Molecular tumor testing in patients with Lynch-like syndrome reveals a de novo mosaic variant of a mismatch repair gene transmitted to offspring

Guillerm, Erell; Svrcek, Magali; Bardier–Dupas, Armelle; Basset, Noémie; Coulet, Florence; Colas, Chrystelle

doi:10.1038/s41431-020-0689-6

Cited by 12 publications

(20 citation statements)

References 19 publications

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“…Due to the de novo variant, the patient developed endometrial cancer (aged 45) and colorectal cancer (CRC) (aged 60). Further analysis of the CRC of this patient, showed MSI and loss of expression in the genes MSH2 and MSH6 [82]; similar analysis was not performed for the endometrial cancer. It should be acknowledged that previous research identified that MSI can be detected with endometrial cancer [83].…”

Section: Microsatellite Instability and Germ Cell Mosaicismmentioning

confidence: 68%

“…Despite the study of Jaruzelska et al [81] described above, reports investigating the impact of germline mosaicism/MSI and infertility in humans are lacking. However, de novo germline mosaicism within MSH2 was identified in one patient with a Lynch-like syndrome [82]. Due to the de novo variant, the patient developed endometrial cancer (aged 45) and colorectal cancer (CRC) (aged 60).…”

Section: Microsatellite Instability and Germ Cell Mosaicismmentioning

confidence: 99%

See 1 more Smart Citation

Genomic instability and the link to infertility: A focus on microsatellites and genomic instability syndromes

Wieland

Buchan

Gupta

et al. 2022

European Journal of Obstetrics & Gynecology and Reproductiv

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Section: Microsatellite Instability and Germ Cell Mosaicismmentioning

confidence: 68%

Section: Microsatellite Instability and Germ Cell Mosaicismmentioning

confidence: 99%

Genomic instability and the link to infertility: A focus on microsatellites and genomic instability syndromes

Wieland

Buchan

Gupta

et al. 2022

European Journal of Obstetrics & Gynecology and Reproductiv

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“…Lynch syndrome is caused by germline pathogenic variants in one of the DNA mismatch repair (MMR) genes where carriers have an increased risk of developing colorectal (CRC) and endometrial (EC) cancer, among other cancers. Mosaicism of hereditary CRC genes is not uncommon [1], but mosaicism in the MMR genes is thought to be rare with only a few cases reported to date (Table 1) [2][3][4][5]. Here, we report the rst case of a mosaic MSH6 gene pathogenic variant in an EC-and CRC-affected individual diagnosed with suspected Lynch syndrome.…”

Section: Introductionmentioning

confidence: 85%

A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report

Walker

Clendenning

Joo

et al. 2023

Preprint

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Germline pathogenic variants in the DNA mismatch (MMR) repair genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely de novo mosaic MSH6:c.1135_1139del p.Arg379* pathogenic variant in a patient diagnosed with suspected Lynch syndrome/Lynch-like syndrome. The patient developed MSH6-deficient EC and CRC at 54 and 58 years of age, respectively, without a detectable germline MMR pathogenic variant. Multigene panel sequencing of tumor and blood-derived DNA identified an MSH6 somatic mutation (MSH6:c.1135_1139del p.Arg379*) common to both the EC and CRC, raising suspicion of mosaicism. A droplet digital polymerase chain reaction (ddPCR) assay detected the MSH6 variant at 5.34% frequency in normal colonic tissue, 3.49% in saliva and 1.64% in blood DNA, demonstrating the presence of the MSH6 variant in all three germ layers. This study highlights the utility of tumor sequencing to guide sensitive ddPCR testing to detect low-level mosaicism in the MMR genes. Further investigation of the prevalence of MMR mosaicism is needed to inform routine diagnostic approaches and genetic counselling.

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“…Limitations of this study are the small sample size and the incomplete information on prior treatment for non-seminoma TC. Studies on MMRd CRC with somatic double or single hit usually lack information on whether these patients received previous anticancer therapy [31,[36][37][38]. However, when combining results from three recent studies with a total of 30 patients with MMRd due to somatic double hit, one of these patients had a previous history of HL and another of leukaemia [39][40][41].…”

Section: Discussionmentioning

confidence: 99%

Somatic hits in mismatch repair genes in colorectal cancer among non-seminoma testicular cancer survivors

et al. 2022

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BACKGROUND: Non-seminoma testicular cancer survivors (TCS) have an increased risk of developing colorectal cancer (CRC) when they have been treated with platinum-based chemotherapy. Previously we demonstrated that among Hodgkin lymphoma survivors (HLS) there is enrichment of rare mismatch repair (MMR) deficient (MMRd) CRCs with somatic hits in MMR genes. We speculate that this phenomenon could also occur among other cancer survivors. We therefore aim to determine the MMR status and its underlying mechanism in CRC among TCS (TCS-CRC). METHODS: Thirty TCS-CRC, identified through the Dutch pathology registry, were analysed for MMR proteins by immunohistochemistry. Next-generation sequencing was performed in MMRd CRCs without MLH1 promoter hypermethylation (n = 4). Data were compared with a male cohort with primary CRC (P-CRC, n = 629). RESULTS: MMRd was found in 17% of TCS-CRCs vs. 9% in P-CRC (p = 0.13). MMRd was more often caused by somatic double or single hit in MMR genes by mutation or loss of heterozygosity in TCS-CRCs (3/30 (10%) vs. 11/629 (2%) in P-CRCs (p < 0.01)). CONCLUSIONS: MMRd CRCs with somatic double or single hit are more frequent in this small cohort of TCS compared with P-CRC. Exposure to anticancer treatments appears to be associated with the development of these rare MMRd CRC among cancer survivors.

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Molecular tumor testing in patients with Lynch-like syndrome reveals a de novo mosaic variant of a mismatch repair gene transmitted to offspring

Cited by 12 publications

References 19 publications

Genomic instability and the link to infertility: A focus on microsatellites and genomic instability syndromes

Genomic instability and the link to infertility: A focus on microsatellites and genomic instability syndromes

A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report

Somatic hits in mismatch repair genes in colorectal cancer among non-seminoma testicular cancer survivors

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