = 31.8 to 5,651.8. The excess risk associated with multiple HPV-type infection persisted after excluding women infected with HPV16 or other high-risk HPV types, or for persistent infections, particularly for any-grade SIL.

This work suggests that infection with multiple HPV types may act synergistically in cervical carcinogenesis, or that harboring multiple HPV types may be a marker for a decreased immune response to HPV and thus to greater risk. This research is supported in part by an EGRP grant to Dr. Franco.

Trottier H, Mahmud S, Costa MC, Sobrinho JP, Duarte-Franco E, Rohan TE, Ferenczy A, Villa LL, Franco EL. Human papillomavirus infections with multiple types and risk of cervical neoplasiaExternal Web Site Policy. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1274-80.

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Colorectal Cancer Risk Associated Jointly With Smoking and NSAID Use

Victoria Chia

Smoking has been associated with an increased risk of colorectal cancer, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with a reduced risk of colorectal cancer. In a population-based case-control study, Victoria M. Chia, Ph.D., of the Fred Hutchinson Cancer Research Center and the University of Washington, and colleagues evaluated the joint association between smoking and regular NSAID use with colorectal cancer risk and examined these associations stratified by tumor microsatellite instability (MSI high/low: MSI-H, MSI-L).

They analyzed 1,792 incident colorectal cancer cases and 1,501 population controls in the Seattle area from 1998 to 2002, and assessed MSI in tumors of 1,202 cases. Individuals who had ever smoked had an increased risk of developing colorectal cancer. Individuals who were currently using NSAIDs had a 30% lower risk of developing colorectal cancer compared to non-NSAID users.

The data also demonstrated that, relative to current NSAID users who never smoked, individuals who had both smoked for more than 40 years and had never used NSAIDs had the highest risk for colorectal cancer. Compared with nonsmokers, a greater number of tumors in smokers were classified as MSI-H than as MSI-L. NSAID use did not reduce the risk of MSI-H or MSI-L tumors in long-term smokers. Yet smokers who never used NSAIDs had a higher likelihood of having MSI-L tumors.

The researchers concluded that there seems to be a synergistic inverse association that implies protection against colorectal cancer overall as a result of NSAID use and nonsmoking, but the risk of MSI-H colorectal cancer remains elevated among smokers even when they have a history of NSAID use. This research was supported in part by an EGRP grant to John Potter, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center and the University of Washington, and through cooperative agreements with members of the Colon Cancer Family Registry and Principal Investigators.

Chia VM, Newcomb PA, Bigler J, Morimoto LM, Thibodeau SN, Potter JD. Risk of microsatellite-unstable colorectal cancer is associated jointly with smoking and nonsteroidal anti-inflammatory drug useExternal Web Site Policy. Cancer Res. 2006 Jul 1;66(13):6877-83.

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Model Predicts Germline Mutations and Risk of Cancer in the Lynch Syndrome

Sining Chen

The Lynch Syndrome (hereditary nonpolyposis colorectal cancer, HNPCC), the most common familial colorectal cancer, can be caused by germline deleterious mutations of DNA mismatch repair (MMR) genes. Sining Chen, Ph.D., of the Johns Hopkins Bloomberg School of Public Health, and colleagues developed the MMRpro model to estimate the probability of an individual carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, and MSH6 and developing colorectal or endometrial cancer.

The probability is assessed on the basis of a detailed family history of colorectal and endometrial cancer for an individual and his or her first- and second-degree relatives. To validate the MMRpro model, the model's predictions were compared with the results of highly sensitive germline mutation detection techniques for 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993 and 2005).

In this independent evaluation, MMRpro provided a concordance index of 0.83 (95% confidence interval (CI) = 0.78 to 0.88) and a ratio of observed-to-predicted cases of 0.94 (95% CI = 0.84 to 1.05), demonstrating that the model is more sensitive and more specific than current clinical guidelines for identifying individuals who may benefit from MMR germline testing. Importantly, this model can be used among individuals for whom tumor samples are not available or whose germline DNA tests find no mutation.

Some patients who were in this study belong to EGRP's Colon Cancer Family Registry, an international research infrastructure for investigators interested in conducting population- and clinic-based interdisciplinary studies on the genetic and molecular epidemiology of colon cancer and its behavioral implications.

Chen S, Wang W, Lee S, Nafa K, Lee J, Romans K, Watson P, Gruber SB, Euhus D, Kinzler KW, Jass J, Gallinger S, Lindor NM, Casey G, Ellis N, Giardiello FM, Offit K, Parmigiani G; Colon Cancer Family Registry. Prediction of germline mutations and cancer risk in the Lynch syndromeExternal Web Site Policy. JAMA. 2006 Sep 27;296(12):1479-87.

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HPV Co-Infections Synergistically Increase Risk for Cervical Cancer

Helen trottier

Simultaneous infection with multiple types of human papillomavirus (HPV) appears to act synergistically to increase the risk of developing lesions that typically precede development of cervical cancer, according to research by Helen Trottier, Ph.D., of McGill University, and colleagues. This study is the first to document the higher risk of cervical cancer with multiple HPV infections.

The researchers studied 2,462 Brazilian women ages 18 to 40 who had repeated measurements of viral infection and lesion outcomes to assess the role of cumulative and concurrent infection with types of HPV in the development of cervical cancer. The greater the number of HPV types involved in the co-infection, the higher the risk of precancerous lesions. The excess risks for lesions from multiple-type infections remained after excluding women infected with HPV-16 and other high-risk HPV types, and women with persistent infections. Co-infections with HPV-16 and -58 appeared to be particularly prone to increase risk for precancerous lesions.

These findings have implications for the management of cervical lesions and prediction of the outcome of HPV infections. They also provide baseline data for analyzing the impact of the newly approved HPV vaccine. The researchers pointed out that the vaccine does not protect against HPV-58 and suggested that it be a target for the next generation of cervical cancer vaccines to be developed. The research was supported in part by an EGRP grant to Eduardo Franco, Dr.P.H., of McGill University.

Trottier H, Mahmud S, Costa MC, Sobrinho JP, Duarte-Franco E, Rohan TE, Ferenczy A, Villa LL, Franco EL. Human papillomavirus infections with multiple types and risk of cervical neoplasiaExternal Web Site Policy. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1274-80.

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Avoiding Weight Gain Reduces Risk for Postmenopausal Breast Cancer

A. Heather Eliassen

Women can reduce their risk of breast cancer, particularly after menopause, by avoiding weight gain in adulthood or by losing the extra pounds, suggest findings by A. Heather Eliassen, Sc.D., of Brigham and Women's Hospital and Harvard Medical School, and colleagues. Other studies have indicated that weight gain since early adulthood is associated with an increased risk of breast cancer in postmenopausal women, but weight change in middle-aged to older women has been studied less extensively.

The researchers analyzed data from the Nurses' Health Study (NHS) I on 87,143 postmenopausal women who were followed for up to 26 years to assess weight change since age 18. Weight change since menopause was assessed among 49,514 women who were followed up to 24 years. They found that women who gained 55 pounds or more since age 18 had a 45 percent increased risk of breast cancer compared with women who maintained their weight, with a stronger association among women who had never taken postmenopausal hormones. Women who gained about 22 pounds or more since menopause had an 18 percent increased risk of breast cancer. On the other hand, women who lost about 22 pounds or more since menopause, kept the weight off, and had never used postmenopausal hormones had a 57 percent reduction in risk of the cancer compared to women who simply maintained their weight.

"Women should be advised to avoid weight gain both before and after menopause to decrease their postmenopausal breast cancer risk," concluded the researchers. The study was supported in part by an EGRP grant to Susan Hankinson, Sc.D., of Brigham and Women's Hospital and Harvard Medical School, who is principal investigator of the Nurses' Health Study I. EGRP has funded this cohort since 1973.

Eliassen AH, Colditz GA, Rosner B, Willett WC, Hankinson SE. Adult weight change and risk of postmenopausal breast cancerExternal Web Site Policy. JAMA. 2006 Jul 12;296(2):193-201.

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Mammographic Density Reflects Exposure to Breast Cancer Risk Factors

Gertraud Maskarinec

Mammographic densities have been hypothesized to reflect cumulative exposure to risk factors that stimulate the growth of breast cells and influence breast cancer incidence. Gertraud Maskarinec, M.D., Ph.D., of the Cancer Research Center of Hawaii, and colleagues, analyzed percent mammographic densities over time and explored predictors of density change in relation to age in the Hawaii component of the Multiethnic Cohort Study.

The study population included 607 breast cancer cases and 667 controls. Eighty-two percent of the women had more than one mammogram, and almost half of the women had three or more mammograms. The researchers used a computer- assisted method to assess densities of mammograms performed over more than 20 years and before a diagnosis of breast cancer. The effects of ethnicity, status (whether the woman was diagnosed with breast cancer or not), reproductive characteristics, hormonal therapy, body mass index, and soy intake on initial status and longitudinal change were assessed using multilevel modeling. They found that cumulative percent mammographic densities and age-specific breast cancer rates increased at similar rates. Japanese ancestry, being overweight, estrogen/progestin therapy, and to a lesser extent, estrogen-only therapy, predicted a slower decline in mammographic densities with age. Case status and adult soy intake were related to higher densities, whereas being overweight and having any children were associated with lower densities at initial status. Age at menarche was not related to density.

The findings agree with the hypothesis that cumulative breast density reflects exposure to risk factors that predict age-specific breast cancer incidence. Risk factors that influence the decline in mammographic densities over time may be important in breast cancer prevention, said the researchers. The study was supported in part by EGRP grants to Dr. Maskarinec and Laurence Kolonel, M.D., Ph.D., also of the Cancer Research Center of Hawaii. EGRP has funded the Multiethnic Cohort Study since 1993, with Dr. Kolonel as principal investigator.

Maskarinec G, Pagano I, Lurie G, Kolonel LN. A longitudinal investigation of mammographic density: the multiethnic cohortExternal Web Site Policy. Cancer Epidemiol Biomarkers Prev. 2006 Apr;15(4):732-9.

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Hormone Use Increases Breast Cancer Risk Among Black Women

Epidemiologic studies have shown a link between recent long-term hormone use among women, particularly the use of estrogen with progestin, and an increased risk of breast cancer. Research also has indicated an increased risk of breast cancer among leaner women who use these hormones, but most participants in these studies were white women.

Lynn Rosenberg

Lynn Rosenberg, Sc.D., of Boston University, and colleagues focused on women in the Black Women's Health Study (BWHS) and found that recent long-term hormone use increased the risk of breast cancer in this population, also. The risk increased with duration of use and was strongest among leaner women, agreeing with previously published results for white women. The study included 32,559 black women who were 40 years of age or older. It was supported by an EGRP grant to Dr. Rosenberg.

The BWHS is a cohort study that has been funded by EGRP since 1994, with Dr. Rosenberg as principal investigator.

Rosenberg L, Palmer JR, Wise LA, Adams-Campbell LL. A prospective study of female hormone use and breast cancer among black womenExternal Web Site Policy. Arch Intern Med. 2006 Apr 10;166(7):760-5.

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Eight Genetic Variants in DNA Repair Pathway Ruled Out as Important in Breast Cancer

Yawei Zhang

Epidemiologic studies have suggested that polymorphisms in genes encoding components of the DNA base-excision repair (BER) function are associated with cancer risk. Impaired BER function can lead to accumulation of DNA damage and initiation of cancer. Yawei Zhang, M.D., Ph.D., of Yale University, and colleagues evaluated the association between variation in six BER pathway genes (XRCC1, ADPRT, APEX1, OGG1, LIG3, and MUTHYH) and breast cancer risk in large population- based case-control studies in the United States and Poland. Eight single nucleotide polymorphisms (SNPs) were assessed; the researchers preferentially selected coding SNPs in the candidate genes.

No significant association was found between breast cancer risk and the SNPs analyzed in samples from the U.S. study. Meta-analyses of the researchers' data and published data from studies of two SNPs in XRCC1 showed no evidence of association between breast cancer risk and homozygous variants versus wild type for Q399R; there was a suggestion of an association for this polymorphism in Asian populations (Odds Ratio (OR) = 1.6).

The researchers concluded that the polymorphisms evaluated in this study do not play a significant role in breast carcinogenesis. The research was supported in part by EGRP grants to Amy Trentham-Dietz, Ph.D., of the University of Wisconsin; Polly Newcomb, Ph.D., of Fred Hutchinson Cancer Research Center; and Linda Titus-Ernstoff, Ph.D., of Dartmouth.

Zhang Y, Newcomb PA, Egan KM, Titus-Ernstoff L, Chanock S, Welch R, Brinton LA, Lissowska J, Bardin-Mikolajczak A, Peplonska B, Szeszenia-Dabrowska N, Zatonski W, Garcia-Closas M. Genetic polymorphisms in base-excision repair pathway genes and risk of breast cancerExternal Web Site Policy. Cancer Epidemiol Biomarkers Prev. 2006 Feb;15(2):353-8.

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Large Study Supports Prophylactic Oophorectomy for BRCA1 and BRCA2 Gene Mutation Carriers

In a large-scale prospective study, Amy Finch, M.Sc., of Toronto-Sunnybrook Regional Cancer Centre (not pictured), and colleagues estimated the absolute risks for developing ovarian, fallopian tube, and peritoneal cancers among women with BRCA1 and BRCA2 gene mutations, and the reduction in risk associated with the removal of ovaries and fallopian tubes.

The study included 1,828 BRCA1 and BRCA2 gene mutation carriers (mean age = 47.3 years) participating in an international registry of 32 centers in Canada, the United States, Europe, and Israel. The women were followed for an average of 3.5 years. A total of 555 (30%) women had prophylactic bilateral salpingo-oophorectomy (removal of the ovaries and fallopian tubes) prior to study entry, and 490 (27%) had the surgery after entry. Prophylactic bilateral salpingooophorectomy reduced the risk of ovarian and fallopian tube cancer by 80 percent. A residual risk of 4.3 percent for peritoneal cancer remained at 20 years after oophorectomy, but the researchers believe the risk was not sufficiently high to recommend against the surgery.

"It is important that both fallopian tubes and ovaries be removed because either site may be the origin of cancer, and both organs should be examined in fine detail to rule out the presence of microscopic disease," said the researchers. The study was supported in part by an EGRP grant to Steven Narod, M.D., Ph.D., of Toronto-Sunnybrook Regional Cancer Centre (pictured).

Finch A, Beiner M, Lubinski J, Lynch HT, Moller P, Rosen B, Murphy J, Ghadirian P, Friedman E, Foulkes WD, Kim-Sing C, Wagner T, Tung N, Couch F, Stoppa-Lyonnet D, Ainsworth P, Daly M, Pasini B, Gershoni-Baruch R, Eng C, Olopade OI, McLennan J, Karlan B, Weitzel J, Sun P, Narod SA; Hereditary Ovarian Cancer Clinical Study Group. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutationExternal Web Site Policy. JAMA. 2006 Jul 12;296(2):185-92.

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High Glycemic Index and Load May Increase Risk for Colorectal Cancer Among Obese Women

The colorectal cancer risk factors of obesity, greater energy consumption, and low physical activity modulate circulating levels of insulin, which may have growth-promoting effects on the colorectum and thus influence carcinogenesis. Dietary glycemic index (GI) and glycemic load (GL) directly affect circulating insulin levels, and the consumption of foods with high GIs leads to more rapid increase in blood insulin levels than foods with low GIs.

Mary McCarl

Mary McCarl, M.P.H., of the University of Minnesota, and colleagues conducted a prospective study to examine associations of GI and GL with colorectal cancer among 35,197 participants in the Iowa Women's Health Study. They found that neither GI nor GL were major colorectal cancer risk factors among older women (ages 55–69). However, among obese women (baseline body mass index (BMI) > 30 kg/m2), colorectal cancer incidence was increased for women in the highest versus lowest quintiles of GI (Relative Risk (RR) = 1.66) and GL RR = 1.79). The increase was observed for both colon and rectal cancer and for women with and without diabetes. For women with a BMI below 30 kg/m2, no statistically significant associations between GI or GL and colorectal cancer risk were found.

The results indicate that although neither GI nor GL are major colorectal cancer risk factors among older women in general, high GI or GL may increase risk for the cancer among obese women. The Iowa Women's Health Study has been funded by EGRP since 1985, with Aaron Folsom, M.D., M.P.H., of the University of Minnesota, as the principal investigator.

McCarl M, Harnack L, Limburg PJ, Anderson KE, Folsom AR. Incidence of colorectal cancer in relation to glycemic index and load in a cohort of womenExternal Web Site Policy. Cancer Epidemiol Biomarkers Prev. 2006 May;15(5):892-6.

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Occupational Exposures Associated With Risk for Esophageal and Stomach Cancer

Karen Wernli

Karen Wernli, Ph.D., of Fred Hutchinson Cancer Research Center, and colleagues analyzed associations between occupational exposures in the Shanghai, China, textile industry and risk of esophageal and stomach cancer. Few occupational exposures have been associated with these highly lethal cancers, which account for a substantial proportion of the cancer burden in developing countries.

In a case-cohort study nested in a cohort of female textile workers in Shanghai, the researchers analyzed and compared data on 102 workers with esophageal cancer and 646 workers with stomach cancer diagnosed between 1989 and 1998 with data from a subcohort of 3,188 workers. Risk for esophageal cancer was increased 15.8-fold with 10 or more years of exposure to silica dust and 3.7-fold with long-term exposure to metals (welding dust, lead fumes, and steel). Risk increased with increasing duration of exposure. In addition, the researchers unexpectedly found that cumulative exposure to endotoxin, a cotton dust contaminant, was inversely related to risk of esophageal and stomach cancer. Endotoxin is known to elicit a systemic inflammatory response after inhalation and somehow may have a protective effect against cancer.

The researchers pointed out that silica, metals, and endotoxin exposures are not unique to the textile industry and might influence the risk of esophageal and stomach cancer in other industries. The study was supported in part by an EGRP grant to Harvey Checkoway, Ph.D., of the University of Washington.

Wernli KJ, Fitzgibbons ED, Ray RM, Gao DL, Li W, Seixas NS, Camp JE, Astrakianakis G, Feng Z, Thomas DB, Checkoway H. Occupational risk factors for esophageal and stomach cancers among female textile workers in Shanghai, ChinaExternal Web Site Policy. Am J Epidemiol. 2006 Apr 15;163(8):717-25. Epub 2006 Feb 8.

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Pancreatic Cancer Genetic Epidemiology Consortium Focuses on Familial Susceptibility

Organized in 2002 with grant support from EGRP, the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium is a foundation for investigating the genetic etiology of familial pancreatic cancer susceptibility. PACGENE has seven data collection centers, a statistical genetics core, and a pathology/archival genotyping core.

Gloria Petersen

In a published paper, Principal Investigator Gloria Petersen, Ph.D., of the Mayo Clinic, and colleagues describe the Consortium and their observations on age at diagnosis of pancreatic cancer among 466 participating probands and 670 affected relatives. (Probands have at least two first-degree relatives with pancreatic cancer.) Probands and affected relatives were diagnosed with the cancer at a significantly younger mean age (64) than pancreatic cancer patients in the general population (70), a finding consistent with other studies. The age for the general population was determined using data from NCI's population-based Surveillance, Epidemiology, and End Results (SEER) Program. The researchers also found that age at diagnosis among the affected relatives did not decrease with increasing number of affected family members.

PACGENE now is conducting linkage analyses to pursue the genetic basis of familial pancreatic cancer. Because pancreatic cancer is relatively rare and rapidly fatal, it is difficult for any single research center to recruit sufficient numbers of study participants and collect sufficient biospecimens from informative families to perform linkage analyses and other research. The research was supported in part by EGRP grants to Dr. Petersen.

Petersen GM, de Andrade M, Goggins M, Hruban RH, Bondy M, Korczak JF, Gallinger S, Lynch HT, Syngal S, Rabe KG, Seminara D, Klein AP. Pancreatic cancer genetic epidemiology consortiumExternal Web Site Policy. Cancer Epidemiol Biomarkers Prev. 2006 Apr; 15(4):704-10.

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Prediagnostic Level of Serum Retinol Associated With Decreased Risk of Hepatocellular Carcinoma

Retinol and its derivatives (retinoids) are antioxidants that promote cell differentiation and may protect against the development of hepatocellular carcinoma (HCC) by controlling hepatocellular differentiation and reducing inflammatory responses. Few prospective epidemiologic studies of serum retinol and other antioxidants in relation to HCC risk have been conducted, however.

Jian-Min Yuan

This study by Jian-Min Yuan, M.D., Ph.D., of the University of Minnesota, and colleagues examined the relationship between concentrations of antioxidant micronutrients in prediagnostic serum samples and the risk of developing HCC in 213 patients with HCC and 1,087 controls from a cohort of 18,244 men in Shanghai, China, who were monitored from 1986 through 2001. The micronutrients measured included retinol, specific carotenoids, tocopherols, and selenium. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by quartile (Q) of serum micronutrient concentrations using logistic regression, with adjustments for smoking status, alcohol intake, history of physician-diagnosed hepatitis or liver cirrhosis, and seropositivity for hepatitis B surface antigen (HBsAg).

The researchers found that higher prediagnostic serum levels of retinol were associated with a statistically significant reduced risk of developing HCC in these middle-aged or older Chinese men (Q2 versus Q1, OR= 0.37, CI = 0.22 to 0.61; Q3 versus Q1, OR = 0.30, CI = 0.17 to 0.50; Q4 versus Q1, OR = 0.13, CI = 0.06 to 0.26; Ptrend < .001).

The association between serum retinol levels and HCC risk was present in both chronic carriers and noncarriers of the hepatitis B virus. Statistically significant interaction regarding HCC risk between low retinol levels and HBsAg positivity also was found; HBsAg-positive men in the lowest tertile of retinol had a greater than 70-fold higher risk (OR = 72.7, CI = 31.6 to 167.4) of HCC than HBsAg-negative men in the highest tertile of retinol (Pinteraction = .018). Given that HCC is highly fatal, these findings may have implications for clinical practice and prevention efforts. This research was supported by EGRP grants to Dr. Yuan.

Yuan JM, Gao YT, Ong CN, Ross RK, Yu MC. Prediagnostic level of serum retinol in relation to reduced risk of hepatocellular carcinomaExternal Web Site Policy. J Natl Cancer Inst. 2006 Apr 5;98(7):482-90.

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New Biomarker Proposed for Lung Cancer Risk

Randa el-Zein

The cytokinesis-blocked micronucleus (CBMN) assay in human lymphocytes is one of the most commonly used methods for measuring DNA damage. Randa El-Zein, M.D., Ph.D., of The University of Texas M.D. Anderson Cancer Center, and colleagues modified the CBMN assay to evaluate susceptibility to the nicotine-derived nitrosamine 4-(methlynitrosamino)- 1-(3-pyridyl)-1-butanone (NNK), which is a carcinogen and a strong inducer of lung cancer.

They measured the frequency of NNK-induced chromosomal damage endpoints (micronuclei, nucleoplasmic bridges, and nuclear buds) per 1,000 binucleated lymphocytes. Spontaneous and NNK-induced chromosomal damage was significantly higher in lung cancer patients compared to controls. Forty-seven percent of patients compared with 12 percent of controls had greater than four spontaneous micronuclei; 66 percent of patients compared with none of the controls had greater than four spontaneous nucleoplasmic bridges; and 25 percent of patients compared with 5 percent of controls had greater than one spontaneous nuclear bud. The study included 139 cases and 130 controls.

These results provide strong evidence that the modified CBMN assay is extremely sensitive to NNK-induced genetic damage, and that the test's simplicity, speed, and sensitivity make it valuable for screening and possibly for prioritizing potential cases for early detection. This research was supported in part by EGRP grants to Dr. El-Zein and Margaret Spitz, M.D., M.P.H., of M.D. Anderson Cancer Center.

El-Zein RA, Schabath MB, Etzel CJ, Lopez MS, Franklin JD, Spitz MR. Cytokinesis blocked micronucleus assay as a novel biomarker for lung cancer riskExternal Web Site Policy. Cancer Res. 2006 Jun 15;66(12):6449-56.

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Striking Ethnic Discrepancies Seen in Smoking-Related Lung Cancer Risk

Christopher Haiman

Lung cancer is more likely to develop in cigarette smokers who are African American or Native Hawaiian than in smokers who are white, Japanese American, or Latino, according to research by Christopher Haiman, Sc.D., of the University of Southern California, and colleagues. The findings are especially noteworthy because of the study's large size and its far broader ethnic and racial representation than other studies. The research team analyzed lung cancer incidence among 183,813 African-American, Japanese-American, Latino, Native-Hawaiian, and white men and women from the Multiethnic Cohort Study (MEC) of more than 215,000 individuals in California and Hawaii. In the analysis, 1,979 lung cancer cases were identified between baseline (1993-96) and 2001.

Among those who smoked less than 30 cigarettes per day, risks for African Americans and Native Hawaiians were significantly greater than for the other groups. The difference between groups was particularly evident among those who smoked 10 or fewer cigarettes per day. Among those who smoked 10 cigarettes or fewer a day, whites had a 55 percent lower risk of lung cancer than African Americans; and among those who smoked 11 to 20 cigarettes a day, a 43 percent lower risk. For Latinos and Japanese Americans, the percentages were lower still. However, once smoking rates reached 30 cigarettes a day—the equivalent of a pack and a half—or more, the risk difference was minimal. The differences in risk were observed for both sexes and all histologic types of lung cancer. Environmental measures looked at—occupation, diet, and education (as a proxy for socioeconomic status)—could not explain what the researchers called "the striking racial and ethnic differences in the risk of lung cancer associated with cigarette smoking."

The findings do not change the public health message on the hazards of smoking. Individuals are far more likely to get lung cancer if they smoke, and they can reduce their risks by quitting. The research was supported by an EGRP grant to Laurence Kolonel, M.D., Ph.D., University of Hawaii, Manoa, for the MEC, which has been funded since 1993.

Haiman CA, Stram DO, Wilkens LR, Pike MC, Kolonel LN, Henderson BE, Le Marchand L. Ethnic and racial differences in the smoking-related risk of lung cancer.External Web Site Policy N Engl J Med 2006 Jan 26;354(4):333-42.

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High-Risk Melanoma Susceptibility Genes and Pancreatic Cancer, Neural System Tumors, and Uveal Melanoma Across GenoMEL

Julia Newton Bishop David Elder Alisa Goldstein

The Melanoma Genetics Consortium (GenoMEL) is an international consortium of familial melanoma research groups from North America, Europe, Asia, and Australia. This study, by Alisa Goldstein, Ph.D., of the National Cancer Institute, David Elder, M.B., Ch.B., of the University of Pennsylvania, Julia Newton Bishop, M.D., of the University of Leeds, UK, and colleagues used the largest familial melanoma sample currently available, taken from across 17 GenoMEL centers, to assess the high-risk melanoma susceptibility genes CDKN2A/alternative reading frames (ARF, which encodes p16 and p14ARF) and CDK4, and their relationship with pancreatic cancer, neural system tumors, and uveal melanoma.

The study included 2,137 cutaneous malignant melanoma patients from 466 melanoma-prone families with at least three melanoma patients per family. Forty-one percent (n = 190) of families had mutations in one of three known high-risk melanoma susceptibility genes, most of which involved p16 (n = 178). There were similar frequencies (2–3%) in mutations in CDK4 (n = 5) and p14ARF (n = 7).

The researchers found a strong association between prostate cancer and CDKN2A mutations (P < 0.0001), which differed by mutation. The group found little evidence of an association between CDKN2A mutations and neural system tumors or uveal melanoma and only a marginally significant association between neural system tumors and ARF (P = 0.05).

They also found that the proportion of families with the most frequent founder mutations differed by locale, with similarities between Sweden and the Netherlands; between France, Spain, and Italy; and between the United Kingdom and Australia (P = 0.0009).

This GenoMEL study provides the most extensive characterization to date of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients. This research was supported in part by EGRP grants to Dr. Elder, Lisa Cannon Albright, Ph.D., of the University of Utah, and Nicholas Hayward, Ph.D., of the Queensland Institute of Medical Research.

Goldstein AM, Chan M, Harland M, Gillanders EM, Hayward NK, Avril MF, Azizi E, Bianchi-Scarra G, Bishop DT, Bressac-de Paillerets B, Bruno W, Calista D, Cannon Albright LA, Demenais F, Elder DE, Ghiorzo P, Gruis NA, Hansson J, Hogg D, Holland EA, Kanetsky PA, Kefford RF, Landi MT, Lang J, Leachman SA, Mackie RM, Magnusson V, Mann GJ, Niendorf K, Newton Bishop J, Palmer JM, Puig S, Puig- Butille JA, de Snoo FA, Stark M, Tsao H, Tucker MA, Whitaker L, Yakobson E; Melanoma Genetics Consortium (GenoMEL). High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMELExternal Web Site Policy. Cancer Res. 2006 Oct 15;66(20):9818-28.

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InterLymph Identifies Genetic Variants Associated With Non-Hodgkin's Lymphoma

Nathaniel Rothman

Increased risk of non-Hodgkin's lymphoma (NHL) has been observed in individuals with a family history of the disease or other hemopoietic cancers, suggesting that genetic susceptibility plays a role. In a study by the InterLymph Consortium, Nathaniel Rothman, M.D., M.P.H., of NCI's Division of Cancer Epidemiology and Genetics (DCEG), and colleagues hypothesized that single-nucleotide polymorphisms (SNPs) in genes important in lymphoid development and pro-inflammatory or anti-inflammatory pathways may be associated with increased risk of NHL.

This study included 3,586 cases of NHL and 4,018 controls from eight case-control studies participating in InterLymph. The researchers analyzed 12 SNPs in nine genes selected on the basis of previous functional or association data: IL1A, IL1RN, IL1B, IL2, IL6, IL10, TNF, LTA, and CARD15. They found that TNF-308→A and IL10-3575T→A were associated with an increased NHL risk, particularly diffuse large B-cell lymphoma. Other NHL studies that have investigated this TNF polymorphism and IL10 polymorphisms were small and not population-based.

The research, which underscores the value of large consortia in identifying genetic associations, was supported in part by EGRP grants to William Isaacs, Ph.D., of The Johns Hopkins University, and Kathleen Cooney, M.D., of the University of Michigan.

InterLymph, short for the International Consortium of Investigators Working on Non-Hodgkin's Lymphoma Epidemiologic Studies, is an open scientific forum for NHL epidemiologic research that is comprised of international researchers with completed or ongoing case-control studies. Its website is epi.grants.cancer.gov/InterLymph.

Rothman N, Skibola CF, Wang SS, Morgan G, Lan Q, Smith MT, Spinelli JJ, Willett E, De Sanjose S, Cocco P, Berndt SI, Brennan P, Brooks-Wilson A, Wacholder S, Becker N, Hartge P, Zheng T, Roman E, Holly EA, Boffetta P, Armstrong B, Cozen W, Linet M, Bosch FX, Ennas MG, Holford TR, Gallagher RP, Rollinson S, Bracci PM, Cerhan JR, Whitby D, Moore PS, Leaderer B, Lai A, Spink C, Davis S, Bosch R, Scarpa A, Zhang Y, Severson RK, Yeager M, Chanock S, Nieters A. Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph ConsortiumExternal Web Site Policy. Lancet Oncol. 2006 Jan;7(1):27-38.

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Vitamin D Intake Associated With a Lower Risk for Pancreatic Cancer in Two Cohort Studies

Charles Fuchs

Vitamin D and its analogs show strong antitumor effects in a variety of tissues, including the pancreas. A study by Halcyon Skinner, Ph.D., of Northwestern University, and colleagues looked at associations between dietary intake of vitamin D, calcium, and retinol and subsequent risk for pancreatic cancer in two large, EGRP-supported prospective cohort studies: the Health Professionals Follow-up Study, which includes 46,771 men ages 40 to 75 years as of 1986, and the Nurses' Health Study, which includes 75,427 women ages 38 to 65 years as of 1984.

Researchers collected information on vitamin D dietary intake, documented incident pancreatic cancer through the year 2000, and identified 365 pancreatic cancer cases. Compared with participants in the lowest category of total vitamin D intake (< 150 IU/d), those participants who consumed ≥ 300 IU/d decreased their risk for pancreatic cancer (relative risk = 0.59). Calcium and retinol intakes were found not to be associated with pancreatic cancer risk.

The researchers concluded that higher intakes of vitamin D were associated with lower risks for pancreatic cancer in these two U.S. cohorts, suggesting a potential role for vitamin D in the pathogenesis and prevention of pancreatic cancer. This research was supported in part by EGRP grants to Walter Willett, M.D., Dr.P.H., and Graham Colditz, M.D., Dr.P.H., both of Harvard University and Brigham and Women's Hospital; and Charles Fuchs, M.D., M.P.H. (pictured), of Harvard University, Brigham andWomen's Hospital, and Dana-Farber Cancer Institute.

Skinner HG, Michaud DS, Giovannucci E, Willett WC, Colditz GA, Fuchs CS. Vitamin D intake and the risk for pancreatic cancer in two cohort studiesExternal Web Site Policy. Cancer Epidemiol Biomarkers Prev. 2006 Sep;15(9):1688-95.

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Recent-Onset Diabetes Mellitus May Be an Early Marker for Pancreatic Cancer

Elizabeth Holly

Diabetes has been hypothesized to be both a risk factor for and a consequence of pancreatic cancer. Patients with diabetes have been shown to have an approximately 2-fold risk of developing pancreatic cancer, and newonset diabetes may be caused by pancreatic cancer.

Furong Wang, M.D., of the University of California, San Francisco, and colleagues performed a population-based case-control study of pancreatic cancer in the San Francisco Bay area, involving 532 cases with newly diagnosed pancreatic cancer and 1,701 controls. They found that participants with pancreatic cancer were more likely to report a history of diabetes than controls (odds ratio = 1.5, 95% confidence interval (CI) = 1.1 to 2.1). Diabetics in the case group reported a shorter duration of diabetes and a larger proportion of insulin users. Risk for pancreatic cancer decreased as the duration of diabetes increased. There was no association with pancreatic cancer and insulin use for 5 or more years, but insulin use for less than 5 years was associated with a 6.8-fold increased risk for pancreatic cancer (95% CI = 3.7 to 12).

The authors concluded that recent-onset diabetes may be a complication of or an early marker for pancreatic cancer. This research was supported by EGRP grants to Elizabeth Holly, Ph.D., M.P.H., (pictured) of the University of California, San Francisco, and Stanford University.

Wang F, Gupta S, Holly EA. Diabetes mellitus and pancreatic cancer in a population-based case-control study in the San Francisco Bay Area, CaliforniaExternal Web Site Policy. Cancer Epidemiol Biomarkers Prev. 2006 Aug;15(8):1458-63.

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LTA May Modify the Association Between NSAID Use and Decreased Risk of Advanced Prostate Cancer

Studies show that nonsteroidal antiinflammatory drugs (NSAIDs) have protective effects against prostate cancer, but this may exist only among certain subgroups of men, such as those with particular variants in inflammatory response genes.

Xin Liu, M.D., Ph.D., of the University of California, San Francisco, and colleagues conducted a case-control study (n = 1,012) of the association between NSAID use and more advanced prostate cancer and evaluated whether the association was modified by a functional polymorphism in the lymphotoxin alpha (LTA) gene (LTA C+80A, where the CC genotype results in higher LTA production). The LTA protein modulates the immune and inflammatory response to pathogens. The researchers found an inverse association between NSAID use and disease (odds ratio (OR) = 0.67, 95% confidence interval (CI) = 0.52 to 0.87), which was modified by the LTA C+80A variant (p for interaction = 0.03). In men with the CC genotype, the inverse association between NSAID use and prostate cancer was substantially stronger (OR = 0.43, 95% CI = 0.28 to 0.67).

NSAID use was not found to be associated with disease for men without the CC genotype (p = 0.30). Similar associations were observed when dose/duration of NSAID use were studied. These results suggest that prostate cancer chemoprevention by NSAIDs may be most appropriate for men with the LTA +80CC genotype.

John Witte Graham Casey

This research was supported by EGRP grants to Graham Casey, Ph.D., of The Cleveland Clinic Foundation, and John Witte, Ph.D., of the University of California, San Francisco (both pictured).

Liu X, Plummer SJ, Nock NL, Casey G, Witte JS. Nonsteroidal antiinflammatory drugs and decreased risk of advanced prostate cancer: modification by lymphotoxin alphaExternal Web Site Policy. Am J Epidemiol. 2006 Nov 15;164(10):984-9. Epub 2006 Aug 24.

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Prostate Cancer Aggressiveness Appears To Be Influenced by Several Genes

Susan Slager

Several independent genome scans have reported evidence of linkage using the Gleason score as a measure of prostate cancer aggressiveness, but with inconsistent results. Susan Slager, Ph.D., of the Mayo Clinic, and colleagues conducted an independent genome-wide scan using the Gleason score as a quantitative trait on brothers participating in the University of Michigan Prostate Cancer Genetics Project.

The researchers genotyped 405 highly polymorphic microsatellite markers in 175 brother pairs from 103 families. The strongest evidence of linkage was to chromosome 6q23 at 137 cM. Other evidence of linkage was found on chromosomes 1p13–q21 and 5p13–q11. Altogether, three interesting regions (P<0.005) and two modest regions of linkage (P<0.05) were identified. For all but one of these regions, there is previous evidence of linkage to tumor aggressiveness.

The findings provide further evidence that tumor aggressiveness has a genetic component, said the researchers, and that the genetic component may be influenced by several independent genes. The study was supported in part by EGRP grants to William Isaacs, Ph.D., of The Johns Hopkins University, and Kathleen Cooney, M.D., of the University of Michigan.

Slager SL, Zarfas KE, Brown WM, Lange EM, McDonnell SK, Wojno KJ, Cooney KA. Genome-wide linkage scan for prostate cancer aggressiveness loci using families from the University of Michigan Prostate Cancer Genetics ProjectExternal Web Site Policy. Prostate. 2006 Feb 1;66(2):173-9.

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Chromosome 8 Region Associated With Prostate Cancer Risk in African Americans

Matthew Freedman

Matthew Freedman, M.D., of Dana-Farber Cancer Institute, Broad Institute of Harvard, and Massachusetts Institute of Technology, and colleagues have identified an area of chromosome 8q24 as a major risk factor for prostate cancer, especially in African- American men. The researchers used their newly developed "admixture mapping" method to screen through the genome of African Americans (who have both African and European ancestry) searching for the differences in inherited DNA from ancestral backgrounds.

They studied 1,597 African Americans with prostate cancer and 873 controls and found that the genetic risk factor nearly doubled the likelihood of prostate cancer in younger African- American men. This finding may explain why younger African Americans have a greater risk of prostate cancer than other populations and why the increased risk attenuates with older age, said the researchers.

The study also shows that admixture mapping can be a powerful and practical way to map genetic variants for complex diseases, they reported. Additional research will be needed to identify the specific gene involved at 8q24. The study was supported in part by grants to Brian Henderson, M.D., of the University of Southern California; Kathleen Cooney, M.D., of the University of Michigan; and Alice Whittemore, Ph.D., of Stanford University.

Freedman M, Haiman CA, Patterson N, McDonald GJ, Tandon A, Waliszewska A, Penney K, Steen RG, Ardlie K, John EM, Oakley-Girvan I, Whittemore AS, Cooney KA, Ingles SA, Altshuler D, Henderson BE, Reich D. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African American menExternal Web Site Policy. Proc Natl Acad Sci USA. 2006 Sep 19;103(38):14068-73. Epub 2006 Aug 31.

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Vaginal Washing Associated With Increased Risk of HIV

R.Scott McClelland

Women who perform vaginal washing are at increased risk for acquiring HIV-1 compared to women who do not perform vaginal washing, according to a study by R. Scott McClelland, M.D., M.P.H., of the University of Washington, and colleagues. The researchers analyzed data from a 10-year study of risk factors for contracting HIV-1 among 1,270 sex workers in Kenya.

The increased risk applied to women who used either water or soap for vaginal washing. Women who used water to cleanse had a 2.6-fold increased risk for contracting HIV-1 compared to women who did not perform vaginal washing, and women who used soap had a 3.8-fold increased risk of infection. Furthermore, women who used soap or other substances were at greater risk (1.47-fold increased risk) of infection compared to women who used only water.

The researchers concluded that vaginal washing may be important in promoting the spread of HIV-1 and that intervention strategies aimed at modifying intra-vaginal practices should be evaluated as a possible female-controlled HIV-1 prevention strategy. The research was supported in part by an EGRP grant to King Holmes, M.D., Ph.D., of the University of Washington.

McClelland RS, Lavreys L, Hassan WM, Mandaliya K, Ndinya-Achola JO, Baeten JM. Vaginal washing and increased risk of HIV-1 acquisition among African women: a 10- year prospective studyExternal Web Site Policy. AIDS. 2006 Jan 9;20(2):269-73.

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Lessons Learned: MSI Testing Inconsistencies Reported by Six-Laboratory Consortium

Microsatellite instability (MSI) testing is almost a standard part of the clinical evaluation of individuals who develop colorectal cancer at young ages or who have family histories suggestive of hereditary nonpolyposis colon cancer syndrome (HNPCC). Despite the high volume of MSI testing conducted clinically, no reports have been published on the agreement of MSI results among laboratories.

Noralane Lindor

Noralane Lindor, M.D., of the Mayo Clinic, and colleagues compared MSI testing performed by six laboratories, all of which are part of the Colon Cancer Family Registry (CFR), and found discordant results with no evident systematic trends. Two laboratories with the longest experience in MSI testing showed a 99 percent concordance of the 100 loci tested, demonstrating that MSI scoring potentially is reproducible. After analysis of possible reasons for the discordance, each laboratory repeated its testing. Agreement of readings improved dramatically, which was attributed in large part to cleaner PCR products. Disregarding mononucleotide single base pair gains, concordance also was improved by greater use of equivocal readings, duplicate readings, and general refinement of MSI reading skills. DNA quality was not an issue.

The researchers proposed five key rules that laboratories should observe when conducting MSI testing. Dr. Lindor is principal investigator of one of the Registry sites. The Colon CFR is an EGRP-funded resource for investigators interested in conducting population- and clinic-based interdisciplinary studies on the genetic and molecular epidemiology of colon cancer. Its website is epi.grants.cancer.gov/CFR.

Lindor NM, Smalley R, Barker M, Bigler J, Krumroy LM, Lum-Jones A, Plummer SJ, Selander T, Thomas S, Youash M, Seminara D, Casey G, Bapat B, Thibodeau SN. Ascending the learning curve—MSI testing experience of a six-laboratory consortium. Cancer Biomarkers. 2006 Jul;2(1-2):5-9.

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What Have We Learned Since Doll and Peto's Analysis on Risk and Preventability of Cancer?

Edward Trapido Thomas Sellers Graham Colditz

"Epidemiology—identifying the causes and preventability of cancer?" reviews studies of cancer incidence using different epidemiologic techniques that have been conducted in the 25 years since Professor Sir Richard Doll and Professor Sir Richard Peto published their landmark comprehensive analysis of evidence on the risk and preventability of cancer. "These studies revealed expanded opportunities for cancer prevention through approaches that include vaccination, increased physical activity, weight control, and avoidance of post-menopausal hormone therapy," write Graham Colditz, M.D., Dr.P.H., of Brigham and Women's Hospital and Harvard School of Public Health, and Thomas Sellers, Ph.D., H. Lee Moffitt Cancer Center & Research Institute, and NCI's Edward Trapido, Sc.D., in the January 2006 issue of Nature Reviews Cancer. The authors make some suggestions for future directions in epidemiologic research, including in method development and method incorporation, and for studies of interactions between behavior, psychological and social mechanisms, and risk indicators to fill gaps in etiology and survivorship studies.

Colditz GA, Sellers TA, Trapido E.Epidemiology—identifying the causes and preventability of cancer?External Web Site Policy Nat Rev Cancer 2006 Jan;6(1):75-83.

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