Herrera-Mullar Jennifer, Carraway Cassidy, Marsh Ashley P L, Hernandez Felicia, Kudalkar Emily, Richardson Marcy E
Ambry Genetics Corporation, Aliso Viejo, CA.
JCO Precis Oncol. 2025 Aug;9:e2500214. doi: 10.1200/PO-25-00214. Epub 2025 Aug 27.
is a proposed colorectal cancer (CRC) predisposition gene, with only four families with putative loss-of-function (pLoF) variants published. The prevalence, phenotypic spectrum, and clinical management recommendations for heterozygotes remain unknown.
Retrospective review of approximately 950,000 individuals undergoing multigene panel testing (MGPT) for cancer predisposition identified 36 individuals with pLoF variants in . Clinical features, tumor prevalence, and age at onset were compared with Lynch syndrome (LS) and wild-type (WT) cohorts.
Thirty-six individuals (0.004%) had 28 unique pLoF variants in and a total of 42 primary tumors, 78.6% of which were CRC with a median age of diagnosis of 50 years. A total of 16.7% of individuals had multiple CRC primaries, and a majority (71.4%) were mismatch repair-proficient (pMMR). Signet ring cell (SRC) pathology was significantly enriched compared with WT ( = <.0001). The odds ratio for CRC was significantly higher than that for the -related LS cohort (odds ratio [OR], 45.3 [95% CI, 21.3 to 101] and OR, 16.9 [95% CI, 14.9 to 19.2], respectively).
is associated with early-onset, pMMR CRC enriched for SRC pathology. Comparison of prevalence showed a statistically significant two-fold increase in the odds of developing CRC compared with an LS cohort. These data confirm the gene-disease relationship between and CRC and support clinical management guidelines similar to -related LS.
[基因名称]是一种被提出的结直肠癌（CRC）易感基因，目前仅有四个携带推定功能丧失（pLoF）变异的家系被报道。杂合子的患病率、表型谱及临床管理建议仍不清楚。
对约950,000例接受癌症易感性多基因检测（MGPT）的个体进行回顾性分析，确定了36例携带[基因名称]pLoF变异的个体。将其临床特征、肿瘤患病率及发病年龄与林奇综合征（LS）和野生型（WT）队列进行比较。
36例个体（0.004%）在[基因名称]中有28种独特的pLoF变异，共有42例原发性肿瘤，其中78.6%为CRC，诊断时的中位年龄为50岁。共有16.7%的个体有多个原发性CRC，大多数（71.4%）为错配修复功能正常（pMMR）。与WT相比，印戒细胞（SRC）病理显著富集（P = <.0001）。CRC的优势比显著高于与[基因名称]相关的LS队列（优势比[OR]分别为45.3 [95% CI，21.3至101]和OR，16.9 [95% CI，14.9至19.2]）。
[基因名称]与早发性、pMMR CRC相关，且SRC病理富集。患病率比较显示，与LS队列相比，患CRC的几率有统计学意义的两倍增加。这些数据证实了[基因名称]与CRC之间的基因-疾病关系，并支持与[基因名称]相关的LS类似的临床管理指南。
