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Multicenter Study
. 2019 Aug;7(8):e850.
doi: 10.1002/mgg3.850. Epub 2019 Jul 12.

Comprehensive mismatch repair gene panel identifies variants in patients with Lynch-like syndrome

Alexandre Xavier  1 , Maren Fridtjofsen Olsen  2   3 , Liss A Lavik  3 , Jostein Johansen  2 , Ashish Kumar Singh  3 , Wenche Sjursen  2   3 , Rodney J Scott  1   4 , Bente A Talseth-Palmer  1   5
Affiliations
Multicenter Study

Comprehensive mismatch repair gene panel identifies variants in patients with Lynch-like syndrome

Alexandre Xavier et al. Mol Genet Genomic Med. 2019 Aug.

Abstract

Background: Lynch-like syndrome (LLS) represents around 50% of the patients fulfilling the Amsterdam Criteria II/revised Bethesda Guidelines, characterized by a strong family history of Lynch Syndrome (LS) associated cancer, where a causative variant was not identified during genetic testing for LS.

Methods: Using data extracted from a larger gene panel, we have analyzed next-generation sequencing data from 22 mismatch repair (MMR) genes (MSH3, PMS1, MLH3, EXO1, POLD1, POLD3 RFC1, RFC2, RFC3, RFC4, RFC5, PCNA, LIG1, RPA1, RPA2, RPA3, POLD2, POLD4, MLH1, MSH2, MSH6, and PMS2) in 274 LLS patients. Detected variants were annotated and filtered using ANNOVAR and FILTUS software.

Results: Thirteen variants were revealed in MLH1, MSH2, and MSH6, all genes previously linked to LS. Five additional genes (EXO1, POLD1, RFC1, RPA1, and MLH3) were found to harbor 11 variants of unknown significance in our sample cohort, two of them being frameshift variants.

Conclusion: We have shown that other genes associated with the process of DNA MMR have a high probability of being associated with LLS families. These findings indicate that the spectrum of genes that should be tested when considering an entity like Lynch-like syndrome should be expanded so that a more inclusive definition of this entity can be developed.

Keywords: Genetics; Lynch syndrome; MMR gene panel; germline mutation; high-throughput sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mismatch repair pathway major steps with genes associated. Genes in red are the one usually screened for mutations in a clinical setting. MLH1, PMS2, MSH2, and MSH6 are all involved in the recognition of DNA damage. PMS2 has an endonuclease function in nicking around the damaged region. EXO1 will then remove the DNA strand containing the error and RPA (Replication Protein A) will protect the remaining single strand of DNA. The DNA polymerase Polδ resynthesises the new DNA strand which is then ligated with a ligase (based on Hsieh & Yamane, 2008)
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