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

Rosario Ferrer-Avargues, María Isabel Castillejo, Estela Dámaso, Virginia Díez-Obrero, Noemí Garrigos, Tatiana Molina, Alan Codoñer-Alejos, Ángel Segura, Ana Beatriz Sánchez-Heras, Adela Castillejo, José Luis Soto

Research output: Contribution to journalArticlepeer-review

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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.

Original languageEnglish
Pages (from-to)218-228
Number of pages11
JournalCancer Communications
Volume41
Issue number3
DOIs
StatePublished - Mar 2021

Bibliographical note

Funding Information:
RFA is a recipient of a Fellowship from the Consellería Educación of the Valencian Community. The studies of ED and ACA are funded by the Acción Juvenil from Consellería Educación of the Valencian Community and the Spanish Ministry of Economy and Competitiveness, respectively. VDO is a recipient of a Fellowship from the Spanish Association Against Cancer (AECC).

Funding Information:
This work was supported by grants from the Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, FISABIO (Grants: UGP‐14‐192 and UGP‐16‐146), and the Carlos III Health Institute (Grant AES: PI17/01082).

Publisher Copyright:
© 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center

Keywords

  • cancer panel
  • hereditary cancer
  • lynch syndrome
  • moderate penetrance genes
  • multilocus inherited neoplasia alleles syndrome
  • next-generation sequencing
  • secondary findings

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