Deep sequencing of early T stage colorectal cancers reveals disruption of homologous recombination repair in microsatellite stable tumours with high mutational burdens

• DOI: 10.1101/2022.03.02.22271810
• Publication Date: 2022-03-04T21:05:21Z
• Authors: Jun Li; Pascal Steffen; Benita C. Y. Tse; Mahsa S. Ahadi; Anthony J Gill; Alexander F. Engel; Mark P. Molloy
• Keywords: Microsatellite Instability

Abstract Early T stage colorectal cancers (CRC) that invade lymph nodes (Stage IIIA) are greatly under-represented in large-scale genomic mapping projects such as TCGA datasets. We retrieved 10 Stage IIIA CRC cases, matched these to 16 1 cases (T1 depth without node metastasis) and carried out deep sequencing of 409 genes using the IonTorrent system. Tumour mutational burdens (TMB) ranged from 2.4-77.2/Mb sequenced. Using mean TMB a cut-point define groups, TMB-low (TMB-L) specimens showed higher frequency KRAS TP53 mutations compared I, consistent with data. TMB-High (TMB-H) consisted both microsatellite instable high (MSI-H) stable (MSS) genotypes. Comparison TMB-H TMB-L groups revealed clear differences ATM, KDM5C, PIK3CA APC. APC was less frequently mutated group although variant composition more diverse. Variants ATM were restricted group, four five MSS we observed co-occurrence homologous recombination repair (HRR) either two CDK12, PTEN or ATR , at least one being truncating mutation. No MSI-H nonsense genes. These findings add our knowledge early highlight potential therapeutic vulnerability HRR pathway CRC.