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Loss of MSH2 and MSH6 due to heterozygous germline defects in MSH3 and MSH6

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Abstract

Lynch Syndrome (LS) is the most common dominantly inherited colorectal cancer (CRC) predisposition and is caused by a heterozygous germline defect in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. High microsatellite instability (MSI-H) and loss of MMR protein expression in tumours reflecting a defective MMR are indicators for LS, as well as a positive family history of early onset CRC. MSH2 and MSH6 form a major functional heterodimer, and MSH3 is an alternative binding partner for MSH2. So far, the role of germline MSH3 variants remains unclear, as to our knowledge heterozygous truncating variants are not regarded causative for LS, but were detected in patients with CRC, and recently biallelic MSH3 defects have been identified in two patients with adenomatous polyposis. By gene screening we investigated the role of MSH3 in 11 LS patients with truncating MSH6 germline variants and an unexplained MSH2 protein loss in their corresponding MSI-H tumours. We report the first two LS patients harbouring heterozygous germline variants c.1035del and c.2732T>G in MSH3 coincidentally with truncating variants in MSH6. In the patient with truncating germline variants in MSH3 and MSH6, two additional somatic second hits in both genes abrogate all binding partners for the MSH2 protein which might subsequently be degraded. The clinical relevance of MSH3 germline variants is currently under re-evaluation, and heterozygous MSH3 defects alone do not seem to induce a LS phenotype, but might aggravate the MSH6 phenotype in affected family members.

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Abbreviations

CRC:

Colorectal cancer

IHC:

Immunohistochemical

LOH:

Loss of heterozygosity

LS:

Lynch Syndrome

MMR:

DNA mismatch repair

MSI-H:

High microsatellite instability

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Acknowledgements

We thank the German Cancer Aid (Deutsche Krebshilfe) and the Wilhelm Sander-Stiftung for their support of this work. We also thank all patients for their participation in this study, as well as their respective doctors for contributing clinical information.

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Authors and Affiliations

  1. Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Ziemssenstr. 1, 80336, Munich, Germany

    Monika Morak, Sarah Käsbauer, Martina Kerscher, Trisari Massdorf & Elke Holinski-Feder

  2. MGZ - Center of Medical Genetics, Bayerstr. 3-5, 80335, Munich, Germany

    Monika Morak, Andreas Laner, Anke M. Nissen, Anna Benet-Pagès & Elke Holinski-Feder

  3. Department of Surgical Research, Universitätsklinikum der TU Dresden, Dresden, Germany

    Hans K. Schackert

  4. Institute of Pathology, Technical University, Munich, Germany

    Gisela Keller

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  1. Monika Morak
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10689_2017_9975_MOESM1_ESM.bmp

Supplementary Fig. S1 Sequences of MSH3 exon 7 in genomic DNA. 1a shows the germline MSH3 nonsense variant c.1035del p.(Leu347*) heterozygously in blood of patient BS in the forward sequence, compared to a control above; 1b shows the MSH3 variant c.1035del p.(Leu347*) with an allelic reduction of the wildtype allele in the tumour DNAs of patient BS. 1c presents an additional somatic MSH3 frameshift c.1148del p.(Lys383Argfs*32) heterozygously or mosaic in the coding A8-tract in the two tumour DNAs of patient BS in the reverse sequence, which is absent in blood of the patient (above), as well as in tumours of other patients. (BMP 1634 KB)

Supplementary Fig. S2 (BMP 1533 KB)

10689_2017_9975_MOESM3_ESM.bmp

Supplementary Fig. S3 Sequences of MSH6 in genomic DNA in forward direction. 2a shows the germline variant in MSH6 exon 9 c.3969_3979del p.(Phe1323Leufs*14) heterozygously in patient BS in blood, compared to a control above; which was also present in both tumour DNAs of the patient (below) without a loss of one allele. 2b shows the hotspot variant in MSH6 exon 5 c.3261del p.(Phe1088Serfs*2) heterozygously in the coding C8-tract in both tumour DNAs of patient BS, which is absent in the germline of the patient (above). (BMP 1511 KB)

Supplementary Fig. S4 (BMP 1072 KB)

10689_2017_9975_MOESM5_ESM.xls

Supplementary Table S1 List of all MSH3 variants detected in the gene screening including rs, allelic frequencies in database and our control cohort, and classification. (XLS 40 KB)

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Morak, M., Käsbauer, S., Kerscher, M. et al. Loss of MSH2 and MSH6 due to heterozygous germline defects in MSH3 and MSH6 . Familial Cancer 16, 491–500 (2017). https://doi.org/10.1007/s10689-017-9975-z

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