Mutational Analysis of Clonality in Multiple Primary Melanoma

描述（由申请人提供）：黑色素瘤患者通常被诊断为第二原发性。事实上，一些患者会经历多次发病。虽然这些现象可以用强烈的遗传易感性来解释，但也有可能这些二级和高阶原发肿瘤的一个重要子集实际上是初始原发肿瘤的（克隆）复发，因为在其他部位的许多研究偶尔证实了新肿瘤的克隆起源，这些肿瘤被认为是独立于经典病理标准的。对继发原发的准确分类具有重要的临床意义，但对流行病学研究也有相当大的相关性，因为多发原发患者越来越被认为是一种重要的资源，特别是对罕见遗传因素的研究。我们在这项研究中的目标是在诊断为双原发性黑色素瘤的患者中进行一项试点克隆调查。具体来说，为了确定肿瘤之间的分子差异和相似性，我们建议：(1)使用微卫星不稳定性标记比较来自双重恶性肿瘤患者的原发性黑色素瘤对的突变谱；(2)在Aim 1中使用CGH阵列而不是候选标记再现该策略。我们将测试25组来自诊断为双原发黑色素瘤的个体的第一和第二原发病变。这项研究将首次评估多发性原发性黑色素瘤的克隆性证据。我们的研究结果将对黑色素瘤的病理分类、第二原发患者的临床决策以及流行病学研究方法产生影响。如果本研究的结果表明皮肤转移经常被诊断为第二恶性肿瘤，那么我们将计划使用国际人群GEM研究（CA83180）中收集的双原发性黑色素瘤患者肿瘤组织的大量人群资源进行后续研究，旨在明确确定误诊的频率，并确定肿瘤的预测因子，这些预测因子将受益于突变谱来验证诊断。

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.