Analysis of Breast/Melanoma Multiple Primary Cancers

描述(申请人提供)：建议的项目以癌症易感基因发现为中心。该项目基于这样的假设，即患有多原发癌的一部分人具有潜在的易感基因突变，该突变在该人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，在被诊断为乳腺癌的女性中，黑色素瘤作为第二种恶性肿瘤的风险增加。相反，在以前被诊断为黑色素瘤的女性中，乳腺癌的风险已经被证明增加。这种双向增加的第二种恶性肿瘤的风险值得进一步关注，并暗示了这两种肿瘤的共同发病机制。为此，我们打算定义和描述一组同时被诊断为乳腺癌和黑色素瘤的女性。 除了明确的症状外，关于多原发癌的文献很少。现有的数据有力地支持了这一假设，即患有多原发癌的女性比患有单一恶性肿瘤的女性更有可能携带生殖系易感等位基因。我们假设，患有多原发癌、乳腺癌和黑色素瘤的女性，其中一种已知候选基因的疾病表型在临床上存在显著差异。我们将对这一人群进行筛查，寻找已知与癌症易感性或进展有关的基因的种系和体细胞突变。此外，我们将使用基于阵列的比较基因组杂交(ACGH)来确定将正常黑素细胞或乳房上皮转化为具有恶性潜能的细胞所必需的关键基因变化。一个基于DNA的微阵列平台，使用细菌人工染色体(BAC)，包含代表整个基因组的人类基因组DNA，间隔1-2 Mb，将被用于使用来自单个个体的乳腺和黑色素瘤肿瘤以及与匹配的散发性肿瘤的DNA来确定染色体获得和丢失的区域。 这项建议的总体目标是识别更多的癌症易感基因，这将使对基因本身的研究成为可能，并促进我们对乳腺癌和恶性黑色素瘤病因的理解。

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.