Ph.D Thesis

Ph.D StudentShakour Khoury Sana
SubjectMolecular Epidemiology of Colorectal and Breast Cancer and
the GH/IGF-1 Axis
DepartmentDepartment of Medicine
Supervisor PROF. Gad Rennert
Full Thesis textFull thesis text - English Version


Background: A large proportion of breast and colorectal cancer might be due to genetic events in common low penetrance genes. The insulin-like growth factors (IGFs) are growth hormone (GH) dependent peptides and play a key role in cell proliferation, differentiation, and apoptosis. A series of laboratory investigations and epidemiological studies have suggested that elevated levels of IGF-1 are a risk factor for the development of several common types of cancer. The IGF-1 and GH1 genes are compelling candidates for cancer association studies. In the present study, we investigated the association of a common GH1 polymorphism with colorectal and breast cancer in the Israeli population. Further, IGF-1 gene variations were characterized, utilizing individual genotype data from a public domain and analyzing them in PHASE and HaploBlockFinder softwares, and studied in relation to breast cancer. Methods: We analyzed data from two population-based case control studies on colorectal and breast cancer and a series of BRCA1/2 founder mutations carriers. The analysis included 1402 cases and 1639 controls from the colorectal cancer case-control study, 312 cases and 346 controls from the breast cancer study and an additional 161 breast cases and 170 controls from the BRCA carriers series. Both, single polymorphisms and haplotype analysis were performed. Results: No overall association between the T1663A GH1 polymorphism and colorectal cancer was found. Nevertheless, evaluation of gene-environment interactions revealed significant interaction of the studied polymorphism with leisure time sports participation (p-interaction=0.0049). The TT genotype was found to further increase colorectal cancer risk among the physically inactive but not among the physically active people. The T1663A polymorphism did not influence breast cancer risk in our study population or have any modification effect on the association of the IGF-1 with the disease. However, two common IGF-1 haplotypes, with more than 20% frequency among controls each, were found to decrease the risk of breast cancer in premenopausal women, non-carriers of BRCA1/2 founder mutations. Age adjusted odds ratios (ORs), and confidence intervals (CI) for the two haplotypes were: 0.5 (95%CI=0.28-0.92) and 0.46 (95%CI=0.24-0.89) respectively.  Conclusions: The IGF-1 gene appears to be associated with breast cancer risk in pre-menopausal Ashkenazi Jewish women. Further, findings of this study support the hypothesis that the effects of physical activity on colorectal cancer development may be mediated by interactions with the GH/IGF axis. The present study improves our understanding of the GH/IGF-1 axis involvement in breast and colorectal cancer.