2007 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 the EGRP-supported principal investigators whose grants are credited in the published papers appear in boldface print.
- Model Developed for Predicting Risk for Bladder Cancer
- Bladder Cancer Risk Associated With Truncated Telomeres
- Hormone Levels and Mammographic Density Independently Linked to Breast Cancer Risk in Postmenopausal Women
- Hispanic Breast Cancer Patients May Have Highest Prevalence of BRCA1 Mutation
- Radiotherapy Reduces Mortality in Patients With Recurrent Contralateral Breast Cancer
- Increased Risk of Second Primary Cancers Found in Men With Breast Cancer
- Cytochrome P450 Gene Variant Associated With Breast Cancer Risk in African Americans
- Breast Cancer Risk Associated With Alleles in FGFR2
Breast and Prostate Cancer
Colorectal and Prostate Cancer
Head and Neck Cancer
- Alcohol and Tobacco Do Not Increase Risk in Patients With HPV16-Related Head and Neck Cancer
- Tobacco and Alcohol Independently Increase Risk of Head and Neck Cancer
- Putative Tumor Suppressor Gene Associated With Aggressive Prostate Cancer
- Prostate Cancer-Associated SNP Identified
- Prostate Cancer Risk Affected by Multiple Regions Within 8q24
- Second Risk Locus for Prostate Cancer Identified at 8q24
Model Developed for Predicting Risk for Bladder Cancer
Bladder cancer is the fourth most common cancer in U.S. men and the second most common urologic malignancy. Screening for bladder cancer in the general population is not recommended currently because there is no model by which risk can be assessed.
Xifeng Wu, M.D., Ph.D.
Xifeng Wu, M.D., Ph.D., of the University of Texas M.D. Anderson Cancer Center, and colleagues developed a model that incorporates both mutagen sensitivity and epidemiologic factors to predict bladder cancer risk. The model was developed based on data from 678 white bladder cancer patients and 678 controls. Risk factors incorporated into the model included pack-years smoked; exposures to diesel, aromatic amines, cleaning fluids, radioactive materials, and arsenic; and results of an in vitro assay to test the sensitivity of blood cells to the mutagens benzo[a]pyrene diol-epoxide (BPDE) and gamma-radiation as a measure of DNA repair capacity.
The model is easy to use, requiring an individual to answer only a few simple questions to project individual risk for the cancer and undergo a simple blood test. It also showed good discriminatory ability and excellent concordance in the internal validation based only on answers to exposure questions (area under the curve [AUC] = 0.70; 95% Confidence Interval [CI] = 0.67 to 0.73), and discrimination was improved by including the results of the mutagen sensitivity assay (AUC = 0.80; 95% CI = 0.72 to 0.82). This work describes the first risk-prediction model for bladder cancer and could prove highly useful for identifying high-risk populations.
This research was funded in part by an EGRP grant to Dr. Wu.
Wu X, Lin J, Grossman HB, Huang M, Gu J, Etzel CJ, Amos CI, Dinney CP, Spitz MR. Projecting individualized probabilities of developing bladder cancer in white individuals. J Clin Oncol. 2007 Nov 1;25(31):4974-81.
Bladder Cancer Risk Associated With Truncated Telomeres
Telomeres maintain the structural integrity of chromosomes. Truncated telomeres are observed in a number of cancers, and cigarette smoking, a risk factor for bladder cancer, may cause oxidative stress that enhances telomere shortening.
Monica McGrath, Sc.D.
Monica McGrath, Sc.D., of Harvard School of Public Health, and colleagues examined the association between relative telomere length, cigarette smoking, and bladder cancer. The researchers analyzed telomere length in peripheral blood leukocytes from 184 cases and 192 controls in case-control studies nested within the Health Professionals Follow-Up Study (HPFS) and the Nurses' Health Study (NHS).
They found that telomeres were significantly shorter in bladder cancer cases than controls; the adjusted odds ratio for bladder cancer was 1.88 (95% confidence interval (CI) = 1.05 to 3.36; Ptrend = 0.006) for individuals in the quartile with the shortest telomeres compared to those in the quartile with the longest telomeres. A significant difference in telomere length also was associated with pack-years of smoking, with controls who had smoked for more than 30 pack-years having relatively shorter telomeres than never smokers. This was the largest population-based study to examine the contributions of telomere length to bladder cancer risk and the first large-scale study that used real-time PCR with peripheral blood leukocytes to determine relative telomere length.
EGRP funds numerous cancer epidemiology cohorts including HPFS, since 1991, and NHS, since 1973. Dr. McGrath's study was funded in part by an EGRP grant to Hoda S. Anton-Culver, Ph.D., of the University of California, Irvine.
McGrath M, Wong JY, Michaud D, Hunter DJ, De Vivo I. Telomere length, cigarette smoking, and bladder cancer risk in men and women. Cancer Epidemiol Biomarkers Prev. 2007 Apr;16(4):815-9.
Hormone Levels and Mammographic Density Independently Linked to Breast Cancer Risk in Postmenopausal Women
Rulla Tamimi, Sc.D.
Circulating sex hormone levels and mammographic density are strongly and independently related to breast cancer risk in postmenopausal women, according to a study by Rulla M. Tamimi, Sc.D., of Brigham and Women's Hospital and Harvard Medical School, and colleagues.
They examined plasma levels of estradiol, free estradiol, testosterone, and free testosterone as well as mammographic density in a cohort of 253 postmenopausal women with breast cancer and 520 healthy women from the Nurses' Health Study (NHS) who were not taking hormones.
Relative risk (RR) of breast cancer associated with mammographic density (RR for highest vs. lowest quartile = 3.8; 95% CI = 2.2 to 6.6; Ptrend < .001) changed little after adjusting for circulating estradiol (RR = 3.9; 95% CI = 2.2 to 6.9; Ptrend < .001) or circulating testosterone (RR = 4.1; 95% CI = 2.3 to 7.2; Ptrend < .001). Circulating levels of estradiol (RR = 2.4; 95% CI = 1.4 to 4.0) and of testosterone (RR = 2.0; 95% CI = 1.2 to 3.1) both were associated with breast cancer risk before and after adjustment for mammographic density.
In a joint analysis of mammographic density and plasma testosterone, the risk of breast cancer was greatest in the highest tertiles of both factors relative to the lowest tertiles (RR = 6.0; 95% CI = 2.6 to 14.0). A joint analysis of mammographic density and plasma estradiol revealed a similar pattern (RR = 4.1; 95% CI = 1.7 to 9.8). This is the first study to indicate that the mechanism by which mammographic density increases breast cancer risk is independent of circulating sex hormone levels. On their own, circulating levels of sex hormones were associated with a twofold increased risk of breast cancer, and mammographic density was associated with an approximately fourfold increased risk of breast cancer.
This research was funded in part by an EGRP grant to Susan E. Hankinson, Sc.D., of Brigham and Women's Hospital and Harvard Medical School.
Tamimi RM, Byrne C, Colditz GA, Hankinson SE. Endogenous hormone levels, mammographic density, and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2007 Aug 1;99(15):1178-87.
Hispanic Breast Cancer Patients May Have Highest Prevalence of BRCA1 Mutation
Hispanic breast cancer patients may have the highest prevalence of BRCA1 mutations when compared to African American, Asian-American, and non-Hispanic white patients without reported Ashkenazi Jewish ancestry, according to a new study.
Esther John, Ph.D.
Esther John, Ph.D., of the Northern California Cancer Center, and colleagues examined the prevalence of BRCA1 mutations in Hispanic, African-American, and Asian-American female breast cancer patients compared with non-Hispanic white patients with and without Ashkenazi Jewish ancestry. All patients in this population-based study of 3,181 women were diagnosed before age 65 and were enrolled at the Northern California Breast Cancer Family Registry during the period 1996-2005. The Registry is part of the Breast Cancer Family Registry (B-CFR), an EGRP-supported research resource.
Among patients without reported Ashkenazi Jewish ancestry, estimated BRCA1 mutation prevalence was 3.5 percent for Hispanic breast cancer patients (95% CI = 2.1% to 5.8%), 2.2 percent for non-Hispanic white patients (95% CI = 0.7% to 6.9%), 1.3 percent for African-American patients (95% CI = 0.6% to 2.6%), and 0.5 percent for Asian-American patients (95% CI = 0.1% to 2.0%). Patients with reported Ashkenazi Jewish ancestry had a BRCA1 mutation prevalence of 8.3 percent (95% CI = 3.1% to 20.1%).
Within each racial/ethnic group, prevalence estimates decreased with age at diagnosis and were higher among patients who reported a family history of breast or ovarian cancer. Among African-American women diagnosed before the age of 35 years, the estimated BRCA1 mutation prevalence was particularly high, 16.7 percent (95% CI = 7.1% to 34.3%).
This research was funded by EGRP grants to Dr. John; Frederick Li, M.D., of the Dana-Farber Cancer Institute; and Alice Whittemore, Ph.D., of Stanford University School of Medicine.
Access EGRP's website for the B-CFR to learn about using this resource.
John EM, Miron A, Gong G, Phipps AI, Felberg A, Li FP, West DW, Whittemore A. Prevalence of pathogenic BRCA1 mutation carriers in 5 U.S. racial/ethnic groups. JAMA. 2007 Dec 26;298(24):2869-911.
Radiotherapy Reduces Mortality in Patients With Recurrent Contralateral Breast Cancer
Radiotherapy following breast-conserving surgery is the standard of care to reduce the risk of same-side recurrence of primary breast cancer in women. However, no studies have been conducted on its effect on mortality in women who subsequently develop a second primary or metachronous contralateral breast cancer (MCBC).
Mario Schootman, Ph.D.
Using data from NCI's Surveillance, Epidemiology, and End Results (SEER) Program, Mario Schootman, Ph.D., of Washington University School of Medicine, and colleagues retrospectively investigated the impact of radiotherapy on cause-specific and all-cause mortality in women who were treated surgically following the diagnosis of MCBC.
The study's analysis was based on data from 1,083 women 40 to 69 years of age diagnosed with stage 0 to III second primary contralateral breast cancer who were identified from SEER data for the period 1985 to 2000 and who subsequently were treated with breast conserving surgery. Based on misclassification-corrected analyses, 43.2 percent of 1,083 women with MCBC did not receive radiotherapy after breast conserving surgery.
The cause-specific and all-cause mortalities were compared in proportional hazard models. The investigators used the method of propensity scores to negate the problem of confounding by indication and adjusted for misclassification of radiotherapy use. After adjustment, the women who had not received radiotherapy had 2.2 times greater risk of cause-specific and 1.7 times greater risk of all-cause mortality.
Based on these findings, the investigators recommended that discussions about the benefits and side effects of radiotherapy be held with patients being treated with breast conserving surgery for stage 0 to III primary MCBC.
This research was funded in part by an EGRP grant to Dr. Schootman.
Schootman M, Jeffe DB, Gillanders WE, Yan Y, Aft R. The effects of radiotherapy for the treatment of contralateral breast cancer. Breast Cancer Res Treat. 2007 May;103(1):77-83. Epub 2006 Oct 11.
Increased Risk of Second Primary Cancers Found in Men With Breast Cancer
Sacha Satram-Hoang, Ph.D.
Men diagnosed with breast cancer may be at increased risk for second cancers. Sacha Satram-Hoang, Ph.D., of the University of California, Irvine, and colleagues performed a retrospective registry-based cohort study to analyze the risk of second primary cancers in men previously diagnosed with breast cancer.
The researchers identified 1,926 male breast cancer cases in the California Cancer Registry. Of the 1,926 cases, 211 developed a second primary cancer (standardized incidence ratio (SIR) = 1.16; 95% CI = 1.01 to 1.32); the men had a 16 percent increased risk of developing a new primary cancer compared with men in the general population. Most of the increased risk was attributable to the development of a second breast cancer (SIR = 52.12; 95% CI = 31.83 to 80.49), cutaneous melanoma (SIR = 2.98; 95% CI = 1.63 to 5.00), and stomach cancer (SIR = 2.11; 95% CI = 1.01 to 3.88). The risk of a second malignancy generally was higher among younger men (< 60 years of age) compared to older men.
This research was funded in part by an EGRP grant to Hoda S. Anton-Culver, Ph.D., of the University of California, Irvine.
Satram-Hoang S, Ziogas A, Anton-Culver H. Risk of second primary cancer in men with breast cancer. Breast Cancer Res. 2007;9(1):R10.
Cytochrome P450 Gene Variant Associated With Breast Cancer Risk in African Americans
Cytochrome P450 enzymes play a key role in the production of steroids, and genes that encode these enzymes could be predictors of breast and prostate cancer risk. P450 oxidoreductase (POR) is required for the activity of other P450 enzymes.
Christopher Haiman, Sc.D.
Christopher Haiman, Sc.D., of the University of Southern California Keck School of Medicine, and colleagues tested candidate polymorphisms at the POR locus for association with breast cancer risk in women in 1,615 cases and 1,962 controls from the Multiethnic Cohort (MEC) Study.
The SNP G5G was common only in African Americans and, when homozygous, was associated modestly with an increased risk of breast cancer (odds ratio = 1.64; 95% CI = 0.89 to 3.04; P = 0.12). The association was stronger in African Americans with advanced disease. These results suggest that this POR genotype increases breast cancer risk in African-American women.
EGRP has funded MEC since 1993. This research was funded in part by EGRP grants to Dr. Haiman; Laurence N. Kolonel, M.D., Ph.D., of the Cancer Research Center of Hawaii; Brian E. Henderson, M.D., of the University of Southern California/Norris Comprehensive Cancer Center; and Leslie Bernstein, Ph.D., of the University of Southern California Keck School of Medicine.
Haiman CA, Setiawan VW, Xia LY, Le Marchand L, Ingles SA, Ursin G, Press MF, Bernstein L, John EM, Henderson BE. A variant in the cytochrome p450 oxidoreductase gene is associated with breast cancer risk in African Americans. Cancer Res. 2007 Apr 15;67(8):3565-8.
Breast Cancer Risk Associated With Alleles in FGFR2
Family history contributes to breast cancer risk, but the degree to which it contributes is uncertain. Fibroblast growth factor receptor-2 (FGFR2) is a tumor suppressor gene that has been observed to be amplified and over-expressed in breast cancer, and splice variants of the gene can transform mammary epithelial cells in culture.
David Hunter, M.D., Sc.D.
David J. Hunter, M.D., Sc.D., of Harvard School of Public Health, and colleagues performed a genome-wide association study (GWAS) of breast cancer by genotyping more than 500,000 SNPs in 1,145 postmenopausal women with invasive breast cancer and 1,142 controls from the Nurses' Health Study I (NHS I).
The researchers identified four SNPs within intron 2 of FGFR2 that were strongly associated with breast cancer. This association was confirmed in 1,776 affected individuals and 2,072 controls from the Nurses' Health Study II (NHS II); Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO); and the American Cancer Society Cancer Prevention Study-II (CPS-II). The association of the SNPs with breast cancer risk did not vary significantly by age of diagnosis. The FGFR2 variants are hypothesized to be associated with risk of sporadic postmenopausal breast cancer.
NHS I and II are cancer epidemiology cohorts that EGRP has funded since 1973 and 1989, respectively. Dr. Hunter's study was conducted as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Project, an NCI initiative to identify common genetic variations associated with risk for prostate and breast cancer. It is coordinated through the Division of Cancer Epidemiology and Genetics (DCEG), Core Genotyping Facility (CGF), and Office of Cancer Genomics (OCG).
The study was funded in part by EGRP grants to Dr. Hunter and Susan E. Hankinson, Sc.D., of Harvard Medical School and Brigham and Women's Hospital; and Walter C. Willett, M.D., Dr.P.H., of Brigham and Women's Hospital and Harvard University.
Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, Wacholder S, Wang Z, Welch R, Hutchinson A, Wang J, Yu K, Chatterjee N, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Hayes RB, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover RN, Thomas G, Chanock SJ. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007 Jul;39(7):870-4. Epub 2007 May 27.
Common Genetic Variation in CYP17 Not Associated With Increased Risk of Breast and Prostate Cancer
The CYP17 gene is involved in the synthesis of steroid hormones, and it is thought that it may be related to risk of developing breast and prostate cancer. Although steroid hormones play an important role in breast and prostate carcinogenesis, genetic variation in CYP17 has been associated only inconsistently with risk of the cancers.
Wendy Setiawan, Ph.D.
To further analyze this association, V. Wendy Setiawan, Ph.D., of the University of Southern California, and colleagues participating in the Breast and Prostate Cancer Cohort Consortium (BPC3), characterized genetic variation in CYP17 by sequencing its coding region and using a haplotype-based analysis to characterize common patterns of variation across the entire CYP17 locus in five racial/ethnic populations.
Nine haplotype-tagged single nucleotide polymorphisms (SNPs) from areas of strong linkage disequilibrium were genotyped in 8,138 prostate cancer cases and 9,033 controls, and 5,333 breast cancer cases and 7,069 controls, from BPC3. Two SNPs, rs2486758 and rs6892, had a borderline significant association with prostate cancer. Two haplotypes and two SNPs also tagged these haplotypes, rs4919687 and rs4919682, and were marginally significantly associated with breast cancer. Because no common variation at CYP17 was associated with levels of circulating hormones, further research is needed to characterize functional SNPs.
"Our analysis provides evidence against a strong main effect between the overall risk of breast and prostate cancer and circulating sex steroid hormone levels and variants in CYP17 that are common among whites [of European ancestry]," concluded the investigators. "Weak associations between several CYP17 SNPs and the cancers should be evaluated in future studies," they added.
This study was funded in part by EGRP grants to David Hunter, M.D., Sc.D., of Harvard School of Public Health; Michael Thun, M.D., of the American Cancer Society; Elio Riboli, M.D., M.Sc., of the Imperial College, London; and Brian Henderson, M.D., of the University of Southern California. The Division of Cancer Epidemiology and Genetics, which is the intramural epidemiology component of NCI, also is part of BPC3 and participated in this research.
With support from EGRP, the BPC3 pools data and biospecimens from 10 large prospective cohorts to conduct research on gene-environment interactions in the etiology of breast and prostate cancer. Access EGRP's website to learn more about the BPC3.
Setiawan VW, Schumacher FR, Haiman CA, Stram DO, Albanes D, Altshuler D, Berglund G, Buring J, Calle EE, Clavel-Chapelon F, Cox DG, Gaziano JM, Hankinson SE, Hayes RB, Henderson BE, Hirschhorn J, Hoover R, Hunter DJ, Kaaks R, Kolonel LN, Kraft P, Ma J, Le Marchand L, Linseisen J, Lund E, Navarro C, Overvad K, Palli D, Peeters PH, Pike MC, Riboli E, Stampfer MJ, Thun MJ, Travis R, Trichopoulos D, Yeager M, Ziegler RG, Spencer Feigelson H, Chanock SJ. CYP17 genetic variation and risk of breast and prostate cancer from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). Cancer Epidemiol Biomarkers Prev. 2007 Nov;16(11):2237-46.
HPV Load May Predict Prevalence of Cervical Cancer
Finding markers that identify which infections will progress to high-grade cervical intraepithelial neoplasia (≥CIN2) potentially could eliminate the need for many unnecessary gynecologic procedures for women who test positive for human papillomavirus (HPV) on Pap smears. Determining whether HPV viral load in cervical specimens is valuable as a marker of progression is an important research question.
Melinda Butsch Kovacic,
Patti Gravitt, Ph.D.
Patti Gravitt, Ph.D., of The Johns Hopkins Bloomberg School of Public Health, and Melinda Butsch Kovacic, Ph.D., M.P.H., formerly of NCI, and colleagues analyzed HPV viral load and risk of prevalent and incident histologically confirmed ≥CIN2 by conducting a prospective, cross-sectional, population-based study of women infected with HPV in Costa Rica, where rates of cervical cancer historically are high.
The final analysis looked at 1,296 women with single HPV infections and 696 women with multiple HPV infections and measured viral load by oligonucleotide probe hybridization signal intensity. In followup over 7 years, investigators found that high viral load for most high-risk HPV genotypes is associated with prevalent ≥CIN2. However, only women infected with HPV16 alone (odds ratio = 27.2; 95% CI = 3.5 to 213.5) had a strong association between high viral load and incident ≥CIN2. Cumulative risk of diagnosis of the cancer was much higher for HPV16 (20.6%) compared to women with non-HPV16 carcinogenic types (5.1%) or other noncarcinogenic types (1.6%).
These findings support emerging evidence that HPV16 possesses unique properties compared to other carcinogenic HPV genotypes. In view of the fact that HPV16 accounts for almost 50 percent of all cervical cancers worldwide, viral load testing for this specific genotype only may be beneficial. The authors advise caution in applying their findings to clinical practice, in part because the complex research assays used to measure viral load are not yet available clinically.
The study was funded by an EGRP grant to Robert Burk, M.D., of Albert Einstein College of Medicine. Dr. Kovacic is now at Cincinnati Children's Hospital Medical Center.
Gravitt PE, Kovacic MB, Herrero R, Schiffman M, Bratti C, Hildesheim A, Morales J, Alfaro M, Sherman ME, Wacholder S, Rodriguez AC, Burk RD. High load for most high risk human papillomavirus genotypes is associated with prevalent cervical cancer precursors but only HPV16 load predicts the development of incident disease. Int J Cancer. 2007 Dec 15;121(12):2787-93.
Physical Activity May Protect Against Colorectal Cancer in Postmenopausal Women
Cohort and case-control studies have determined that physical activity is inversely associated with colon cancer, particularly among men. This risk reduction has not been shown consistently for women, however. Hormone replacement therapy is associated with reduced colon cancer risk among postmenopausal women, studies have shown, and may mask any beneficial effects of physical activity for women who take these medications.
Phuong Mai, M.D.
Phuong L. Mai, M.D., of the University of Southern California, and colleagues analyzed physical activity and colon cancer incidence among the 120,147 female participants in the California Teachers Study (CTS). When comparing women who did more than 4 hours per week per year of recreational physical activity with women who did less than 0.5 hours per week per year, the researchers found that lifetime moderate and strenuous physical activity were associated only modestly with a reduction in colon cancer risk (relative risk (RR) = 0.75; 95% CI = 0.57 to 1.00; Ptrend = 0.23). Among women who had never used hormone therapy, lifetime physical activity was associated with reduced colon cancer risk (RR = 0.51; 95% CI = 0.31 to 0.85; Ptrend = 0.02).
Postmenopausal women who had used hormone therapy had a lower risk of colon cancer, but their risk was not associated with physical activity. With hormone use declining, physical activity may offer a means to reduce women's colon cancer risk, the researchers suggest.
This research was funded in part by an EGRP grant to Leslie Bernstein, Ph.D., University of Southern California Keck School of Medicine.
Mai PL, Sullivan-Halley J, Ursin G, Stram DO, Deapen D, Villaluna D, Horn-Ross PL, Clarke CA, Reynolds P, Ross RK, West DW, Anton-Culver H, Ziogas A, Bernstein L. Physical activity and colon cancer risk among women in the California Teachers Study. Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):517-25.
Colorectal and Prostate Cancer Share a Common Genetic Risk Factor
Variants within three unlinked regions of chromosome 8q24 have been shown to contribute to prostate cancer risk. Although the region contains no known genes, it is frequently amplified in both prostate and colorectal cancer.
Brian Henderson, M.D.
Christopher Haiman, Sc.D., of the University of Southern California Keck School of Medicine, and colleagues tested whether previously identified variants in 8q24 also affect colorectal cancer risk. They genotyped the variants in a total of 1,807 affected individuals and 5,511 controls in samples from the Multiethnic Cohort (MEC) Study (African Americans, Japanese Americans, Native Hawaiians, Latinos, and European Americans) and from two other studies of Japanese Americans and European Americans.
One variant within the region, rs6983267, was associated significantly with colorectal cancer risk (odds ratio = 1.22, 95% CI = 1.12 to 1.32). Other variants slightly affected risk, but the contributions of these variants to colorectal cancer risk differed from that for prostate cancer risk, indicating differences in the etiologic contributions of these variants to the two cancers.
EGRP has funded MEC since 1993. This study was funded in part by EGRP grants to Dr. Haiman; Laurence N. Kolonel, M.D., Ph.D., of the Cancer Research Center of Hawaii; Löic Le Marchand, M.D., Ph.D., of the University of Hawaii, Honolulu; and Brian E. Henderson, M.D., of the University of Southern California/Norris Comprehensive Cancer Center and senior author of the paper (pictured).
Haiman CA, Le Marchand L, Yamamato J, Stram DO, Sheng X, Kolonel LN, Wu AH, Reich D, Henderson BE. A common genetic risk factor for colorectal and prostate cancer. Nat Genet. 2007 Aug;39(8):954-6. Epub 2007 Jul 8.
Alcohol and Tobacco Do Not Increase Risk in Patients With HPV16-Related Head and Neck Cancer
Kate Applebaum, Sc.D.
The effect of human papillomavirus type 16 (HPV16) infection on the association between smoking and drinking alcohol and risk of head and neck squamous cell carcinoma (HNSCC) is not fully understood. Research conducted by Kate Applebaum, Sc.D., while at the Harvard School of Public Health, and colleagues suggests that the etiology of HPV16-related HNSCC may be distinct from cancers of those sites attributed to tobacco or alcohol use. These findings of different patterns of risk for differing cancer sites have important implications for the development of targeted treatments.
The investigators conducted a case-control study of 485 patients in the Boston area who were diagnosed with HNSCC between 1999 and 2003 and 549 control subjects who were cancer-free. The study groups were matched closely for age, gender, and town of residence. All participants completed questionnaires about smoking and alcohol consumption and received antibody tests to detect the presence of HPV16 in the blood.
Polytomous logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of HPV serology, alcohol, and tobacco use for oral, pharyngeal, and laryngeal cancer.
Although HPV16 serology was not a strong confounder for the association of HNSCC risk and smoking and alcohol, HPV16 seropositivity was a strong risk factor for HNSCC (OR = 4.5, 95% CI = 3.1 to 6.5). The strongest risk factors by tumor site were smoking for laryngeal cancer, alcohol consumption for oral cancer, and HPV16 for pharyngeal cancer.
The research was funded in part by EGRP grants to Karl Kelsey, M.D., M.O.H., of Brown University. Dr. Applebaum is now on the faculty at Boston University and is a Visiting Scientist at Harvard University.
Applebaum KM, Furniss CS, Zeka A, Posner MR, Smith JF, Bryan J, Eisen EA, Peters ES, McClean MD, Kelsey KT. Lack of association of alcohol and tobacco with HPV16-associated head and neck cancer. J Natl Cancer Inst. 2007 Dec 5;99(23):1801-10.
Tobacco and Alcohol Independently Increase Risk of Head and Neck Cancer
A combination of cigarette smoking and alcohol consumption is implicated in at least 75 percent of head and neck cancers. To understand the mechanism of head and neck carcinogenesis and assess the efficacy of interventions to control these risk factors, an understanding of the independent association of each risk factor with cancer risk is needed.
Mia Hashibe, Ph.D., of the International Agency for Research on Cancer (IARC), and colleagues performed a pooled analysis of data from 15 case-control studies of head and neck cancer risk and cigarette smoking or alcohol consumption in the absence of the other risk factor. A total of 10,302 head and neck cancer cases and 15,329 controls were obtained from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, an international collaboration of research groups conducting large molecular epidemiology studies on head and neck cancer.
The researchers found that cigarette smoking in never drinkers was associated with an increased risk of head and neck cancer (OR = 2.13 compared to never smokers). Alcohol consumption in the absence of tobacco use was associated with increased risk only at high frequencies of consumption (OR = 2.04 for 3 or more drinks per day versus never drinking). One-quarter of head and neck cancers in never drinkers were attributable to smoking and 7 percent of cancers in never smokers were attributable to alcohol consumption.
Paolo Boffeta, M.D., M.P.H.
The major strength of the pooled analyses, say the authors, was assembly of a very large series of never users of tobacco and never drinkers among head and neck cancer patients and control subjects, which allowed detailed examination of head and neck cancer risks and exploration of differences in risks by cancer subsite, geographic region, and sex. Paolo Boffeta, M.D., M.P.H. (pictured), of IARC, directed this pooled analysis. Establishment of the INHANCE Consortium has allowed generation of large sample sizes for analysis of rare subgroups, such as head and neck cancer patients who are never smokers and/or never drinkers. EGRP is a major facilitator of the INHANCE Consortium and provided funding for this pooled analysis. It also provided grant support for some of the individual epidemiologic studies that contributed to the analysis.
EGRP supports cancer epidemiology consortia in numerous ways, such as through grant support, assistance in identifying partners with similar research interests, advice on policies and processes that have proven successful with other consortia, participation on steering committees, and in evaluating established consortia.
Access EGRP's Consortia Web section to learn about the many ways in which the Program supports cancer epidemiology consortia.
Hashibe M, Brennan P, Benhamou S, Castellsague X, Chen C, Curado MP, Dal Maso L, Daudt AW, Fabianova E, Wunsch-Filho V, Franceschi S, Hayes RB, Herrero R, Koifman S, La Vecchia C, Lazarus P, Levi F, Mates D, Matos E, Menezes A, Muscat J, Eluf-Neto J, Olshan AF, Rudnai P, Schwartz SM, Smith E, Sturgis EM, Szeszenia-Dabrowska N, Talamini R, Wei Q, Winn DM, Zaridze D, Zatonski W, Zhang ZF, Berthiller J, Boffetta P. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst. 2007 May 16;99(10):777-89.
Newly Published Research on Non-Hodgkin Lymphoma Shows the Power of Consortia
Ten papers on non-Hodgkin lymphoma (NHL) were published in the March 2007 issue of Cancer Epidemiology, Biomarkers & Prevention. These papers stem from a symposium focusing on the role of the environment in NHL risk that was held at the April 2006 annual meeting of the InterLymph Consortium. The information presented at the symposium and published in the journal contributes to our understanding of how behavioral and environmental factors, such as infectious agents, sunlight exposure, obesity, and chemical exposure, affect the risk of developing NHL.
InterLymph is an EGRP-sponsored consortium for epidemiologic research on lymphoma. Members have completed or have ongoing case-control studies of lymphoma and participate in collaborative research by undertaking projects that pool data across studies. Consortia like InterLymph facilitate large-scale collaborations that are needed to address complex questions that cannot be answered through the efforts of investigators at a single institution or from a single discipline. Access EGRP's Consortia page to learn about the many ways in which the Program supports cancer epidemiology consortia.
Hartge P, Smith MT. Environmental and behavioral factors and the risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):367-8. Epub 2007 Mar 7. No abstract available.
Boffetta P, de Vocht F. Occupation and the risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):369-72.
Engel LS, Lan Q, Rothman N. Polychlorinated biphenyls and non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):373-6. Epub 2007 Mar 2. Review.
Krishnan B, Morgan GJ. Non-Hodgkin lymphoma secondary to cancer chemotherapy. Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):377-80. Review.
Vineis P, Miligi L, Costantini AS. Exposure to solvents and risk of non-Hodgkin lymphoma: clues on putative mechanisms. Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):381-4. Epub 2007 Mar 2.
Smith MT, Jones RM, Smith AH. Benzene exposure and risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):385-91. Epub 2007 Mar 2. Review.
Skibola CF. Obesity, diet and risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):392-5. Epub 2007 Mar 2. Review.
Armstrong BK, Kricker A. Sun exposure and non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):396-400. Epub 2007 Mar 2. Review.
Engels EA. Infectious agents as causes of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):401-4. Epub 2007 Mar 2. Review.
Grulich AE, Vajdic CM, Cozen W. Altered immunity as a risk factor for non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):405-8. Epub 2007 Mar 2. Review.
Ovarian Cancer Risk May Vary With Hormone Therapy
Mary Anne Rossing,
Few studies have examined whether ovarian cancer risk varies according to the recency and duration of the specific menopausal hormone therapy (HT) used. A study by Mary Anne Rossing, D.V.M., Ph.D., of Fred Hutchinson Cancer Research Center, and colleagues assessed the risk of ovarian cancer among users of unopposed menopausal estrogen (ET) and combined estrogen/progestogen therapy (EPT).
In a population-based study in Washington State, the investigators interviewed 812 women diagnosed with ovarian cancer between 2002 and 2005 and 1,313 controls about HT use and other characteristics. Women who used a single form of HT (ET or EPT) were compared with women who never used HT. Women who had used only ET had a slightly higher increased risk, and women who had used only EPT had a slightly reduced risk of ovarian cancer. Among current users, the increased risk among women who used ET for 5 years or more remained evident (OR = 1.6; 95% CI = 1.1 to 2.5). Among former ET users, a 5 years or more duration of use was associated with increased risk primarily among women who last used ET relatively recently. The OR was 1.8 (95% CI = 0.8 to 3.7) among women with 5 or more years of use who had stopped less than 3 years earlier, and 1.2 (95% CI = 0.6 to 2.7) among women who had used ET for a similar duration but had stopped 3 or more years earlier. In contrast, no increase in risk was found among women who used only EPT, regardless of duration. Compared with women who never used HT, current EPT users had an OR of 1.1 (95% CI = 0.8 to 1.5), and risk declined with increasing time since stoppage. Long-term ET use may be associated with an increased ovarian cancer risk that wanes after use ceases. No similar increased risk was observed with EPT use, and a reduction in risk became increasingly evident as time after stoppage increased. If replicated, these results may have public health implications and influence future chemoprevention strategies.
This research was funded by an EGRP grant to Dr. Rossing.
Rossing MA, Cushing-Haugen KL, Wicklund KG, Doherty JA, Weiss NS. Menopausal hormone therapy and risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2007 Dec;16(12):2548-56.
Putative Tumor Suppressor Gene Associated With Aggressive Prostate Cancer
Lilly Zheng, Ph.D.
David Duggan, Ph.D.
A variant of a tumor suppressor gene, DAB21P, may be associated with an increased risk of aggressive prostate cancer, according to a study by David Duggan, Ph.D., of the Translational Genomics Research Institute, S. Lilly Zheng, Ph.D., of Wake Forest University, and colleagues. Consistent findings that prostate cancer has a genetic component have led investigators to suspect there are genetic variants that predispose some men to develop the disease. The investigative team combined the results from two genome-wide association studies (GWAS) on aggressive prostate cancer to identify single nucleotide polymorphisms (SNPs) that may be associated with aggressive disease.
In the first phase of the study, the investigators performed an exploratory GWAS scan in 498 men with aggressive prostate cancer and 494 men who were cancer-free from a population-based study in Sweden. The results of the scan were combined with data on 737 patients with aggressive prostate cancer and 1,105 controls from a GWAS performed by NCI's Cancer Genetic Markers of Susceptibility (CGEMS) project. By combining results of these two studies, the investigators identified 11 SNPs that had statistically significant associations with aggressive prostate cancer, based on a threshold of P < 0.01, seven of which had consistent risk associations in both studies.
These exploratory findings then were confirmed in two independent populations: one cohort consisting of 1,032 European Americans and 571 controls, and the other cohort of 210 African Americans and 346 controls. The investigators found a statistically significant association with aggressive prostate cancer for the SNP rs1571801 at 9q33 in the European Americans (P = 0.004) and African Americans (P = 0.02). This SNP, located in the DAB2IP gene, was associated with aggressive prostate cancer among men of European and African-American descent. DAB2IP encodes a novel Ras GTPase-activating protein and putative prostate tumor suppressor. Reduced DAB2IP expression has been shown to correlate with increased expression of EZH2, which is one of the strongest markers for aggressive prostate cancer.
This research was funded in part by EGRP grants to William Isaacs, Ph.D., of The Johns Hopkins Medical Institutions, and Jianfeng Xu, M.D., Dr.P.H., of Wake Forest University School of Medicine.
CGEMS is an NCI initiative to identify common genetic variants associated with risk for prostate and breast cancer. It is coordinated through the NCI's Division of Cancer Epidemiology and Genetics, Core Genotyping Facility, and Office of Cancer Genomics.
Duggan D, Zheng SL, Knowlton M, Benitez D, Dimitrov L, Wiklund F, Robbins C, Isaacs SD, Cheng Y, Li G, Sun J, Chang BL, Marovich L, Wiley KE, Bälter K, Stattin P, Adami HO, Gielzak M, Yan G, Sauvageot J, Liu W, Kim JW, Bleecker ER, Meyers DA, Trock BJ, Partin AW, Walsh PC, Isaacs WB, Grönberg H, Xu J, Carpten JD. Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP. J Natl Cancer Inst. 2007 Dec 19;99(24):1836-44. Epub 2007 Dec 11.
Prostate Cancer-Associated SNP Identified
Recent studies have found chromosomal region 8q24 amplified in several tumor types, including prostate and breast. In addition, a region of 8q24 has been identified as being associated with prostate cancer in a linkage analysis of Icelandic families, and the findings have been replicated in three case-control studies of men with European ancestry in Iceland, Sweden, and the United States, and in a case-control study of African Americans.
Frederick R. Schumacher, Ph.D., M.P.H., of Harvard School of Public Health, and colleagues validated the association between a SNP in 8q24 (rs1447295) and prostate cancer in a large nested case-control study from the EGRP-funded Breast and Prostate Cancer Cohort Consortium (BPC3). This study included 6,637 prostate cancer cases and 7,361 controls. The researchers also examined whether this polymorphism was associated with breast cancer in 2,604 Caucasian breast cancer cases and 3,118 controls.
They found a strong association of this SNP and prostate cancer in Caucasians (P = 1.23 x 10-13) and a significant association in African-American men diagnosed with prostate cancer at an early age. The authors found no significant difference in risk when tumors were classified by Gleason score, stage, or mortality. They also found no association between this SNP and the risk of breast cancer.
"Although the gene responsible has yet to be identified, the validation of this marker in this large sample of prostate cancer cases leaves little room for the possibility of a false-positive result," the authors report.
This research was funded in part by EGRP grants to David J. Hunter, M.D., Sc.D., Michael J. Thun, M.D., of the American Cancer Society; Elio Riboli, M.D., M.Sc., then with the International Agency for Research on Cancer (IARC); and Brian E. Henderson, M.D., of the University of Southern California/Norris Comprehensive Cancer Center.
With support from EGRP, the BPC3 pools data and biospecimens from 10 large prospective cohorts to conduct research on gene-environment interactions in the etiology of breast and prostate cancer. Access EGRP's website to learn more about BPC3.
Schumacher FR, Feigelson HS, Cox DG, Haiman CA, Albanes D, Buring J, Calle EE, Chanock SJ, Colditz GA, Diver WR, Dunning AM, Freedman ML, Gaziano JM, Giovannucci E, Hankinson SE, Hayes RB, Henderson BE, Hoover RN, Kaaks R, Key T, Kolonel LN, Kraft P, Le Marchand L, Ma J, Pike MC, Riboli E, Stampfer MJ, Stram DO, Thomas G, Thun MJ, Travis R, Virtamo J, Andriole G, Gelmann E, Willett WC, Hunter DJ. A common 8q24 variant in prostate and breast cancer from a large nested case-control study. Cancer Res. 2007 Apr 1;67(7):2951-6.
Prostate Cancer Risk Affected by Multiple Regions Within 8q24
This study's authors previously conducted an admixture scan in African Americans with prostate cancer and identified a 3.8-Mb region of chromosome 8q24 that contained risk alleles that differed in frequency between West Africans and European Americans. A second group of researchers identified additional specific variants within this region that also were associated with increased risk of prostate cancer.
Christopher A. Haiman, Sc.D., of the University of Southern California Keck School of Medicine, and colleagues searched for additional variants in 8q24 that might contribute to prostate cancer risk. The group genotyped 1,521 variants in 1,175 African Americans diagnosed with prostate cancer who were under age 72 at diagnosis and 837 African-American controls, as well as 465 European-American cases and 446 European-American controls.
The researchers identified seven risk variants that independently predicted risk for prostate cancer. The variants spanned a more than fivefold range of cancer susceptibility in some populations. Several of the SNPs associated most strongly with prostate cancer also were genotyped in cases and controls from African-American, Japanese-American, Native-Hawaiian, Latino, and European-American (4,266 cases and 3,252 controls) populations.
This analysis strengthened the evidence for an association between these SNPs, with the strongest association with one in particular, rs16901979 (P = 1.5 x 10-18), and risk for prostate cancer. It also demonstrated that the risk allele at this SNP is more common in West Africans (54%) than European Americans (3%).
Although none of the risk variants aligned with known genes or altered the coding sequence of a known protein, this work suggests that there may be multiple unknown prostate cancer susceptibility genes located in 8q24. Additionally, the somatic amplification at 8q commonly observed in prostate tumors implies that the risk alleles make this entire region, including oncogenes such as MYC, prone to amplification.
David Reich, Ph.D.
The senior author of this study, David Reich, Ph.D., of Harvard Medical School and Broad Institute of Harvard and MIT, is pictured. This research was funded in part by EGRP grants to Sue Ingles, Dr.P.H., of the University of Southern California/Norris Comprehensive Cancer Center; Kathleen S. Cooney, M.D., of the University of Michigan; and Alice S. Whittemore, Ph.D., of Stanford University.
Haiman CA, Patterson N, Freedman ML, Myers SR, Pike MC, Waliszewska A, Neubauer J, Tandon A, Schirmer C, McDonald GJ, Greenway SC, Stram DO, Le Marchand L, Kolonel LN, Frasco M, Wong D, Pooler LC, Ardlie K, Oakley-Girvan I, Whittemore AS, Cooney KA, John EM, Ingles SA, Altshuler D, Henderson BE, Reich D. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet. 2007 May;39(5):638-44. Epub 2007 Apr 1.
Second Risk Locus for Prostate Cancer Identified at 8q24
A family history of prostate cancer and ethnic background are the only established risk factors for this cancer. Previous studies have identified SNPs in chromosome 8q24 that are associated with increased risk of prostate cancer, particularly among African-American men.
Meredith Yeager, Ph.D.
Focusing on men of Eastern European origin, Meredith Yaeger, Ph.D., of the SAIC-NCI Frederick Cancer Research and Development Center (FCRDC) and the Division of Cancer Epidemiology and Genetics (DCEG), and colleagues conducted a genome-wide association study (GWAS) of 550,000 SNPs in a nested case-control study of 1,172 affected men (484 with nonaggressive prostate cancer; 688 with aggressive prostate cancer) and 1,157 controls.
The researchers confirmed in men of Eastern European descent an association between risk for prostate cancer and the SNP rs1447295, which has been associated with increased risk for the cancer in African-American men and with aggressive prostate cancer. In addition, they identified a new association with SNP rs6983267 and confirmed this finding in a combined analysis with four additional replication studies including 3,123 affected men and 3,142 controls. These findings indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European descent, the researchers report.
The research was performed as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Project, an NCI initiative to identify common genetic variations associated with risk for prostate and breast cancer. It is coordinated through the Division of Cancer Epidemiology and Genetics (DCEG), Core Genotyping Facility (CGF), and Office of Cancer Genomics (OCG).
This study was funded in part by EGRP grants to Walter C. Willett, M.D., Dr.P.H., of Harvard University and Brigham and Women's Hospital; David J. Hunter, M.D., Sc.D., of the Harvard School of Public Health; and Michael J. Thun, M.D., of the American Cancer Society.
Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft P, Wacholder S, Minichiello MJ, Fearnhead P, Yu K, Chatterjee N, Wang Z, Welch R, Staats BJ, Calle EE, Feigelson HS, Thun MJ, Rodriguez C, Albanes D, Virtamo J, Weinstein S, Schumacher FR, Giovannucci E, Willett WC, Cancel-Tassin G, Cussenot O, Valeri A, Andriole GL, Gelmann EP, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover R, Hunter DJ, Chanock SJ, Thomas G. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet. 2007 May;39(5):645-9. Epub 2007 Apr 1.