Dataset Information

Deep Sequencing of Early T Stage Colorectal Cancers Reveals Disruption of Homologous Recombination Repair in Microsatellite Stable Tumours with High Mutational Burdens.

ABSTRACT: Early T stage colorectal cancers (CRC) that invade lymph nodes (Stage IIIA) are rare and greatly under-represented in large-scale genomic mapping projects. We retrieved 10 Stage IIIA CRC cases, matched these to 16 Stage 1 CRC cases (T1 depth without lymph node metastasis) and carried out deep sequencing of 409 genes using the IonTorrent system. Tumour mutational burdens (TMB) ranged from 2.4 to 77.2/Mb sequenced. No stage-related mutational differences were observed, consistent with reanalysis of The Cancer Genome Atlas (TCGA) Stage I and IIIA datasets. We next examined mutational burdens and observed that the top five cancers were microsatellite stable (MSS) genotypes (mean TMB 49.3/Mb), while the other 16 MSS cancers had a mean TMB of 5.9/Mb. To facilitate comparison with TCGA hypermutator CRC, we included four microsatellite instability-high (MSI-H) samples with the high mutation burden MSS cases to form a TMB-High group. Comparison of TMB-High with TMB-Low groups revealed differences in mutational frequency of ATM, ALK, NSD1, UBR5, BCL9, CARD11, KDM5C, MN1, PTPRT and PIK3CA, with ATM and UBR5 validated in reanalysis of TCGA hypermutator Stages I and IIIA samples. Variants in ATM were restricted to the TMB-High group, and in four of five MSS specimens, we observed the co-occurrence of mutations in homologous recombination repair (HRR) genes in either two of ATM, CDK12, PTEN or ATR, with at least one of these being a likely pathogenic truncating mutation. No MSI-H specimens carried nonsense mutations in HRR genes. These findings add to our knowledge of early T stage CRC and highlight a potential therapeutic vulnerability in the HRR pathway of TMB-H MSS CRC.

SUBMITTER: Li J

PROVIDER: S-EPMC9221133 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Publications

Deep Sequencing of Early T Stage Colorectal Cancers Reveals Disruption of Homologous Recombination Repair in Microsatellite Stable Tumours with High Mutational Burdens.

Li Jun J Steffen Pascal P Tse Benita C Y BCY Ahadi Mahsa S MS Gill Anthony J AJ Engel Alexander F AF Molloy Mark P MP

Cancers 20220614 12

Early T stage colorectal cancers (CRC) that invade lymph nodes (Stage IIIA) are rare and greatly under-represented in large-scale genomic mapping projects. We retrieved 10 Stage IIIA CRC cases, matched these to 16 Stage 1 CRC cases (T1 depth without lymph node metastasis) and carried out deep sequencing of 409 genes using the IonTorrent system. Tumour mutational burdens (TMB) ranged from 2.4 to 77.2/Mb sequenced. No stage-related mutational differences were observed, consistent with reanalysis o ...[more]

PMID: 35740599

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Project description:BackgroundRevealing the impacts of endogenous and exogenous mutagenesis processes is essential for understanding the etiology of somatic genomic alterations and designing precise prognostication and treatment strategies for cancer. DNA repair deficiency is one of the main sources of endogenous mutagenesis and is increasingly recognized as a target for cancer therapeutics. The role and prevalence of mechanisms that underly different forms of DNA repair deficiencies and their interactions remain to be elucidated in gynecological malignancies.MethodsWe analyzed 1231 exomes and 268 whole-genomes from three major gynecological malignancies including uterine corpus endometrial carcinoma (UCEC) as well as ovarian and cervical cancers. We also analyzed data from 134 related cell lines. We extracted and compared de novo and refitted mutational signature profiles using complementary and confirmatory approaches and performed interaction analysis to detect co-occurring and mutually exclusive signatures.ResultsWe found an inverse relationship between homologous recombination deficiency (HRd) and mismatch repair deficiency (MMRd). Moreover, APOBEC co-occurred with HRd but was mutually exclusive with MMRd. UCEC tumors were dominated by MMRd, yet a subset of them manifested the HRd and APOBEC signatures. Conversely, ovarian tumors were dominated by HRd, while a subset represented MMRd and APOBEC. In contrast to both, cervical tumors were dominated by APOBEC with a small subsets showing the POLE, HRd, and MMRd signatures. Although the type, prevalence, and heterogeneity of mutational signatures varied across the tumor types, the patterns of co-occurrence and exclusivity were consistently observed in all. Notably, mutational signatures in gynecological tumor cell lines reflected those detected in primary tumors.ConclusionsTaken together, these analyses indicate that application of mutation signature analysis not only advances our understanding of mutational processes and their interactions, but also it has the potential to stratify patients that could benefit from treatments available for tumors harboring distinct mutational signatures and to improve clinical decision-making for gynecological malignancies.

Dataset Information

Deep Sequencing of Early T Stage Colorectal Cancers Reveals Disruption of Homologous Recombination Repair in Microsatellite Stable Tumours with High Mutational Burdens.

Publications

Deep Sequencing of Early T Stage Colorectal Cancers Reveals Disruption of Homologous Recombination Repair in Microsatellite Stable Tumours with High Mutational Burdens.

Similar Datasets

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