Research Highlights - 2008
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. Your suggestions
on additions to make to the Web page are welcome. The names of the first
authors and the EGRP-supported principal investigators whose grants are
credited in the published papers appear in boldface print.
Colorectal Cancer
Lung Cancer
Endogenous Estrogens May Increase Colorectal Cancer Risk
Marc Gunter,
Ph.D. Despite evidence strongly suggesting that obesity and hyperinsulinemia are risk factors for colorectal cancer, few prospective studies have directly measured the effects of insulin or insulin-like growth factor-1 (IGF-1) on risk. Additionally, estrogen may affect colorectal cancer risk, and studies suggest that use of oral hormone replacement therapy is associated with decreased risk. However, no studies have evaluated the association between endogenous estradiol and risk of colorectal cancer.
Marc Gunter, Ph.D., of Albert Einstein College of Medicine, and colleagues conducted a case-cohort investigation of colorectal cancer among nondiabetic women enrolled in the Women's Health Initiative Observational Study. The investigators collected fasting baseline serum specimens from 438 women with colorectal cancer and 816 women in a random subcohort and measured insulin, glucose, total IGF-1, free IGF-1, IGF binding protein-3 (IGFBP-3), and estradiol. Insulin, waist circumference, and free IGF-1 were each positively associated with colorectal cancer incidence, but these associations became nonsignificant when adjusted for one another.
In contrast, endogenous estradiol levels were positively associated with risk of colorectal cancer (hazard ratio for high versus low levels = 1.53; 95% confidence interval (CI) = 1.05 to 2.22), even after controlling for insulin, free IGF-1, and waist circumference. The authors suggest that these data indicate two independent biological pathways affecting colorectal cancer risk: the first involves endogenous estradiol, and the second is associated broadly with obesity, hyperinsulinemia, and free IGF-1.
This research was funded by an EGRP grant to Howard Strickler, M.D., M.P.H., of Albert Einstein College of Medicine.
Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE, Howard BV, Wylie-Rosett J, Anderson GL, Ho GY, Kaplan RC, Li J, Xue X, Harris TG, Burk RD, Strickler HD. Insulin, insulin-like growth factor-I, endogenous estradiol, and risk of colorectal cancer in postmenopausal women. Cancer Res. 2008 Jan 1;68(1):329-37.
Strong Evidence of Lung Cancer Susceptibility Locus at 15q25.1
Christopher Amos,
Ph.D. 
Rayjean Hung,
Ph.D. 
James McKay,
Ph.D. Lung cancer presents a significant public health burden with more than 1 million cases diagnosed annually. It is the most common cause of cancer deaths worldwide. Two teams of investigators completed genome-wide association studies (GWAS) and have independently uncovered an important genetic region that is associated with lung cancer risk.
Christopher Amos, Ph.D., of the University of Texas M.D. Anderson Cancer Center, and colleagues performed a GWAS of histologically confirmed non-small cell lung cancer to identify common low-penetrance alleles influencing lung cancer risk. The researchers identified 10 single nucleotide polymorphisms (SNPs) that were significantly associated with susceptibility to lung cancer in 1,154 lung cancer cases and 1,137 controls of European ancestry. They replicated these in two case-control datasets with 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the United Kingdom. Elevated risk for lung cancer was validated for two of the SNPs, rs8034191 and rs1051730, both of which mapped to chromosome 15. The combined P values were 3.15 x 10-18 and 7.00 x 10-18, respectively. The combined adjusted odds ratios (OR) for lung cancer associated with both SNPs was 1.32. The genetic variants that may influence lung cancer risk were present in about half of the people studied by Amos et al.
Rayjean Hung, Ph.D., formerly of the International Agency for Research on Cancer (IARC) and the University of California at Berkeley, James McKay, Ph.D., also of IARC, and colleagues led the largest genetic study of lung cancer ever conducted, involving more than 10,000 people from 18 countries, about half of whom had lung cancer. The researchers compared 310,023 SNPs between 1,926 cases of primary lung cancer and 2,522 controls. They also identified the same two SNPs on chromosome 15q25, rs8034191 and rs1051730, as having a strong association with lung cancer (P = 9 x 10-10 and P = 5 x 10-9 , respectively). The OR for carrying one copy of the most significant marker (rs8034191) was 1.27 and for carrying two copies of the allele was 1.80. The findings were replicated in five independent lung cancer studies, comprising 2,513 more cases and 4,752 more controls. After pooling across studies, the ORs were 1.21 and 1.77 for heterozygous and homozygous carriers, respectively.
The small genomic region containing the lung cancer risk variants contains several genes that interact with nicotine and other tobacco toxins. These genes are nicotinic acetylcholine receptor genes and are studied widely for their potential involvement in tobacco dependence. Interestingly, the two teams did not find that cancer risk was mediated through nicotine addiction as other research has suggested. Identifying genes that are involved in lung cancer may help to identify treatment targets or allow for identification of individuals who are at high risk of disease in combination with smoking or other factors.
This research was funded in part by EGRP grants to Dr. Amos and Margaret Spitz, M.D., M.P.H., University of Texas M.D. Anderson Cancer Center, and Paul Brennan, Ph.D., IARC.
Dr. Hung is now on the faculty at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto, Canada.
Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J, Sullivan K, Matakidou A, Wang Y, Mills G, Doheny K, Tsai YY, Chen WV, Shete S, Spitz MR, Houlston RS. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. 2008 May;40(5):616-22. Epub 2008 Apr 2.
Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Chen C, Goodman G, Field JK, Liloglou T, Xinarianos G, Cassidy A, McLaughlin J, Liu G, Narod S, Krokan HE, Skorpen F, Elvestad MB, Hveem K, Vatten L, Linseisen J, Clavel-Chapelon F, Vineis P, Bueno-de-Mesquita HB, Lund E, Martinez C, Bingham S, Rasmuson T, Hainaut P, Riboli E, Ahrens W, Benhamou S, Lagiou P, Trichopoulos D, Holcátová I, Merletti F, Kjaerheim K, Agudo A, Macfarlane G, Talamini R, Simonato L, Lowry R, Conway DI, Znaor A, Healy C, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, Brennan P. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. 2008 Apr 3;452(7187):633-7.
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