Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental aetiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families and the causes of familial clustering in the remainder is unknown. We hypothesise that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni corrected t-test P = 1.5 × 10⁻⁵ and 6.3 × 10⁻⁴⁵, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate new high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.

中文翻译：

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多发性黑色素瘤家族因多基因风险而丰富。


癌症，包括皮肤黑色素瘤，可以在家族中聚集。除了紫外线等环境病因外，皮肤黑色素瘤还有很强的遗传因素。皮肤黑色素瘤的遗传风险范围从罕见的高外显率突变到常见的低外显率变异。已知的高外显率突变仅占所有严重受影响的皮肤黑色素瘤家族的一半左右，其余家族聚集的原因尚不清楚。我们假设某些聚类是由于大量个体效应较小的变体的累积效应造成的。常见的、低外显率的遗传风险变异可以组合成多基因风险评分。我们使用皮肤黑色素瘤的多基因风险评分来比较没有已知高外显率突变的家庭与不相关的黑色素瘤病例和无黑色素瘤对照。家庭成员的皮肤黑色素瘤平均多基因负荷显着高于无关病例或无黑色素瘤的健康对照（Bonferroni 校正 t 检验 P 分别 = 1.5 × 10 ^-5和 6.3 × 10 ^-45 ）。对 21 个黑色素瘤多基因风险低的家族的 51 个成员的种系 DNA 进行全基因组测序，发现单个家族中存在CDKN2A p.G101W 突变，但没有发现其他候选的新高外显率黑色素瘤易感基因。这项工作提供了进一步的证据，表明黑色素瘤与许多其他常见的复杂疾病一样，可能是由多种诱发因素的联合作用引起的，包括罕见的高外显率突变，以及大量效应较小的等位基因的组合。