Melanoma Pathogenesis

描述（由申请人提供）：我们提出黑色素瘤发病机制的研究涉及两个平行和相互信息的主要目的。首先，我们将跟踪黑色素瘤病例（之前在我们的病例对照研究中登记的患者），寻找第二原发性黑色素瘤。事实上，以前所有关于多发性原发性黑色素瘤的研究都是基于临床或注册数据库，缺乏对高危人群的随访。因此，这种疾病的发病率和风险基本上仍然是未知的。其次，我们将描述与黑色素瘤发病机制（良性痣、非典型痣和黑色素瘤）相关的黑色素细胞病变进展谱中的9p21染色体改变。染色体9p21包含肿瘤抑制基因p16，我们的初步研究表明，该区域的改变先于形态非典型性的发展。我们将研究9p21的改变（染色体9p21 LOH， p16缺失和p16甲基化），使用通过亲本研究已经获得的病变，以及通过后续研究获得的新病变。我们假设染色体9p21的改变表征了一种变异的黑色素瘤发病机制，包括非典型痣、浅表扩散黑色素瘤和多发原发性黑色素瘤的高风险。因此，我们将研究染色体9p21改变与非典型痣、黑色素瘤组织学亚型和多发性原发性黑色素瘤风险的关系。我们还将研究非典型痣和浅表扩散黑色素瘤与多发性原发性黑色素瘤的风险的关系。最后，我们将探讨与9p21染色体改变和多发性原发性黑色素瘤风险相关的传统流行病学危险因素。这一创新且具有成本效益的建议在很大程度上得益于我们最近完成的病例对照研究所完成的工作，包括事先收集访谈数据，皮肤科医生指导的皮肤检查，所有黑素细胞病变的病理回顾，病理标本的检索和取样（即，玻片制备），以及分析染色体9p21改变的实验室技术的改进。

DESCRIPTION (provided by applicant): We propose a study of melanoma pathogenesis involving two parallel and mutually informative primary aims. First, we will follow melanoma cases (who were previously enrolled in our case-control study) for a second primary melanoma. Virtually all previous studies of multiple primary melanoma were based on clinical or registry databases, which lack follow-up of the cohort at risk. Thus, the rates and risks of this disease remain essentially unknown. Second, we will characterize chromosome 9p21 alterations in a progressive spectrum of melanocytic lesions pertinent to melanoma pathogenesis (benign nevi, atypical nevi, and melanoma). Chromosome 9p21 contains the tumor suppressor gene p16, and our pilot studies indicate that alterations of this region precede the development of morphologic atypia. We will investigate 9p21 alterations (chromosome 9p21 LOH, p16 deletion, and p16 methylation) using lesions already obtained through the parent study, and new lesions obtained through the proposed follow-up effort. We hypothesize that chromosome 9p21 alterations characterize a variant melanoma pathogenesis involving atypical nevi, superficial spreading melanoma, and high risk for multiple primary melanomas. Thus, we will examine chromosome 9p21 alterations in relation to atypical nevi, melanoma histologic subtype, and risk of multiple primary melanoma. We will also examine atypical nevi and superficial spreading melanoma in relation to risk of multiple primary melanoma. Finally, we will explore traditional epidemiologic risk factors in relation to chromosome 9p21 alterations and in relation to risk of multiple primary melanoma. This innovative and costeffective proposal benefits substantially from the work accomplished in our recently completed case-control study, including the prior collection of interview data, the dermatologist-conducted skin examination, the pathology review of all melanocytic lesions, the retrieval and sampling (i.e., slide preparation) of pathology specimens, and the refinement of laboratory techniques for analyzing chromosome 9p21 alterations.