Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Medicine, Weill Cornell Medical College, New York, New York.
Cancer Epidemiol Biomarkers Prev. 2022 Feb;31(2):362-371. doi: 10.1158/1055-9965.EPI-21-0820. Epub 2021 Nov 22.
Cancer survivors are developing more subsequent tumors. We sought to characterize patients with multiple (≥2) primary cancers (MPC) to assess associations and genetic mechanisms.
Patients were prospectively consented (01/2013-02/2019) to tumor-normal sequencing via a custom targeted panel (MSK-IMPACT). A subset consented to return of results of ≥76 cancer predisposition genes. International Agency for Research on Cancer (IARC) 2004 rules for defining MPC were applied. Tumor pairs were created to assess relationships between cancers. Age-adjusted, sex-specific, standardized incidence ratios (SIR) for first to second cancer event combinations were calculated using SEER rates, adjusting for confounders and time of ascertainment. Associations were made with germline and somatic variants.
Of 24,241 patients, 4,340 had MPC (18%); 20% were synchronous. Most (80%) had two primaries; however, 4% had ≥4 cancers. SIR analysis found lymphoma-lung, lymphoma-uterine, breast-brain, and melanoma-lung pairs in women and prostate-mesothelioma, prostate-sarcoma, melanoma-stomach, and prostate-brain pairs in men in excess of expected after accounting for synchronous tumors, known inherited cancer syndromes, and environmental exposures. Of 1,580 (36%) patients who received germline results, 324 (21%) had 361 pathogenic/likely pathogenic variants (PV), 159 (44%) in high penetrance genes. Of tumor samples analyzed, 55% exhibited loss of heterozygosity at the germline variant. In those with negative germline findings, melanoma, prostate, and breast cancers were common.
We identified tumor pairs without known predisposing mutations that merit confirmation and will require novel strategies to elucidate genetic mechanisms of shared susceptibilities.
If verified, patients with MPC with novel phenotypes may benefit from targeted cancer surveillance.
癌症幸存者出现了更多后续肿瘤。我们试图对患有多发性（≥2）原发性肿瘤（MPC）的患者进行特征描述，以评估其相关性和遗传机制。
患者前瞻性同意（2013 年 1 月至 2019 年 2 月）通过定制靶向面板（MSK-IMPACT）进行肿瘤-正常测序。部分患者同意返回≥76 个癌症易感性基因的结果。应用国际癌症研究机构（IARC）2004 年定义 MPC 的规则。创建肿瘤对以评估癌症之间的关系。使用 SEER 率计算首次至第二次癌症事件组合的年龄调整、性别特异性、标准化发病比（SIR），并调整混杂因素和确定时间。与种系和体细胞变异相关联。
在 24241 名患者中，有 4340 名患者患有 MPC（18%）；20%为同步性。大多数（80%）有两个原发性肿瘤；然而，有 4%的患者患有≥4 种癌症。SIR 分析发现，女性中存在淋巴瘤-肺、淋巴瘤-子宫、乳腺癌-脑和黑色素瘤-肺对，以及男性中存在前列腺-间皮瘤、前列腺-肉瘤、黑色素瘤-胃和前列腺-脑对，这些对超过了考虑到同步肿瘤、已知遗传性癌症综合征和环境暴露因素后的预期。在接受种系结果的 1580 名（36%）患者中，有 324 名（21%）有 361 种致病性/可能致病性变异（PV），159 种（44%）为高外显率基因。在分析的肿瘤样本中，55%显示种系变异的杂合性丢失。在种系检测结果为阴性的患者中，黑色素瘤、前列腺癌和乳腺癌较为常见。
我们发现了没有已知易感性突变的肿瘤对，这些肿瘤对需要进一步确认，并需要新的策略来阐明共同易感性的遗传机制。
如果得到证实，具有新型表型的 MPC 患者可能会受益于靶向癌症监测。
