Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Mol Cancer. 2024 Nov 25;23(1):264. doi: 10.1186/s12943-024-02173-x.
Co-occurring mutations in pairs of genes can pinpoint clinically relevant subgroups of cancer. Most colorectal cancers (CRCs) are microsatellite stable (MSS) and have few frequent mutations. Large patient cohorts and broad genomic coverage are needed for comprehensive co-mutation profiling.
Co-mutations were identified in a population-based Swedish cohort analyzed by whole-genome sequencing (n=819 stage I-IV MSS CRCs). Prognostic value was further evaluated in a publicly available dataset of clinically sequenced metastatic CRCs (MSK-IMPACT; n=934 MSS). Multivariable Cox proportional hazards analyses with clinicopathological parameters were performed for locoregional (stage I-III) and metastatic (stage IV and recurrent) cancers separately.
Prevalent co-mutations were detected in 23 unique gene pairs, 20 of which included APC, TP53, KRAS and/or PIK3CA. Several co-mutations involving APC were associated with good overall survival in locoregional CRC, including APC-TCF7L2 (multivariable HR: 0.49, 95% CI 0.27-0.89). This co-mutation was prognostic also in metastatic cancers (multivariable HR: 0.49 and 0.37, 95% CI: 0.24-0.98 and 0.17-0.82 in the Swedish and MSK cohorts, respectively). APC-SOX9 co-mutations were mutually exclusive with APC-TCF7L2, and the co-mutations combined had stronger prognostic associations than APC alone in both metastatic cohorts. BRAF p.V600E-RNF43 co-mutations were associated with poor overall and recurrence-free survival in locoregional CRC (multivariable HR: 4.13 and 3.2, 95% CI: 1.78-9.54 and 1.53-8.04, respectively).
We report a genome-wide evaluation of co-occurring mutations in MSS CRCs, and suggest that co-mutations can improve the prognostic stratification compared to single mutations alone.
基因对的共突变可以精确定位具有临床相关性的癌症亚组。大多数结直肠癌（CRC）为微卫星稳定（MSS），且突变频率较低。为了进行全面的共突变分析，需要大型的患者队列和广泛的基因组覆盖。
通过全基因组测序（n=819 例 I-IV 期 MSS CRC）对基于人群的瑞典队列进行共突变分析。在一个公开的临床测序转移性 CRC（MSK-IMPACT；n=934 MSS）数据集进一步评估了预后价值。针对局部区域（I-III 期）和转移性（IV 期和复发）癌症，分别进行包含临床病理参数的多变量 Cox 比例风险分析。
共检测到 23 对独特基因对的常见共突变，其中 20 对包括 APC、TP53、KRAS 和/或 PIK3CA。APC 中涉及多个共突变与局部区域 CRC 的总生存良好相关，包括 APC-TCF7L2（多变量 HR：0.49，95%CI 0.27-0.89）。该共突变在转移性癌症中也是预后因素（多变量 HR：0.49 和 0.37，95%CI：0.24-0.98 和 0.17-0.82，在瑞典和 MSK 队列中）。APC-SOX9 共突变与 APC-TCF7L2 互斥，在两个转移性队列中，共突变组合比 APC 单独具有更强的预后相关性。BRAF p.V600E-RNF43 共突变与局部区域 CRC 的总生存和无复发生存不良相关（多变量 HR：4.13 和 3.2，95%CI：1.78-9.54 和 1.53-8.04）。
我们报告了 MSS CRC 中共同突变的全基因组评估，并表明与单个突变相比，共突变可以改善预后分层。
