Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene

Tavera-Tapia, Alejandra; Pérez-Cabornero, Lucía; Macías, José A.; Ceballos, Maria I; Roncador, Giovanna; Hoya, Miguel de la; Barroso, Alicia; Felipe-Ponce, Vanesa; Serrano‐Blanch, Raquel; Hinojo, Carmen Aisha Butrón; Miramar-Gallart, María Dolores; Urioste, Miguel; Caldés, Trinidad; Santillan-Garzón, S.; Benı́tez, Javier; Osorio, Ana

doi:10.1007/s10549-016-4058-7

Cited by 18 publications

(13 citation statements)

References 17 publications

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“…This mutation was previously reported in an Ataxia-Telangiectasia family [17]. In addition, other cancer types in this family have been associated with ATM mutations such as thyroid [18], ovarian [16] and breast tumours [15].…”

Section: Discussionsupporting

confidence: 64%

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

Velázquez

Leeneer

Esteban-Cardeñosa

et al. 2020

Cancers

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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).

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Section: Discussionsupporting

confidence: 64%

“…ATM had been known to be linked to breast cancer predisposition in BRCA-negative families [14,15]. Furthermore, ATM mutations have been found in ovarian cancer [16].…”

Section: Discussionmentioning

confidence: 99%

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

Velázquez

Leeneer

Esteban-Cardeñosa

et al. 2020

Cancers

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“…With the aim to explore new approaches, we have performed WES in two BRCAX families that were compatible with the presence of a recessive high‐risk gene, however, we have not found any suitable candidate under this model. Interestingly, though, we found heterozygous deleterious variants in the already known moderate‐risk susceptibility gene ATM (Tavera‐Tapia et al, ) and in what we present as a novel candidate gene, RECQL5 .…”

Section: Introductionmentioning

confidence: 54%

RECQL5: Another DNA helicase potentially involved in hereditary breast cancer susceptibility

et al. 2019

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There is still around 50% of the familial breast cancer (BC) cases with an undefined genetic cause, here we have used next-generation sequencing (NGS) technology to identify new BC susceptibility genes. This approach has led to the identification of RECQL5, a member of RECQL-helicases family, as a new BC susceptibility candidate, which deserves further study. We have used a combination of whole exome sequencing in a family negative for mutations in BRCA1/2 throughout (BRCAX), in which we found a probably deleterious variant in RECQL5, and targeted NGS of the complete coding regions and exon-intron boundaries of the candidate gene in 699 BC Spanish BRCAX families and 665 controls. Functional characterization and in silico inference of pathogenicity were performed to evaluate the deleterious effect of detected variants. We found at least seven deleterious or likely deleterious variants among the cases and only one in controls. These results prompt us to propose RECQL5 as a gene that would be worth to analyze in larger studies to explore its possible implication in BC susceptibility. K E Y W O R D S breast cancer, germline pathogenic variant, RECQL5, whole exome sequencing Human Mutation. 2019;40:566-577. wileyonlinelibrary.com/journal/humu 566 |

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“…Results showed that enrichment of multiple defects in DDR genes are related to BC predisposition in those high-risk families, opening the possibility of further studies. Tavera-Tapia et al [52] analyzed the exome of a non-BRCA Spanish family and found a novel germline ATM mutation (c.5441delT; p.Leu1814Trpfs*14). In the same study, the ATM gene was further analyzed in a cohort of 392 non-BRCA cancer families and showed 1.78% prevalence of mutations in non-BRCA familial BC/OC and a 1.94% frequency in BC, suggesting that testing of this gene in Spanish non-BRCA families should occur.…”

Section: Wes Approach In Familial Non-brca Breast/ovarian Cancermentioning

confidence: 99%

Applications of Next Generation Sequencing to the Analysis of Familial Breast/Ovarian Cancer

et al. 2020

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Next generation sequencing (NGS) provides a powerful tool in the field of medical genetics, allowing one to perform multi-gene analysis and to sequence entire exomes (WES), transcriptomes or genomes (WGS). The generated high-throughput data are particularly suitable for enhancing the understanding of the genetic bases of complex, multi-gene diseases, such as cancer. Among the various types of tumors, those with a familial predisposition are of great interest for the isolation of novel genes or gene variants, detectable at the germline level and involved in cancer pathogenesis. The identification of novel genetic factors would have great translational value, helping clinicians in defining risk and prevention strategies. In this regard, it is known that the majority of breast/ovarian cases with familial predisposition, lacking variants in the highly penetrant BRCA1 and BRCA2 genes (non-BRCA), remains unexplained, although several less penetrant genes (e.g., ATM, PALB2) have been identified. In this scenario, NGS technologies offer a powerful tool for the discovery of novel factors involved in familial breast/ovarian cancer. In this review, we summarize and discuss the state of the art applications of NGS gene panels, WES and WGS in the context of familial breast/ovarian cancer.

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Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene

Abstract: ATM mutation prevalence in Spanish population highlights the importance of considering ATM pathogenic variants linked to breast cancer susceptibility.

Cited by 18 publications

References 17 publications

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

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

RECQL5: Another DNA helicase potentially involved in hereditary breast cancer susceptibility

Applications of Next Generation Sequencing to the Analysis of Familial Breast/Ovarian Cancer

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