Co-occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome

Abstract

Background: Lynch syndrome (LS) is a hereditary condition characterized by a high risk of colorectal cancer, endometrial cancer, and other neoplasia associated with germline alterations in DNA mismatch repair genes. The classical genetic diagnostic strategy for LS consists of the Sanger sequencing of genes associated with the suspected syndrome. Next-generation sequencing (NGS) enables the simultaneous sequencing of a large number of hereditary cancer genes. Here, we aimed to study whether other germline pathogenic variants of hereditary cancer genes are present in patients with LS.

Methods: A cohort of 84 probands with a previous genetic diagnosis of LS by Sanger sequencing was reanalyzed using NGS via a commercial panel of 94 hereditary cancer genes by hybrid capture. The American College of Medical Genetics and Genomics criteria were used to classify the clinical significance of the variants. The findings of NGS were confirmed by Sanger sequencing. When possible, genetic analyses of the new findings in the proband's relatives were also performed by Sanger sequencing.

Results: We identified five families (6%), out of 84, with at least two germline pathogenic variants conferring to high or moderate risk in different dominant cancer-predisposing genes: [MLH1-BRCA2-NBN], [MLH1-BRCA1], [MSH2-ATM], [MSH6-NF1], and [MLH1-FANCA]. Interestingly, only one out of these five families exhibited a clinical phenotype associated with the new pathogenic variants. The family with three pathogenic variants of the [MLH1-BRCA2-NBN] genes showed a high aggregation of tumors associated with LS and breast and ovarian cancer syndrome.

Conclusions: Our results showed that the co-occurrence of more than one pathogenic variant in cancer-predisposing genes was remarkable among cases of LS. In most cases, no clinicial manifestations were associated with the secondary pathogenic variants. Further studies are needed to confirm these findings and elucidate their clinical impact. Reanalysis of LS families should be considered only in families with mixed clinical phenotypes.

Keywords: cancer panel; hereditary cancer; lynch syndrome; moderate penetrance genes; multilocus inherited neoplasia alleles syndrome; next-generation sequencing; secondary findings.

FIGURE 1

Pedigree of family LS9. The pathogenic variants found in the family are shown at the top. Filled symbols indicate patients affected by cancer (each color refers to a specific type). Age when the pedigree was drawn, age of death (symbol “ɨ”), and age at diagnosis, when available, are also detailed. The proband is marked by an arrow. Carrier status was studied in the available relatives, and those carrying or not carrying the pathogenic variants are marked with + and –, respectively: in black for MMR gene variant, blue for the second, and red for the third pathogenic/likely pathogenic variant, if any. BC, breast cancer; BrC, brain cancer; CRC, colorectal cancer; EC, endometrial cancer; MMR, mismatch repair; OC, ovarian cancer; ThC, throat cancer

FIGURE 2

Pedigrees of the Lynch syndrome families with a second pathogenic variant in other hereditary cancer genes: A) Pedigree of family F‐LS15; B) Pedigree of family F‐LS30; C) Pedigree of family F‐LS44; D) Pedigree of family F‐LS49 The pathogenic variants found in the family are shown at the top. Filled symbols indicate patients affected by cancer (each color refers to a specific type). Age when the pedigree was drawn, age of death, and age at diagnosis, when available, are also detailed. The proband is marked by an arrow. Carrier status was studied in the available relatives, and those carrying or not carrying the pathogenic variants are marked with + and –, respectively: in black for the MMR gene pathogenic variant, and in red for the second pathogenic variant. BoC, bone cancer; BrC, brain cancer; CRC, colorectal cancer; EC, endometrial cancer; GC, gastric cancer; LC, lung cancer; MMR, mismatch repair; PC, pancreatic cancer; TyC, thyroid cancer