ASCO 2018: Large Study of DNA Mismatch Repair Genes Determines Mutation Frequency in Several Types of Cancer

Results from a study evaluating the relationship between the number of somatic mutations (SMs) in four mismatch repair (MMR) genes and the microsatellite instability (MSI) phenotype showed specific mutations in DNA repair genes associated with younger age, and specific cancer types. Researchers reported results from a large genomic study of over 24,000 tumour samples at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held 1 to 5 June in Chicago, USA.

Somatic mutations (SM) that disrupt DNA repair mechanisms are commonly detected in cancer. SM in the mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2 contribute to MMR deficiency, leading to the accumulation of mutation within the cell and to the MSI phenotype.

The frequency of mutation in DNA repair genes determined for distinct tumour types

MSI is a genomic marker that indicates a defect in the ability of a tumour cell to repair damaged DNA. Bi-allelic SMs (bSM) of an MMR gene are known to cause MMR deficiency in colorectal and endometrial cancers. However, the frequency of mono-allelic SM (mSM) and bSM of MMR genes in othefined and ther tumours was unde clinical or molecular correlates of MMR gene mSM and bSM were not well described.

Therefore, Joseph Nicholas Bodor of the Fox Chase Cancer Centre in Philadelphia, USA and colleagues assessed 24,223 tumour samples in the Caris Life Sciences database tumours harbouring one or more SM of an MMR gene using next generation sequencing (NGS; Illumina NextSeq 592 gene panel).

The investigators also determined the association of mSM or bSM with clinical factors, and MSI, tumour mutational burden (TMB), as well as examining SM in non-MMR DNA repair pathways. Associations were tested by Fisher’s exact test and logistic regression.

Younger age of patient associated with bSM MMR mutations

The investigators found that470 of the tumours had ≥1 SM; of these, 80 had bSM within an MMR gene. The highest frequency (46) of bSM was found in the MSH6 gene. The bSM in MSH6 were primarily due to recurrent SM at F1088fs, a coding microsatellite.

An evaluation of the association of bSM with clinical characteristics revealed that tumours with bSM were more commonly detected in younger patients having a medium age of 57.5 years (median 57.5 years bSM versus 63 years mSM; p = 0.003).

In addition, bi-allelic (bSM) MMR gene mutations were associated with high TMB, and also with more mutations in non-MMR DNA repair genes, including those for nucleotide excision repair and homologous recombination (HR) genes, such as BRCA1/2. They found that bSM associated with high TMB (p < 0.001), with SM in nucleotide excision repair genes (p = 0.003), and with HR genes (p = 0.01), such as ATM where 62 of 470 (13.2%) tumours contained bSM. bSM also associated with BRCA1 and 2, with 91 of 470 (19.4%) tumours having bSM.

At the single gene level, mono-allelic (mSM) in MSH2 (p = 0.001) and MSH6 (p = 0.01) were positively associated with TMB, but inversely with PMS2 (p < 0.001).

MSI was only found to associate with mSM in MLH1 (p < 0.001). Furthermore, SMs in HR genes were associated with mSM in MLH1, MSH2, and MSH6 (all p < 0.01), but SM in nucleotide excision repair genes were associated only with mSM in MSH6 (p = 0.004).

An analysis of SM by tumour type showed that mSM were common in endometrial (n = 84), colorectal (n = 90), and lung (n = 45) cancers. Frequency of MMR bSM by tumour histology showed next distribution: endometrial cancer (n = 34), colorectal cancer (n = 21), ovarian cancer (n = 14) and other. Differences in bSM frequency in left- (30%) versus right-sided (12.5%) colorectal cancer were not seen (p = 0.10).

bSM are nearly entirely restricted to Lynch syndrome spectrum tumours

Nearly all bi-allelic MMR somatic mutations (98%) were found in tumours within the Lynch syndrome spectrum, which are hereditary non-polyposis colorectal cancers and the most common form of hereditary colorectal cancer. Lynch syndrome cancers are most frequently diagnosed in younger individuals.

Study limitations

The authors pointed out that the study has some limitations: no paired germline data, therefore it is uknown if the somatic mutations observed are also found in germline, though a number of the mutations identified have been reported in germline series. The bSM were assumed to be in trans as the likelyhood of two pathogenic mutations on the same MMR gene allele is very low. Loss of heterozigosity studies was not conducted. There is no individual-level family history data or treatment data.


These findings demonstrate that MMR gene mSM occur in diverse tumour types, but bSM occur almost exclusively in Lynch syndrome-spectrum tumours.

The occurrence of mSM in tumours of patients with a younger age suggested to the authors that germline mutations may precede some bSM events.

The investigators concluded that the observed association of the number of MMR gene mutations and high TMB, MSI-H and non-MMR DNA repair gene mutations suggests cascade effects of DNA repair deficiency and reveals possible treatment targets.


Caris Life Sciences provided the tumour bank used in this study.


Bodor JN, Handorf EA, Feldman R, et al.Pathogenic somatic mutation (SM) of mismatch repair (MMR) genes and associations with microsatellite instability (MSI), tumor mutational burden (TMB) and SM in other DNA repair pathways in 24,223 tumor genomic profiles.J Clin Oncol 36, 2018 (suppl; abstr 1505).