Mutational Analysis of Clonality in Multiple Primary Melanoma

描述(由申请人提供)：黑色素瘤患者经常被诊断为第二原发。事实上，一些患者经历了多次这种疾病的发生。虽然这些现象可以用强烈的遗传易感性来解释，但也有可能这些第二和更高级别的原代细胞中的一个重要子集实际上是最初的原代细胞的(克隆性)复发，因为其他地方的许多研究偶尔证实了新肿瘤的克隆起源，根据经典的病理学标准，这些新肿瘤被认为是独立的。对后续原发疾病的准确分类具有重要的临床意义，但对于流行病学研究也具有相当大的相关性，因为具有多个原发疾病的患者越来越被认为是一种重要的资源，特别是对于稀有遗传因素的研究。我们在这项研究中的目标是在被诊断为双原发黑色素瘤的患者中进行一项试点克隆性调查。具体地说，为了识别肿瘤之间的分子差异和相似之处，我们建议：(1)使用微卫星不稳定性标记比较来自两种恶性肿瘤患者的一对原发黑色素瘤的突变特征；以及(2)使用阵列CGH而不是候选标记来重现目标1中的策略。我们将测试25组来自被诊断为双原发黑色素瘤的人的第一和第二原发皮损。这项研究将是第一次评估多发性原发黑色素瘤克隆性的证据。我们的结果将对黑色素瘤的病理分类、第二原发瘤患者的临床决策和流行病学研究方法具有重要意义。如果这项研究的结果表明皮肤转移经常被诊断为第二种恶性肿瘤，那么我们将计划进行一项后续研究，使用从国际基于人群的GEM研究(CA83180)收集的双原发黑色素瘤患者的大量基于人群的肿瘤组织资源，旨在最终确定误诊率，并确定将受益于突变图谱的肿瘤预测因素以验证诊断。

DESCRIPTION (provided by applicant): Melanoma patients are very frequently diagnosed with putative second primaries. Indeed, some patients experience multiple occurrences of the disease. While these phenomena could be explained by strong genetic predisposition, it is also possible that a significant subset of these second and higher-order primaries are actually (clonal) recurrences of the initial primary, since many studies in other sites have occasionally confirmed a clonal origin for new tumors that are presumed to be independent on the basis of classical pathological criteria. Accurate classification of subsequent primaries has important clinical implications, but it is also of considerable relevance for epidemiologic research, since patients with multiple primaries are increasingly being recognized as an important resource, especially for studies of rare genetic factors. Our goal in this study is to conduct a pilot clonality investigation in patients diagnosed with double primary melanoma. Specifically, in order to identify molecular differences and similarities between tumors we propose to: (1) compare the mutational profiles of pairs of primary melanomas from individual patients with double malignancies using micro-satellite instability markers; and (2) reproduce the strategy in Aim 1 using array CGH rather than candidate markers. We will test 25 sets of first and second primary lesions from individuals diagnosed with double primary melanoma. This study will be the first to assess evidence for clonality in multiple primary melanoma. Our results will have implications for the pathologic classification of melanoma, clinical decision making for a patient with a second primary, and epidemiologic research methods. If results from this study suggest that cutaneous metastases are frequently diagnosed as second malignancies, then we will plan a subsequent study using the large population-based resource of tumor tissues from patients with double primary melanoma collected from the international population-based GEM Study (CA83180), designed to determine definitively the frequency of mis-diagnosis, and to determine predictors of tumors that would benefit from mutational profiling to validate the diagnosis.