The 5-10% of breast/ovarian cancers (BC and OC) are inherited, and germline pathogenic (P) variants in DNA damage repair (DDR) genes BRCA1 and BRCA2 explain only 10-20% of these cases. Currently, new DDR genes have been related to BC/OC and to pancreatic (PC) cancers, but the prevalence of P variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogenic variants in DDR pathway genes other than BRCA1/2 and to correlate the genotype with the clinical phenotype. A cohort of 113 non-BRCA patients was analyzed by next-generation sequencing using a multigene panel of the 25 DDR pathways genes related to BC, OC, and PC. We found 43 unique variants in 18 of 25 analyzed genes, 14 classified as P/likely pathogenic (LP) and 28 as variants of uncertain significance (VUS). Deleterious variants were identified in 14% of index cases, whereas a VUS was identified in 20% of the probands. We observed a high incidence of deleterious variants in the CHEK2 gene, and a new pathogenic variant was detected in the RECQL gene. These results supported the clinical utility of multigene panel to increase the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches.

Beyond BRCA1 and BRCA2: deleterious variants in DNA repair pathway genes in italian families with breast/ovarian and pancreatic cancers / Germani, Aldo; Petrucci, Simona; De Marchis, Laura; Libi, Fabio; Savio, Camilla; Amanti, Claudio; Bonifacino, Adriana; Campanella, Barbara; Capalbo, Carlo; Lombardi, Augusto; Maggi, Stefano; Mattei, Mauro; Osti, Mattia Falchetto; Pellegrini, Patrizia; Speranza, Annarita; Stanzani, Gianluca; Vitale, Valeria; Pizzuti, Antonio; Torrisi, Maria Rosaria; Piane, Maria. - In: JOURNAL OF CLINICAL MEDICINE. - ISSN 2077-0383. - 9:9(2020). [10.3390/jcm9093003]

Beyond BRCA1 and BRCA2: deleterious variants in DNA repair pathway genes in italian families with breast/ovarian and pancreatic cancers

Germani, Aldo
Co-primo
;
Petrucci, Simona
Co-primo
;
De Marchis, Laura;Libi, Fabio;Amanti, Claudio;Bonifacino, Adriana;Capalbo, Carlo;Lombardi, Augusto;Maggi, Stefano;Osti, Mattia Falchetto;Pellegrini, Patrizia;Speranza, Annarita;Vitale, Valeria;Pizzuti, Antonio;Torrisi, Maria Rosaria
Penultimo
;
Piane, Maria
Ultimo
2020

Abstract

The 5-10% of breast/ovarian cancers (BC and OC) are inherited, and germline pathogenic (P) variants in DNA damage repair (DDR) genes BRCA1 and BRCA2 explain only 10-20% of these cases. Currently, new DDR genes have been related to BC/OC and to pancreatic (PC) cancers, but the prevalence of P variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogenic variants in DDR pathway genes other than BRCA1/2 and to correlate the genotype with the clinical phenotype. A cohort of 113 non-BRCA patients was analyzed by next-generation sequencing using a multigene panel of the 25 DDR pathways genes related to BC, OC, and PC. We found 43 unique variants in 18 of 25 analyzed genes, 14 classified as P/likely pathogenic (LP) and 28 as variants of uncertain significance (VUS). Deleterious variants were identified in 14% of index cases, whereas a VUS was identified in 20% of the probands. We observed a high incidence of deleterious variants in the CHEK2 gene, and a new pathogenic variant was detected in the RECQL gene. These results supported the clinical utility of multigene panel to increase the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches.
2020
DNA repair genes; gene panel; hereditary breast/ovarian cancer; next-generation sequencing; pancreatic cancer
01 Pubblicazione su rivista::01a Articolo in rivista
Beyond BRCA1 and BRCA2: deleterious variants in DNA repair pathway genes in italian families with breast/ovarian and pancreatic cancers / Germani, Aldo; Petrucci, Simona; De Marchis, Laura; Libi, Fabio; Savio, Camilla; Amanti, Claudio; Bonifacino, Adriana; Campanella, Barbara; Capalbo, Carlo; Lombardi, Augusto; Maggi, Stefano; Mattei, Mauro; Osti, Mattia Falchetto; Pellegrini, Patrizia; Speranza, Annarita; Stanzani, Gianluca; Vitale, Valeria; Pizzuti, Antonio; Torrisi, Maria Rosaria; Piane, Maria. - In: JOURNAL OF CLINICAL MEDICINE. - ISSN 2077-0383. - 9:9(2020). [10.3390/jcm9093003]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1442555
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