Vande Perre Pierre, Al Saati Ayman, Cabarrou Bastien, Plenecassagnes Julien, Gilhodes Julia, Monselet Nils, Lignon Norbert, Filleron Thomas, Villarzel Carine, Gourdain Laure, Selves Janick, Martinez Mathilde, Chipoulet Edith, Collet Gaëlle, Mallet Ludovic, Bonnet Delphine, Guimbaud Rosine, Toulas Christine
Oncogenetics Laboratory, Oncopole Claudius Regaud, IUCT-Oncopole, 31059 Toulouse, France.
DIAD Team, INSERM U1037, Centre de Recherches en Cancérologie de Toulouse, 31100 Toulouse, France.
Int J Mol Sci. 2025 May 14;26(10):4672. doi: 10.3390/ijms26104672.
The majority of early-onset colorectal cancers (EOCRCs) are not substantiated by germline variants in the main CRC predisposition genes (the "DIGE" panel). To identify potentially novel EOCRC-specific predisposition genes, we analyzed 585 cancer pathway genes in an EOCRC patient cohort (n = 87, diagnosis ≤ 40 years, DIGE-), and compared their variant spectrum to the GnomAD cancer-free database. We identified high-impact variants (HVs) in 15 genes significantly over-represented in EOCRC. Among the 32 unrelated patients with a CRC family history (i.e., with a potentially dominant transmission pattern), 9 presented HVs in ten genes, four of which had a DNA repair function. We subsequently sequenced these 15 genes in a cohort of 82 late-onset CRCs (diagnosis ≥ 50 years, DIGE-) and found variants in 11 of these genes to be specific to EOCRC. We then screened these 11 genes in our patient database (n = 6482), which only contained 2% of EOCRCs (DIGE-), and identified two other EOCRC cases diagnosed after our cohort constitution, with HVs in and . Altogether, we found that 37.5% and 18.75% of patients carrying heterozygous and HVs, respectively, in our database were diagnosed with EOCRC. Our work has identified a pattern of germline variants not previously associated with EOCRC.
大多数早发性结直肠癌（EOCRC）无法通过主要结直肠癌易感基因（“DIGE” panel）中的种系变异得到证实。为了鉴定潜在的新型 EOCRC 特异性易感基因，我们在一个 EOCRC 患者队列（n = 87，诊断年龄≤40 岁，DIGE-）中分析了 585 个癌症通路基因，并将其变异谱与 GnomAD 无癌数据库进行比较。我们在 EOCRC 中显著富集的 15 个基因中鉴定出高影响变异（HV）。在 32 名有结直肠癌家族史（即具有潜在显性遗传模式）的无关患者中，9 名患者在 10 个基因中出现 HV，其中 4 个基因具有 DNA 修复功能。随后，我们在一个 82 例晚发性结直肠癌队列（诊断年龄≥50 岁，DIGE-）中对这 15 个基因进行测序，发现其中 11 个基因的变异是 EOCRC 特有的。然后，我们在我们的患者数据库（n = 6482）中筛选这 11 个基因，该数据库中仅包含 2%的 EOCRC（DIGE-），并鉴定出另外两例在我们的队列构建后诊断出的 EOCRC 病例，分别在 和 基因中存在 HV。总体而言，我们发现我们数据库中分别携带杂合 和 HV 的患者中，有 37.5%和 18.75%被诊断为 EOCRC。我们的工作确定了一种以前与 EOCRC 无关的种系变异模式。
