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Open AccessArticle

Germline Genetic Findings Which May Impact Therapeutic Decisions in Families with a Presumed Predisposition for Hereditary Breast and Ovarian Cancer

1
Cancer Genetics Group, Instituto de Biología y Genética Molecular (UVa-CSIC), 47003 Valladolid, Spain
2
Center for Medical Genetics, Ghent University Hospital, and Cancer Research Institute Ghent (CRIG), Ghent University, 9000 Ghent, Belgium
3
Unit of Genetic Counseling in Cancer, Complejo Hospitalario de Burgos, 09006 Burgos, Spain
4
Unit of Genetic Counseling in Cancer, Hospital Universitario Rio Hortega, 47012 Valladolid, Spain
*
Author to whom correspondence should be addressed.
Present Adress: IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, 34298 Montpellier, France.
Permanent Adress: Fundaciόn Pública Galega de Medicina Xenόmica-SERGAS, 15782 Santiago de Compostela, Spain.
Cancers 2020, 12(8), 2151; https://doi.org/10.3390/cancers12082151
Received: 24 June 2020 / Revised: 29 July 2020 / Accepted: 1 August 2020 / Published: 3 August 2020
(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)
In this study, we aim to gain insight in the germline mutation spectrum of ATM, BARD1, BRIP1, ERCC4, PALB2, RAD51C and RAD51D in breast and ovarian cancer families from Spain. We have selected 180 index cases in whom a germline mutation in BRCA1 and BRCA2 was previously ruled out. The importance of disease-causing variants in these genes lies in the fact that they may have possible therapeutic implications according to clinical guidelines. All variants were assessed by combined annotation dependent depletion (CADD) for scoring their deleteriousness. In addition, we used the cancer genome interpreter to explore the implications of some variants in drug response. Finally, we compiled and evaluated the family history to assess whether carrying a pathogenic mutation was associated with age at diagnosis, tumour diversity of the pedigree and total number of cancer cases in the family. Eight unequivocal pathogenic mutations were found and another fourteen were prioritized as possible causal variants. Some of these molecular results could contribute to cancer diagnosis, treatment selection and prevention. We found a statistically significant association between tumour diversity in the family and carrying a variant with a high score predicting pathogenicity (p = 0.0003). View Full-Text
Keywords: HBOC; genetic testing; variant prioritisation; therapeutic selection; family history; clinical guidelines HBOC; genetic testing; variant prioritisation; therapeutic selection; family history; clinical guidelines
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Velázquez, C.; K., D.L.; Esteban-Cardeñosa, E.M.; Avila Cobos, F.; Lastra, E.; Abella, L.E.; de la Cruz, V.; Lobatón, C.D.; Claes, K.B.; Durán, M.; Infante, M. Germline Genetic Findings Which May Impact Therapeutic Decisions in Families with a Presumed Predisposition for Hereditary Breast and Ovarian Cancer. Cancers 2020, 12, 2151.

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