TY - JOUR
T1 - Co-occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome
AU - Ferrer-Avargues, Rosario
AU - Castillejo, María Isabel
AU - Dámaso, Estela
AU - Díez-Obrero, Virginia
AU - Garrigos, Noemí
AU - Molina, Tatiana
AU - Codoñer-Alejos, Alan
AU - Segura, Ángel
AU - Sánchez-Heras, Ana Beatriz
AU - Castillejo, Adela
AU - Soto, José Luis
N1 - Publisher Copyright:
© 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - cancer panel
KW - hereditary cancer
KW - lynch syndrome
KW - moderate penetrance genes
KW - multilocus inherited neoplasia alleles syndrome
KW - next-generation sequencing
KW - secondary findings
UR - http://www.scopus.com/inward/record.url?scp=85101589740&partnerID=8YFLogxK
U2 - 10.1002/cac2.12134
DO - 10.1002/cac2.12134
M3 - Artículo
AN - SCOPUS:85101589740
SN - 1000-467X
VL - 41
SP - 218
EP - 228
JO - Cancer Communications
JF - Cancer Communications
IS - 3
ER -