Dataset Information

Somatic CpG hypermutation is associated with mismatch repair deficiency in cancer

ABSTRACT: Somatic hypermutation in cancer has gained momentum with the increased use of tumour mutation burden as a biomarker for immune checkpoint inhibitors. Spontaneous deamination of 5-methylcytosines to thymines at CpG dinucleotides is one of the most ubiquitous endogenous mutational processes in normal and cancer cells. Here, we performed a systematic investigation of somatic CpG hypermutations at a pan-cancer level. We studied 30,191 cancer patients and 103 cancer types and developed an algorithm to classify somatic CpG hypermutation. Across cancer types, we observed the highest prevalence in paediatric leukaemia (3.5%), paediatric high-grade glioma (1.7%), and colorectal cancer (1%). We discovered germline and somatic mutations in the mismatch repair complex MutSα (MSH2-MSH6) as genetic drivers of somatic CpG hypermutation, which frequently converged on CpG sites and driver mutations in TP53. We further observe an association between somatic CpG hypermutation and response to immune checkpoint inhibitors. Overall, our study identified novel cancer types that display somatic CpG hypermutation, strong association with MutSα-deficiency, and potential utility in cancer immunotherapy.

SUBMITTER: Prof Joachim Weischenfeldt

PROVIDER: S-SCDT-10_1038-S44320-024-00054-5 | biostudies-other |

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:The inclusion of DNA mismatch repair (MMR) evaluation as a standard of care for endometrial cancer management will result in a growing population of patients with MMR deficiency and negative germline Lynch syndrome testing (MMR-deficient). In this systematic review and study, the clinicopathologic features of endometrial cancer in patients with MMR-intact, MLH1 methylation positive, MMR-deficient or Lynch syndrome are evaluated. A systematic search of online databases between 1990 and 2018 identified studies of endometrial cancer patients with tumour testing (MMR protein immunohistochemistry or microsatellite instability) and germline assessment for Lynch syndrome. Extracted data included tumour testing, germline genetic testing, age, body mass index (BMI), family history, tumour stage, grade and histologic type. Associations between MMR-intact, MLH1 methylation positive, MMR-deficient and Lynch syndrome groups were analysed using descriptive statistics. The comprehensive search produced 4,400 publications, 29 met inclusion criteria. A total of 7,057 endometrial cancer cases were identified, 1,612 with abnormal immunohistochemistry, 977 with microsatellite instability. Nine-hundred patients underwent germline genetic testing, identifying 212 patients with Lynch syndrome. Patients in the Lynch syndrome and MMR-deficient groups were significantly younger than patients in the MMR-intact and MLH1 methylation positive groups. Patients with MMR-intact tumours had the highest BMI, followed by MMR-deficient, then Lynch syndrome. MMR-intact tumours were more likely to be grade I at diagnosis than other groups. Patients with Lynch syndrome and MMR-deficient tumours were less likely to have stage I disease as compared to patients with MMR-intact tumours. Endometrial cancer patients with MMR-deficient tumours have similar features to those with germline Lynch syndrome mutations, including age, grade, histology and stage. Even in the absence of a germline mutation, tumour evaluation for MMR status may have important clinical implications.

Dataset Information

Somatic CpG hypermutation is associated with mismatch repair deficiency in cancer

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets