Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers

被引:11
作者
Germani, Aldo [1 ,2 ]
Petrucci, Simona [1 ,2 ]
De Marchis, Laura [3 ,4 ]
Libi, Fabio [2 ]
Savio, Camilla [2 ]
Amanti, Claudio [2 ,5 ]
Bonifacino, Adriana [2 ,5 ]
Campanella, Barbara [6 ]
Capalbo, Carlo [2 ,7 ]
Lombardi, Augusto [2 ,5 ]
Maggi, Stefano [2 ,5 ]
Mattei, Mauro [2 ]
Osti, Mattia Falchetto [2 ,6 ]
Pellegrini, Patrizia [1 ,2 ]
Speranza, Annarita [2 ]
Stanzani, Gianluca [2 ]
Vitale, Valeria [2 ]
Pizzuti, Antonio [8 ,9 ]
Torrisi, Maria Rosaria [1 ,2 ]
Piane, Maria [1 ,2 ]
机构
[1] Sapienza Univ Rome, Dept Clin & Mol Med, I-00100 Rome, Italy
[2] St Andrea Univ Hosp, I-00100 Rome, Italy
[3] Sapienza Univ Rome, Dept Radiol Anatomopathol, Oncol Sci, I-00100 Rome, Italy
[4] Umberto I Univ Hosp, I-00100 Rome, Italy
[5] Sapienza Univ Rome, Dept Med & Surg Sci & Translat Med, I-00100 Rome, Italy
[6] Sapienza Univ Rome, St Andrea Hosp, Unit Radiat Oncol, I-00100 Rome, Italy
[7] Sapienza Univ Rome, Dept Mol Med, I-00100 Rome, Italy
[8] Sapienza Univ Rome, Dept Expt Med, I-00100 Rome, Italy
[9] IRCCS Casa Sollievo Sofferenza, Clin Genom Unit, I-71013 San Giovanni Rotondo, Italy
关键词
hereditary breast; ovarian cancer; pancreatic cancer; next-generation sequencing; gene panel; DNA repair genes; HEREDITARY BREAST-CANCER; ATAXIA-TELANGIECTASIA; GERMLINE MUTATIONS; GASTRIC-CANCER; SUSCEPTIBILITY GENES; FUNCTIONAL-ANALYSIS; RISK; CHEK2; ATM; DAMAGE;
D O I
10.3390/jcm9093003
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
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页码:1 / 22
页数:22
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