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. 2019 Jul;18(3):331-342.
doi: 10.1007/s10689-019-00128-6.

Implication of DNA repair genes in Lynch-like syndrome

Rosa M Xicola  1 , Julia R Clark  2 , Timothy Carroll  2 , Jurgis Alvikas  2 , Priti Marwaha  2 , Maureen R Regan  2 , Francesc Lopez-Giraldez  3 , Jungmin Choi  4 , Rajyasree Emmadi  5 , Victoria Alagiozian-Angelova  6 , Sonia S Kupfer  7 , Nathan A Ellis  8 , Xavier Llor  9
Affiliations

Implication of DNA repair genes in Lynch-like syndrome

Rosa M Xicola et al. Fam Cancer. 2019 Jul.

Abstract

Many colorectal cancers (CRCs) that exhibit microsatellite instability (MSI) are not explained by MLH1 promoter methylation or germline mutations in mismatch repair (MMR) genes, which cause Lynch syndrome (LS). Instead, these Lynch-like syndrome (LLS) patients have somatic mutations in MMR genes. However, many of these patients are young and have relatives with cancer, suggesting a hereditary entity. We performed germline sequence analysis in LLS patients and determined their tumor's mutational profiles using FFPE DNA. Six hundred and fifty-four consecutive CRC patients were screened for suspected LS using MSI and absence of MLH1 methylation. Suspected LS cases were exome sequenced to identify germline and somatic mutations. Single nucleotide variants were used to characterize mutational signatures. We identified 23 suspected LS cases. Germline sequence analysis of 16 available samples identified five cases with LS mutations and 11 cases without LS mutations, LLS. Most LLS tumors had a combination of somatic MMR gene mutation and loss of heterozygosity. LLS patients were relatively young and had excess first-degree relatives with cancer. Four of the 11 LLS patients had rare likely pathogenic variants in genes that maintain genome integrity. Moreover, tumors from this group had a distinct mutational signature compared to tumors from LLS patients lacking germline mutations in these genes. In summary, more than a third of the LLS patients studied had germline mutations in genes that maintain genome integrity and their tumors had a distinct mutational signature. The possibility of hereditary factors in LLS warrants further studies so counseling can be properly informed.

Keywords: Colorectal cancer; DNA repair genes; Lynch syndrome; Lynch syndrome-like; Lynch-like syndrome.

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Conflict of interest statement

Disclosures of Potential Conflicts of Interest: None of the authors have any potential conflicts of interest to disclose that are relevant to the manuscript. The results published here are in whole or part based upon data generated by The Cancer Genome Atlas managed by the NCI and NHGRI. Information about TCGA can be found at http://cancergenome.nih.gov.

Figures

Figure 1.
Figure 1.. Flow chart of the different tests performed to identify suspected Lynch syndrome cases
Figure 2:
Figure 2:. Somatic signatures that characterize colorectal tumors
A: Mutation spectrum of the different CRC phenotypes. In the X axis there is a representation of all the 96 possible nucleotide triplets, 16 combinations per each type of mutation. B: Composition of somatic signatures estimated with the non-negative matrix factorization (NMF) represented as a bar chart. C: Contribution of the different signatures to the distinct CRC phenotypes estimated with the NMF represented as a bar chart. LLS-1, cases of Lynch-like syndrome with DNA repair gene mutations; LLS-2, cases of Lynch-like syndrome without DNA repair gene mutations; LS, Lynch syndrome; MSI, MSI colorectal cancers from The Cancer Genome Atlas.
Figure 3:
Figure 3:. Hierarchical cluster analysis of colorectal tumor phenotypes
AU (Approximately Unbiased) p-value (on the left) and BP (Bootstrap Probability) value (on the right). LLS-1: Lynch-like syndrome with DNA repair gene variants; LLS-2: Lynch-like syndrome without DNA repair gene variants; LS: Lynch Syndrome; MSI: MSI colorectal cancers from The Cancer Genome Atlas.
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