We are exploring inter-individual variations in cancer risk defined by allele variant genes and environmental and endogenous risk factors. We are currently testing the hypothesis that allele variants of genes in the inflammation, hormone and angiogenesis pathways modulate the risk of human breast and prostate cancer. The program will explore both the aspect of cancer susceptibility in a population, based solely on risk association, and the underlying molecular mechanisms that cause the increased risk. Our research will combine traditional epidemiology with laboratory investigations. Our objective is to identify inherited genetic risk factors and novel gene-environment interactions. We will develop and validate biomarkers of cancer risk that should improve current methods of risk assessment. Ultimately, our research is aimed to implement new and more effective cancer prevention strategies for breast and prostate cancer, and to elucidate mechanisms of human carcinogenesis. Breast cancer is the most common cancer in women in the United States, with an estimated 192,000 new cases and 42,000 deaths in 2001. Demographic characteristics associated with an increased risk include increasing age, birth in North America and Europe, high socioeconomic status, never been married and, for breast cancer diagnosed after age of 45, being Caucasian. Epidemiological studies and experience with anti-estrogen therapy indicate that most risk factors for breast cancer are related to reproductive and hormonal factors. Premenopausal women are at higher risk of breast cancer than postmenopausal women at the same age, indicating the significance of female sex hormones in the etiology of breast cancer. Early age of menarche, late age at menopause, late age at first full-term pregnancy, and low parity, increase risk while the removal of the ovaries at an early age is protective. Women who experience menopause at a late age are at a higher risk than those who end menstruating earlier. A two-fold increased risk has been observed among postmenopausal women with high blood estradiol concentrations, when compared with women with a low blood concentration of the hormone. The risk of breast cancer is moderately increased for women who use oral contraceptives. The implication of reproductive hormones in the pathogenesis of breast cancer has triggered strong interest in genetic variations of genes that regulate the steroid hormone metabolism. We have established a breast cancer case-control study of 279 cases and 279 age- and race-matched controls from the greater Baltimore area. We have identified candidate functional polymorphisms in genes of the 1) estrogen, 2) inflammation, 3) DNA repair/cell cycle, and 4) angiogenesis pathways, of which 36 are currently analyzed in the breast cancer case-control set. Snap-frozen tissue from breast reduction surgery will be used to explore the association of genotypes with gene expression. We also built up two collaborations to study genotype-cancer risk associations in inflammatory breast cancer (IBC). IBC is an aggressive form of locally advanced breast cancer that affects women at an earlier age than other types of breast carcinoma. IBC is characterized by a high tumor microvessel density, fast disease progression and by extremely poor survival. Although the frequency of IBC among breast cancer cases in the US is only 3-5%, it is much more common in other geographic areas, such as North Africa (estimated 10-30%). The causes of IBC are unknown and both environmental and genetic risk factors are thought to be involved. The early onset of the disease, the strong angiogenicity and propensity of IBC to invade vessels and the large disparity in the IBC incidence among various populations are indicators of genetic predisposition and inherited susceptibility. Both low- and high-risk cancer susceptibility genes may determine the risk for IBC. Prostate cancer is a leading cause of cancer death among men in Western countries. The prostate cancer incidence is still increasing, and disease rates have risen during recent decades in virtually every population-based registry around the world. Large racial and geographic differences have been observed with a 40-fold difference in incidence between high and low-risk populations. The highest incidence rates were found among US African-Americans with 130 reported prostate cancer rates per age-adjusted 100,000 man-years for 1988-1992, versus only 3 cases per 100,000 man-years among men in China. However, a very high rate of 304 per 100,000 man-years has recently been reported in Jamaica suggesting that certain genetic predispositions for prostate cancer exist in men of African ancestry. Rates are also relatively high among Caucasians in the US, but they are generally lower in Europeans. High rates are found in Scandinavia and the incidence decreases toward the southern parts of Europe. Genetic risk factors are particularly important at a younger age, and the attributable risk of inherited susceptibility has been estimated to be as high as 40-45% among men diagnosed with prostate cancer at age 55 years or younger. There is an apparent relationship between the incidence of prostate and breast cancer, but not with any other cancer, in various societies. Androgens are essential for the growth of the prostate gland, and they are believed to be significant in the etiology of prostate cancer. Large doses of androgen can induce prostate cancer in rodents, and eunuchs rarely develop prostate cancer. Androgen ablation, or anti-androgen therapy, frequently causes the regression of prostate tumors. Men with serum testosterone in the upper quartile of the population have an approximately two-fold higher risk for developing prostate cancer. Non-androgenic mediators of prostatic growth have been described. High blood concentrations of insulin-like growth factor-I are associated with an increased risk of advanced prostate cancer. Available data suggest that several endothelial-derived factors and mediators of inflammation, such as interleukin-6 and -8, endothelin-1, vascular endothelial growth factor (VEGF), eicosanoids and nitric oxide, contribute to prostate cancer progression. Mediators of inflammation, such as eicosanoids and nitric oxide, have also pro-angiogenic properties and induce functional changes in the vasculature that will lead to vessel remodeling, stimulation of endothelial cell mitosis and vessel growth. Chronic inflammation of the prostate may, therefore, promote cancer progression through the angiogenesis pathway. Acute and chronic inflammation is commonly observed in prostate biopsies and will lead to atrophic acini and hyperplasia. Recently, the inflammation-carcinoma sequence has been invoked as a significant mechanism in prostatic carcinogenesis. Focal prostatic glandular atrophy and post-atrophic hyperplasia are potential precursors of prostatic adenocarcinoma and occur in close association with chronic inflammation. Chronic inflammation has been linked to the development of carcinoma in liver and colon, and may also lead to the development of atypical adenomatous hyperplasia and prostatic intraepithelial neoplasia in the prostate. Our program will conduct genotype analysis on genes that are thought to modulate inflammation, angiogenesis, and metastasis in prostate cancer progression. Initially, we will study the various genotypes in a Danish prostate cancer case-control study. We are in the planning phase of a prostate cancer case-control study in the greater Baltimore area. We intend to recruit 300-400 prostate cancer patients and the same number of matched, population-based controls. We are also collecting snap-frozen surgery specimens from patients with benign prostate hyperplasia (BPH). The samples will be used to explore the association of genotypes with gene expression. Candidate genotypes should be risk factors for cancer as indicated by our ongoing genotype analysis.
| Boersma, Brenda J; Howe, Tiffany M; Goodman, Julie E et al. (2006) Association of breast cancer outcome with status of p53 and MDM2 SNP309. J Natl Cancer Inst 98:911-9 |
