Stoffel Elena M, Koeppe Erika, Everett Jessica, Ulintz Peter, Kiel Mark, Osborne Jenae, Williams Linford, Hanson Kristen, Gruber Stephen B, Rozek Laura S
Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan.
Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan.
Gastroenterology. 2018 Mar;154(4):897-905.e1. doi: 10.1053/j.gastro.2017.11.004. Epub 2017 Nov 14.
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.
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.
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.
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.
50岁以下个体的结直肠癌（CRC）发病率正在上升。我们试图确定与遗传易感性相关的年轻CRC病例的比例。
我们对1998年至2015年在一家三级医疗癌症中心的临床遗传学服务部门评估的50岁以下被诊断为CRC的个体进行了一项回顾性研究。我们收集了患者病史、肿瘤表型和种系DNA测序结果的数据。对于临床评估无信息的受试者，使用基于研究的下一代测序多基因panel对种系DNA样本进行（重新）测序。主要结果是鉴定与癌症易感性相关的致病性种系突变。
在430例年轻CRC病例中，111例（26%）有一级亲属患CRC。41例CRC受试者（10%）的肿瘤有组织学证据表明存在错配修复缺陷。在315例接受临床种系测序的受试者中，79例有与遗传性癌症综合征相关的突变，21例有意义不确定的变异。56例受试者有与林奇综合征相关的致病性变异（25例MSH2突变，24例MLH1突变，5例MSH6突变，2例PMS2突变），10例受试者有与家族性腺瘤性息肉病相关的致病性变异。13例受试者在其他癌症相关基因中有突变（8例MUTYH突变，2例SMAD4突变，1例BRCA1突变，1例TP53突变，1例CHEK2突变），均通过多基因panel检测鉴定。在117例临床评估无信息的患者中，使用多基因panel进行的下一代序列分析在6例患者（5%）中检测到可操作的种系变异。在85例与遗传性癌症综合征相关的种系突变受试者中，只有43例（51%）报告一级亲属中有CRC诊断。
在50岁以下被诊断为CRC的个体中，约五分之一携带与癌症相关的种系突变；其中近一半没有通常与所鉴定综合征相关的临床病史。对于所有年轻的CRC患者，应考虑使用多基因癌症panel进行种系检测。
