Background & Aims

The incidence of colorectal cancer (CRC) in individuals younger than 50 years is increasing. We sought to ascertain the proportion of young CRC cases associated with genetic predisposition.

Methods

We performed a retrospective study of individuals diagnosed with CRC at an age younger than 50 years, evaluated by the clinical genetics service at a single tertiary care cancer center from 1998 through 2015. We collected data on patient histories, tumor phenotypes, and results of germline DNA sequencing. For subjects with uninformative clinical evaluations, germline DNA samples were (re)sequenced using a research-based next-generation sequencing multigene panel. The primary outcome was identification of a pathogenic germline mutation associated with cancer predisposition.

Results

Of 430 young CRC cases, 111 (26%) had a first-degree relative with CRC. Forty-one of the subjects with CRC (10%) had tumors with histologic evidence for mismatch repair deficiency. Of 315 subjects who underwent clinical germline sequencing, 79 had mutations associated with a hereditary cancer syndrome and 21 had variants of uncertain significance. Fifty-six subjects had pathogenic variants associated with Lynch syndrome (25 with mutations in MSH2, 24 with mutations in MLH1, 5 with mutations in MSH6, and 2 with mutations in PMS2) and 10 subjects had pathogenic variants associated with familial adenomatous polyposis. Thirteen subjects had mutations in other cancer-associated genes (8 in MUTYH, 2 in SMAD4, 1 in BRCA1, 1 in TP53, and 1 in CHEK2), all identified through multigene panel tests. Among 117 patients with uninformative clinical evaluations, next-generation sequence analysis using a multigene panel detected actionable germline variants in 6 patients (5%). Only 43 of the 85 subjects with germline mutations associated with a hereditary cancer syndrome (51%) reported a CRC diagnosis in a first-degree relative.

Conclusions

Approximately 1 in 5 individuals diagnosed with CRC at age younger than 50 years carries a germline mutation associated with cancer; nearly half of these do not have clinical histories typically associated with the identified syndrome. Germline testing with multigene cancer panels should be considered for all young patients with CRC.

中文翻译：

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结直肠癌青年个体的种系遗传特征

背景与目标

在50岁以下的人群中，结直肠癌（CRC）的发病率正在增加。我们试图确定与遗传易感性相关的年轻CRC病例的比例。

方法

我们进行了一项回顾性研究，研究对象是1998年至2015年间在一家三级癌症中心的临床遗传学服务机构评估的50岁以下被诊断患有CRC的患者。我们收集了有关患者病史，肿瘤表型和种系结果的数据DNA测序。对于没有提供临床信息的受试者，使用基于研究的下一代测序多基因组对种系DNA样品进行（重新）测序。主要结果是鉴定与癌症易感性有关的致病性生殖系突变。

结果

在430名年轻的CRC病例中，有111名（26％）与CRC有一级亲戚关系。CRC受试者中有41名（10％）的肿瘤具有组织学修复失配的组织学证据。在接受临床种系测序的315位受试者中，有79位具有与遗传性癌症综合征相关的突变，而21位具有不确定意义的变异。五十六名受试者有与Lynch综合征相关的病原体变异（25例MSH2突变，24例MLH1突变，5例MSH6突变，2例PMS2突变）和10例受试者与家族性腺瘤性息肉病相关。13名受试者的其他癌症相关基因发生了突变（MUTYH中有8个突变，MUTYH中有2个突变）。SMAD4，BRCA1中的1，TP53中的1以及CHEK2中的1 ），均通过多基因面板测试确定。在117例临床资料不详的患者中，使用多基因面板进行的下一代序列分析在6例患者中检测到了可行的种系变异（5％）。在与遗传性癌症综合征相关的种系突变的85名受试者中，只有43名（51％）报告了一级亲属的CRC诊断。

结论

年龄在50岁以下且被诊断患有CRC的患者中，约有五分之一患有与癌症相关的种系突变；这些患者中有将近一半没有通常与所识别出的综合征相关的临床病史。对于所有年轻的CRC患者，都应考虑使用多基因癌症专栏进行生殖细胞测试。