Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2023 Jul 14;29(14):2631-2637. doi: 10.1158/1078-0432.CCR-22-3956.
More than 10% of assessed patients with appendiceal adenocarcinoma have a pathogenic (P) or likely pathogenic (LP) germline variant, including genes implicated in heritable gastrointestinal cancer syndromes, such as Lynch syndrome. We defined the clinical and molecular impact of heritable alterations in appendiceal adenocarcinoma to evaluate the need for dedicated appendiceal screening and prevention strategies in patients with LP/P germline variants.
We performed an integrated germline and somatic molecular analysis for patients with confirmed appendiceal adenocarcinoma. Patients underwent paired tumor-normal sequencing for up to 90 hereditary cancer risk genes and 505 genes for somatic mutation profiling. We defined the cooccurrence of LP/P germline variants and second-hit pathogenic somatic alterations. The associations between germline variants and patient clinicopathologic features were also evaluated.
Twenty-five of 237 patients (10.5%) carried pathogenic or likely pathogenic germline variants in cancer susceptibility genes. Clinicopathologic characteristics and appendiceal adenocarcinoma-specific survival were similar in patients with or without germline variants. Most (92%, N = 23/25) patients with germline variants demonstrated no second-hit somatic alterations, including loss of heterozygosity. Two patients with a germline APC I1307K low-penetrance founder variant exhibited secondary somatic pathogenic alterations in APC. However, only one patient tumor exhibited APC-mediated WNT signaling dysregulation: a plausible consequence of multiple somatic APC mutations with no germline variant contribution. Four patients had germline variants in PMS2 or MSH2 associated with Lynch syndrome, yet their cancers were microsatellite-stable.
Germline variants are likely incidental without a contributory driver role in appendiceal adenocarcinoma. Appendiceal adenocarcinoma screening in patients with germline variants is not clearly merited.
超过 10%评估的阑尾腺癌患者存在致病变异 (P) 或可能致病变异 (LP)，包括遗传性胃肠道癌症综合征相关基因，如 Lynch 综合征。我们定义了阑尾腺癌中遗传性改变的临床和分子影响，以评估 LP/P 种系变异患者是否需要专门的阑尾筛查和预防策略。
我们对确诊的阑尾腺癌患者进行了种系和体细胞分子综合分析。患者接受了配对肿瘤-正常测序，最多可检测 90 种遗传性癌症风险基因和 505 种体细胞突变分析基因。我们定义了 LP/P 种系变异与第二击致病变体改变的共同发生。还评估了种系变异与患者临床病理特征之间的关系。
在 237 例患者中，有 25 例 (10.5%) 携带癌症易感性基因的致病变异或可能致病变异。有或没有种系变异的患者的临床病理特征和阑尾腺癌特异性生存相似。大多数 (92%，N=23/25) 种系变异患者没有第二击致病变体改变，包括杂合性缺失。两名携带 APC I1307K 低外显率种系变异的患者在 APC 中表现出继发性致病变体改变。然而，只有一名患者肿瘤显示 APC 介导的 WNT 信号失调：这可能是由于体细胞 APC 突变多个但没有种系变异贡献的结果。四名患者存在与 Lynch 综合征相关的 PMS2 或 MSH2 种系变异，但他们的癌症是微卫星稳定的。
种系变异可能是偶然的，在阑尾腺癌中没有贡献的驱动作用。在种系变异患者中进行阑尾腺癌筛查没有明显意义。
