Research Highlights from EGRP Grantees - 2012

Extramural investigators supported by the Epidemiology and Genomics Research Program (EGRP) were invited to nominate manuscripts published in 2012 based on their potential public health impact. EGRP Program staff made the final selections based on potential scientific and/or potential public health impact.

EGRP funds research in human populations to understand determinants of cancer occurrence and outcomes. EGRP is the largest funder of cancer epidemiology grants nationally and worldwide, supporting more than 400 grants and cooperative agreements annually. View a full list of active EGRP grantsExternal Web Site Policy.

The research featured below was funded in full or in part by EGRP:

Brain Cancer

Breast Cancer

Cervical Cancer

Colorectal Cancer

Early Life Exposures

Pancreatic Cancer

Testicular Cancer

Allergies May Reduce Glioblastoma Risk

Judith Schwartzbaum

Having allergies may protect against glioblastoma and all glioma, according to a recent study. Researchers found a decreased risk of glioblastoma among women who tested positive for allergen-specific IgE. Men who tested positive were not similarly protected, although those with elevated total IgE levels may experience lower rates. The benefits of elevated total IgE were observed at least 20 years before diagnosis among both sexes combined.

For this nested case-control study, researchers analyzed serum stored in the Janus Serum Bank in Norway from 594 patients and 1,177 participants without tumors matched on age at blood collection, date of collection, and sex.

Schwartzbaum J, Ding B, Johannesen TB, et al. Association between prediagnostic IgE levels and risk of gliomaExternal Web Site Policy. J Natl Cancer Inst. 2012 Aug 22;104(16):1251-9. Epub 2012 Aug 1.

The study was funded by an EGRP grant to Judith Schwartzbaum, Ph.D., of The Ohio State University.

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CHEK2*1100delC Mutation Associated with Increased Risk of Death from Breast Cancer

This study tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women who have had a first breast cancer. CHEK2*1100delC is a founder mutation carried by 0.5-1.6% of individuals of Northern and Eastern European descent, is inherited from the parents, and present in germline DNA.

From 22 studies participating in the EGRP-supported Breast Cancer Association Consortium, 25,571 white women of Northern and European descent with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median 6.6 years). In prospective studies, risks of early death, breast cancer-specific death, and development of a second breast cancer were measured and stratified by estrogen receptor status.

Per Hall

Fergus Couch

Hoda Anton-Culver

Esther John

Irene Andrulis

Among women with estrogen receptor-positive breast cancer, the scientists found that CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of second breast cancer.

The poorer survival has been suggested before, the authors say, but this study provides stronger evidence for the association and demonstrates it is restricted to estrogen receptor-positive disease. Moreover, Stig Bojesen, M.D., Ph.D., D.M.Sci., of Copenhagen University Hospital, senior author, said "This is one of the few examples of a genetic factor influencing long-term prognosis documented in an extensive series of women with breast cancer, and it raises the possibility that other genetic factors influencing breast cancer prognosis could be identified."

Weischer M, Nordestgaard BG, Pharoah P, et al. CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of second breast cancerExternal Web Site Policy. J Cin Oncol. 2012 Dec 10;30(35):4308-16. Epub 2012 Oct 29.

Funded in part by EGRP grants to Irene Andrulis, Ph.D., of the Samuel Lunenfeld Research Institute; Esther John, Ph.D., M.S.P.H., of the Cancer Prevention Institute of California; Hoda Anton-Culver, Ph.D., of the University of California at Irvine; Fergus Couch, Ph.D., of the Mayo Clinic; and Per Hall, M.D., Ph.D., of the Karolinska Institute.

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Tumor Morphology Predicts Breast Cancer Risk for an Affected Woman's Relatives

High-risk mutations in susceptibility genes are rare and explain only about 25% of the familial risk of breast cancer. Breast cancer morphology, including trabecular growth pattern and mitotic index, are strong predictors of BRCA1 mutation status, and therefore, of breast cancer risk for an affected woman's relatives. This study examined if tumor morphology predicts familial risk of breast cancer by studying 1,041 relatives (sisters and mothers) of a population-based sample of 452 women diagnosed with invasive breast cancer before the age of 40 that was not caused by BRCA1 and BRCA2 mutations.

The researchers found a wide variation in risks for relatives based on tumor characteristics. The absence of extensive sclerosis, extensive intraductal carcinoma, absence of acinar and glandular growth patterns, and the presence of trabecular and lobular growth patterns were independent predictors of risk for relatives (all P <0.02). Close relatives with two or more of these features were at high risk (a 25% lifetime risk) of developing breast cancer, similar to that for close relatives of BRCA1 and BRCA2 mutation carriers. Relatives with none of these tumor characteristics were not at increased risk of breast cancer.

Breast Cancer
Family Registry

Being able to quantify an unaffected woman's risk of breast cancer is important for prevention and screening. Currently, risk estimates associated with family history are based on the ages at diagnosis of cancer, but the researchers have shown that these estimates could be improved by taking into account the cancer's morphological features. These findings also suggest that there is a substantial proportion of early-onset breast cancer that may not have a genetic cause, as well as revealing that there might be as yet undiscovered strong non-genetic risk factors for early-onset breast cancers with particular morphological features.

Dite GS, Makalic E, Schmidt DF, Giles GG, Hopper JL, Southey MC. Tumour morphology of early-onset breast cancers predicts breast cancer risk for first-degree relatives: the Australian Breast Cancer Family RegistryExternal Web Site Policy. Breast Cancer Res. 2012 Aug 28. 14(4). R122.

The research was funded in part by an EGRP grant to John Hopper, Ph.D., of the University of Melbourne. These findings are based on data from the Breast Cancer Family Registry, which was supported by EGRP grants from 1995-2011.

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Injectable Contraceptive May Increase Risk of Invasive Breast Cancer in Pre-Menopausal Women

Christopher Li

Depo-medroxyprogesterone acetate (also known as depo-provera or DMPA) is an injectable contraceptive that contains the same progestin as the menopausal hormone therapy regimen found to increase breast cancer risk among postmenopausal women. DMPA was approved for use as a contraceptive in the U.S. in 1992. Previous case-control studies conducted in other countries suggested an association between DMPA use and increased risk of breast cancer; however, the results have been inconsistent and may not be generalizable to the U.S. population.

This study was the first large-scale U.S. study to examine the link between use of DMPA and breast cancer risk. After conducting a study among a population of 1,028 women 20 to 44 years old diagnosed with invasive breast cancer and 919 controls, researchers found that recent DMPA use of 12 months or longer was associated with a 2.2-fold increased risk of invasive breast cancer. These findings suggest the importance of identifying the potential risks of available contraceptives when alternative options are available.

Li CI, Beaber EF, Tang MT, Porter PL, Daling JR, Malone KE. Effect of Depo-Medroxyprogesterone Acetate on Breast Cancer Risk among Women 20 to 44 Years of AgeExternal Web Site Policy. Cancer Res. 2012 Apr. 1572(8). 2028-35.

The research was supported in part by an EGRP grant to Christopher Li, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center.

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HIV-Infected Women with Negative HPV Co-Test Results Have Similar Low Risk of Precancer/Cancer as Those Who Are HIV-uninfected

Howard Strickler

U.S. cervical cancer screening guidelines for HIV-uninfected women age 30 years or older recommend increasing the cervical cancer screening interval from every 3 years among those with a normal Pap test to every 5 years if they also test negative for oncogenic HPVā€“negative (i.e., HPV co-test negative). For HIV-infected women, however, U.S. Public Health Service guidelines currently recommend two Pap tests at 6-month intervals in the first year following diagnosis of HIV infection, then annually if the Pap test is normal. There is little data regarding HPV co-testing in HIV-infected women.

This study therefore determined the 5-year risk of cervical pre-cancer/cancer among 420 HIV-infected women and 279 HIV-uninfected women in the Women's Interagency HIV Study (WIHS) who were Pap normal and oncogenic HPV negative. The risk pre-cancer/cancer was very low in HPV co-test negative HIV-infected women, no different than in HIV-uninfected subjects. No invasive cancers were observed in either group over 9 years of follow-up.

These findings are generalizable only to HIV-infected women undergoing long-term clinical follow-up. Additional observational studies or a randomized clinical trial may be necessary before clinical guideline committees consider whether to expand current recommendations regarding HPV co-testing to HIV-infected women.

Keller MJ, Burk RD, Xie X, Anastos K, Massad LS, Minkoff H, Xue X, D'Souza G, Watts DH, Levine AM, Castle PE, Colie C, Palefsky JM, Strickler HD. Risk of Cervical Precancer and Cancer Among HIV-Infected Women With Normal Cervical Cytology and No Evidence of Oncogenic HPV InfectionExternal Web Site Policy. JAMA. 2012 Jul 25. 308(4). 362-9.

This research was funded in part by an EGRP grant to Howard Strickler, M.D., of the Albert Einstein College of Medicine at Yeshiva University.

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Gene Mutation Predicts Colorectal Cancer Patients Who May Benefit from Aspirin

Aspirin therapy may extend the lives of patients with colorectal cancer whose tumors carry a mutation in the PIK3CA gene, according to a study. "Our results suggest that aspirin can be particularly effective in prolonging survival among patients whose colorectal cancer tests positive for a mutation in PIK3CA," said senior author Shuji Ogino, M.D., Ph.D. "PIK3CA may be a tumor genetic marker that can help doctors determine which colorectal cancers are likely to respond to a particular therapy."

Walter Willett

Andrew Chan

Jeffrey Meyerhardt

Shuji Ogino

Patients whose tumors had PIK3CA mutation experienced a sharp jump in five-year survival, but patients who lacked the mutation did not benefit. This interdisciplinary, molecular pathological epidemiology study focused on more than 900 patients with colon and rectal cancer from the EGRP-funded Nurses' Health Study and Health Professionals Follow-up Study. About 15-20% of patients carry PIK3CA mutations.

The study was funded in part by EGRP grants to Shuji Ogino, M.D., Ph.D., of Dana-Farber Cancer Institute and Harvard Medical School; Andrew Chan, M.D., of Massachusetts General Hospital; Jeffrey Meyerhardt, M.D., M.P.H., of Dana-Farber Cancer Institute and Harvard Medical School; Meir Stampfer, M.D., Dr.P.H., of Brigham and Women's Hospital, Dana-Farber Cancer Center, and Harvard School of Public Health; and Walter Willett, M.D., M.P.H., Dr.P.H., of Harvard School of Public Health.

Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survivalExternal Web Site Policy. N Engl J Med. 2012 Oct 25;367(17):1596-606.

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Web-Based Risk Stratification Tool for Advanced Colorectal Neoplasia A Work in Progress

Paul C. Schroy III

The Your Disease Risk (YDR) is an interactive, Web-based tool that provides personalized risk estimates for several common chronic diseases, including colorectal cancer, and tailored behavioral risk reduction messages. The scientists' goal was to assess its accuracy for stratifying average risk patients into low-versus intermediate/high-risk categories for advanced adenomas and presymptomatic cancers, collectively known referred to as "advanced colorectal neoplasia (ACN)", and see if it could be optimized for cost-effective screening.

Although YDR-derived Relative Risk (RR) scores were linearly associated with ACN after adjusting for age and gender, they found the index was not able to discriminate "below average" from "above/average" risk patients. The tool was administered to 3,317 asymptomatic average risk patients 50 to 79 years of age before their screening colonoscopy.

Further, they found the YDR index lacked discriminative accuracy for stratifying average risk patients. Several factors may explain the lack of discriminative power, the scientists point out: (1) exclusion of several key potential determinants of ACN (e.g., smoking), (2) potential differences in the duration of select chemopreventive agents needed to alter the natural history of advanced adenomas compared to cancers, and (3) potential differences in the assigned RRs of certain exposures on disease progression.

Schroy PC 3rd, Coe AM, Mylvaganam SR, et al. The Your Disease Risk Index for colorectal cancer is an inaccurate risk stratification tool for advanced colorectal neoplasia at screening colonscopyExternal Web Site Policy. Cancer Prev Res. 2012 Aug;5(8):1045-52. Epub 2012 June 11.

The research was supported by an EGRP grant to Paul C. Schroy III, M.D., M.P.H., of Boston University.

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Naphthalene Associated with Chromosomal Aberrations in Youths

Manuela Orjuela

Children exposed to high levels of naphthalene are at increased risk for chromosomal aberrations which have been previously associated with cancer, according to a study by the Columbia Center for Children's Environmental Health.

Sources of naphthalene include automotive exhaust, biomass fuels for indoor cooking, tobacco smoke, and mothballs. The International Agency for Cancer Research has classified the chemical as a possible carcinogen.

The researchers followed 113 children, age 5, who were part of a larger cohort study in New York City, and assessed their exposure to naphthalene. The researchers found chromosomal aberrations associated with exposure to naphthalene, including a dose-response relation between urinary naphthalene metabolite levels and translocations. They hypothesized that exposure was primarily a household exposure, potentially from mothballs, which can release high levels of the chemical.

Orjuela MA, Liu X, Miller RL, et al. Urinary naphthol metabolites and chromosomal aberrations in 5-year-old childrenExternal Web Site Policy. Cancer Epidemiol Biomarkers Prev. 2012 Jul;21(7):1191-202.

Funded in part by an EGRP grant to Manuela Orjuela, M.D., Sc.M., of Columbia University Mailman School of Public Health.

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Risk of Pancreatic Cancer Associated with Gum Disease

Jacques Georges Izard

Dominique Michaud

Periodontal disease may increase risk of pancreatic cancer. Researchers found that people with high levels of antibodies for an infectious oral bacterium involved in periodontal disease severity, Porphyromonas gingivalis, had double the risk for developing the disease.

Whereas, individuals who had high antibody levels for other oral bacteria were at reduced risk (45%) compared to individuals who had low antibody levels to the same bacteria, suggesting a role of the humoral response in cancer protection.

The study drew upon the European Prospective Investigation into Cancer and Nutrition (EPIC), which includes 519,978 participants aged 35-70 years, who were recruited from 23 centers in 10 European countries. Pre-diagnostic plasma samples from individuals who later died from pancreatic cancer and matching controls were used in this study.

Michaud DS, Izard J, Wilhelm-Benartzi CS, et al. Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort studyExternal Web Site Policy. Gut. 2012 Sep 18. [Epub ahead of print]

The research was funded by an EGRP grant to Co-principal investigators Dominique Michaud, Sc.D., of Brown University; and Jacques Georges Izard, Ph.D., of The Forsyth Institute and Harvard University.

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Association Confirmed Between Marijuana Use and Nonseminoma Risk

Victoria Cortessis

Leslie Bernstein

Testicular germ cell tumors are becoming more common in men ages 15 to 45, suggesting changing exposure to environmental factors. Potential factors may include abnormal effects of steroid hormones during the perinatal and peripubertal periods, variation in endogenous hormone levels during puberty, and exposure to exogenous compounds with possible or demonstrated endocrine function, such as constituents of marijuana smoke.

In this study, researchers evaluated the relationship between testicular cancer and use of recreational drugs including marijuana and cocaine in 163 patients and 292 controls. The researchers confirmed findings from two previous studies that suggested a link between marijuana use and testicular cancer. Men in this study with a self-reported history of using marijuana were twice as likely to have subtypes of testicular cancer called nonseminoma and mixed germ cell tumors, but did not appear to experience elevated risk of the seminoma subtype. The authors speculate that marijuana may lead to carcinogenesis through the endocannabinoid system. This should be considered if cannabinoid agonists or antagonists are to be used as therapeutic agents, as has been proposed for specific conditions, including endocrine-related cancers and infertility.

The study also found that men with a history of using cocaine had a reduced risk of all subtypes of testicular cancer examined. Although further study is needed to validate these results, cocaine has detrimental effects on human fertility, and in experimental animal models cocaine killed sperm-producing germ cells. It is therefore possible that any protection cocaine may confer against testicular cancer occurs by damaging sperm-producing cells and thus fertility.

Lacson JC, Carroll JD, Tuazon E, Castelao EJ, Bernstein L, Cortessis VK. Population-based case-control study of recreational drug use and testis cancer risk confirms an association between marijuana use and nonseminoma riskExternal Web Site Policy. Cancer. 2012 Nov 1. 118(21). 5374-83.

This research was supported in part by EGRP grants to Leslie Bernstein, Ph.D.. of the City of Hope and Victoria Cortessis, M.S.P.H., Ph.D., of the University of Southern California.

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