Analysis of Breast/Melanoma Multiple Primary Cancers

项目描述（由申请人提供）：本项目主要研究癌症易感基因的发现。这个项目是基于这样一种假设，即患有多种原发癌症的个体子集具有潜在的易感基因突变，这种突变在该个体的所有肿瘤中都是常见的。早期使用基于人群的肿瘤登记的研究表明，在诊断为乳腺癌的妇女中，黑色素瘤作为第二恶性肿瘤的风险增加。相反，先前被诊断患有黑色素瘤的女性患乳腺癌的风险增加。这种双向增加的第二种恶性肿瘤的风险值得进一步关注，并提示这两种肿瘤的病因有共同的机制。为此，我们打算定义和描述被诊断患有乳腺癌和黑色素瘤的妇女群体。

DESCRIPTION (provided by applicant): The proposed project is centered on cancer susceptibility gene discovery. This project is based on the hypothesis that a subset of individuals with multiple primary cancers has an underlying susceptibility gene mutation that is common to all tumors in that individual. Earlier studies using population-based tumor registries have demonstrated an increased risk of melanoma as a second malignancy in women diagnosed with breast cancer. Conversely, an increased risk of breast cancer has been demonstrated in women who have been previously diagnosed with melanoma. This bi-directional increased risk of a second malignancy deserves further attention and is suggestive of a common mechanism as the etiology of these two tumors. To this end, we intend to define and characterize a population of women who have been diagnosed with both breast cancer and melanoma. Outside of defined syndromes, little had been documented regarding multiple primary cancers. What data exist strongly support the hypothesis that women with multiple primary cancers are more likely to harbor germline susceptibility alleles than those with a single malignancy. We hypothesize that women with the multiple primary cancers, breast and melanoma, represent a clinically significant variation in disease phenotype for one of the known candidate genes. We will screen this population for germline and somatic mutations in genes known to be involved in cancer predisposition or progression. In addition, we will use array-based comparative genomic hybridization (aCGH) to identify the critical genetic changes that are necessary to transform normal melanocytes or breast epithelium into cells with malignant potential. A DNA-based microarray platform using bacterial artificial chromosomes (BACs) containing human genomic DNA representative of the entire genome at 1-2 Mb intervals, will be utilized to define regions of chromosomal gain and loss using DNA from breast and melanoma tumors both from a single individual as well as versus matched sporadic tumors. The overall objective of this proposal is the identification of additional cancer susceptibility genes, which will enable the study of the genes themselves and advance our understanding of the etiology of breast cancer and malignant melanoma.