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Gloria Y.F. Ho, PhD
In an ongoing NIH-funded and WHI approved case-cohort study, serum levels of insulin and the IGF system (total IGF-I, free IGF-I, and IGFBP-3) are measured in 900 breast, 500 colorectal, and 300 endometrial cancer cases and a subcohort of 900 subjects to examine the associations between these growth factors and risk of the 3 cancers in postmenopausal women. A supplement to this ancillary study is proposed to examine insulin/IGF system at the genetic level. Multiple polymorphisms spanning the 4 genes encoding IGF-I, IGFBP-3, insulin, and insulin receptor substrate-1 will be studied for their associations with risk of breast, colorectal, and endometrial cancers and the clinical characteristics of these cancers. Whether sequence variations in these genes correlate with their serologic gene product levels will be investigated. This study will have significant implications for the health of menopausal women: (1) Aging is associated with insulin resistance, and it is important to understand how insulin and genetic predisposition to altered level of insulin influence cancer risk in menopausal women. (2) As levels of many growth factors decline with age, studying them at both the serologic and genetic levels may provide a better indication of an individual’s lifetime exposure. (3) This study will also explore the synergistic interaction between estrogen and sequence variations in the insulin/IGF genes. The results may have significant implications for the use of hormone replacement therapy in postmenopausal women who are genetically predisposed to high level of a growth factor.
This proposal is a supplement to an ongoing NIH-funded ancillary study using WHI-approved serum samples to investigate several growth factors (IGF-I, IGFBP-3, and insulin) in breast, colorectal, and endometrial cancers. The supplement aims to add a genetic component to this ancillary study by examining polymorphisms of genes encoding these growth factors.
The insulin-like growth factor (IGF) system has been implicated in carcinogenesis due to its important role in regulating cell proliferation, differentiation, apoptosis, and transformation.1 Insulin may also involve in carcinogenesis due to its structural and regulatory relationships with the IGF system. Moreover, insulin is a mitogen and growth factor.2-5 Risk for several cancer sites, such as prostate, lung, breast, colon, and endometrium, is associated with high serum levels of IGF-I and insulin/C peptide as well as decreased levels of IGFBP-3, the most abundant IGFBP in the circulation.6-11 Nevertheless, epidemiological data to date were, in general, based on small cross-sectional studies.
To further examine the etiological roles of insulin and the IGF system in cancer, an ancillary study, entitled “Insulin and IGF-I in female colon, breast, uterine cancer,” is being conducted by Dr. Howard Stickler. In this case-cohort study, a subcohort composed of 900 subjects randomly selected from the entire OS cohort will be compared to 900 breast, 500 colorectal, and 300 endometrial cancer cases to examine the effects of baseline serum levels of free IGF-I, IGFBP-3, and insulin on the subsequent risk for these 3 cancers.
The objectives are as follows:
1. To examine the polymorphisms of genes encoding IGF-I, IGFBP-3, insulin, and insulin receptor substrate-1 (an intracellular docking protein involved in the signaling pathways of both IGF-I and insulin) for their associations with the risk of breast, colorectal, and endometrial cancers.
Each gene has at least one polymorphism that is known to correlate with the level of gene product or have a functional effect. These polymorphisms will be assayed
By relying on only one polymorphism of a gene to study its disease association, one could easily miss a susceptibility gene. A comprehensive approach is warranted. Novel polymorphisms that have a minor allele frequency of ³ 5% will be identified in GenBank. Multiple markers spanning the gene (5’ promoter, exons, and 3’ untranslated region) will be selected and tested.
A total of about 3-5 polymorphisms per gene will be assayed, depending on the size of the gene. Disease association will be examined for each polymorphism.
2. To determine among the cancer cases if sequence variations of these genes are associated with clinical characteristics such as tumor stage and age at diagnosis.
3. To examine in the subcohort if sequence variations in the genes encoding IGF-I, IGFBP-3, and insulin are associated with altered levels of gene products at baseline, namely serum levels of free IGF-I, IGFBP3, and insulin, respectively.
Some of the publications related to this ancillary study are: 689, 1507.
For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.
1. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK. SEER Cancer Statistics Review, 1973-1999. Bethesda, MD, http://seer.cancer.gov/csr/1973_1999/: National Cancer Institute, 2002.
2. Hopper JL: Genetic epidemiology of female breast cancer. Semin Cancer Biol 11:367-74, 2001.
3. Burt RW: Familial association. Adv Exp Med Biol 470:95-8, 1999.
4. Peltomäki P: Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet 10:735-40, 2001.
5. van Es JH, Giles RH, Clevers HC: The many faces of the tumor suppressor gene APC. Exp Cell Res 264:126-34, 2001.
6. Johnson GCL, Esposito L, Barratt BJ, Smith AN, Heward J, Di Genova G, Ueda H, Cordell HJ, Eaves IA, Dudbridge F, Twells RCJ, Payne F, Hughes W, Nutland S, Stevens H, Carr P, Tuomilehto-Wolf E, Tuomilehto J, Gough SCL, Clayton DG, Todd JA: Haplotype tagging for the identification of common disease genes. Nat Genet 29:233-7, 2001.
7. Greenlee RT, Hill-Harmon MB, Murray T, Thun M: Cancer Statistics, 2001. CA Cancer J Clin 51:15-36, 2001.
8. Nathanson KL, Wooster R, Weber BL: Breast cancer genetics: what we know and what we need. Nat Med 7:552-6, 2001.
9. Mucci LA, Wedren S, Tamimi RM, Trichopoulos D, Adami H-O: The role of gene-environment interaction in the aetiology of human cancer: examples from cancers of the large bowel, lung and breast. J Int Med 249:477-93, 2001.
10. Lander ES, Schork NJ: Genetic dissection of complex traits. Science 265:2037-48, 1994.
11. Bartsch H, Nair U, Risch A, Rojas M, Wikman H, Alexandrov K: Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers. Cancer Epidemiol Biomarkers Prev 9:3-28, 2000.