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Genetic Variants Associated with Breast and Ovarian Cancer Risk

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Informatics and Big Data".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 42867

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Dr. Eladio A. Velasco

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Guest Editor

Splicing and Genetic Susceptibility to Cancer. Instituto de Biología y Genética Molecular. Consejo Superior de Investigaciones Científicas. Valladolid, Spain
Interests: breast/ovarian cancer genes; variants of uncertain clinical significance; VUS; RNA splicing; aberrant splicing; alternative splicing; minigenes; atypical exons; splicing regulation

Dr. Maaike P. G. Vreeswijk

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Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
Interests: functional analysis of genetic variants; variants of uncertain clinical significance; hereditary breast and ovarian cancer; BRCA1; BRCA2; PALB2; RNA splicing; homologous recombination

Dr. Miguel De la Hoya

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Molecular Oncology Laboratory. Fundación Investigación Biomédica del Hospital Clínico San Carlos. Hospital Clínico San Carlos, Madrid, Spain
Interests: BRCA1/2; PALB2; CHEK2; ATM; RAD51C/D; BRIP1; BARD1; RNA splicing; standarizing variants classification and reporting
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Dear Colleagues,

Hereditary breast and ovarian cancer is a highly heterogeneous genetic disease with more than 20 known or proposed susceptibility genes. The advent of next-generation sequencing has opened up the opportunity for testing many breast and/or ovarian cancer genes and the detection of thousands of variants. However, a significant proportion of them are variants of unknown clinical significance (VUS) with an undefined cancer risk. The elucidation of their role in carcinogenesis will guide clinical management and thus contribute to cancer prevention and the development of tailored therapies. Variant classification has significantly improved through the research efforts of multidisciplinary international consortia (such as the Evidence-based Network for the Interpretation of Mutant Alleles (ENIGMA), or ClinGen Variant Curation Expert Panels) focused on developing and applying methods to identify and report clinically actionable variants in breast–ovarian cancer genes. Clinical and epidemiological data of patients in combination with functional studies addressing the impact on RNA splicing and protein function provide key information for the clinical interpretation of variants. We therefore welcome articles on the clinical interpretation of genetic variants (particularly VUS) in susceptibility genes via genetic, multifactorial approaches or their impact on protein function, RNA splicing or other gene-expression mechanisms. We will also consider reports on the mutation screening of multigene panel testing in important cohorts of breast/ovarian cancer patients. Articles developing gene specific ACMG standards and guidelines are also welcome.

Dr. Eladio A. Velasco
Dr. Maaike P. G. Vreeswijk
Dr. Miguel De la Hoya
Guest Editors

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Keywords

breast/ovarian cancer susceptibility genes
VUS
protein function
RNA splicing
multifactorial likelihood analysis
multigene panel sequencing

Published Papers (12 papers)

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Research

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17 pages, 1935 KiB

Open AccessArticle

Role of Splicing Regulatory Elements and In Silico Tools Usage in the Identification of Deep Intronic Splicing Variants in Hereditary Breast/Ovarian Cancer Genes

by Alejandro Moles-Fernández, Joanna Domènech-Vivó, Anna Tenés, Judith Balmaña, Orland Diez and Sara Gutiérrez-Enríquez

Cancers 2021, 13(13), 3341; https://doi.org/10.3390/cancers13133341 - 03 Jul 2021

Cited by 15 | Viewed by 4370

Abstract

The contribution of deep intronic splice-altering variants to hereditary breast and ovarian cancer (HBOC) is unknown. Current computational in silico tools to predict spliceogenic variants leading to pseudoexons have limited efficiency. We assessed the performance of the SpliceAI tool combined with ESRseq scores to identify spliceogenic deep intronic variants by affecting cryptic sites or splicing regulatory elements (SREs) using literature and experimental datasets. Our results with 233 published deep intronic variants showed that SpliceAI, with a 0.05 threshold, predicts spliceogenic deep intronic variants affecting cryptic splice sites, but is less effective in detecting those affecting SREs. Next, we characterized the SRE profiles using ESRseq, showing that pseudoexons are significantly enriched in SRE-enhancers compared to adjacent intronic regions. Although the combination of SpliceAI with ESRseq scores (considering ∆ESRseq and SRE landscape) showed higher sensitivity, the global performance did not improve because of the higher number of false positives. The combination of both tools was tested in a tumor RNA dataset with 207 intronic variants disrupting splicing, showing a sensitivity of 86%. Following the pipeline, five spliceogenic deep intronic variants were experimentally identified from 33 variants in HBOC genes. Overall, our results provide a framework to detect deep intronic variants disrupting splicing. Full article

(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)

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17 pages, 4252 KiB

Open AccessArticle

5′ Region Large Genomic Rearrangements in the BRCA1 Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints

by Sandrine M. Caputo, Dominique Telly, Adrien Briaux, Julie Sesen, Maurizio Ceppi, Françoise Bonnet, Violaine Bourdon, Florence Coulet, Laurent Castera, Capucine Delnatte, Agnès Hardouin, Sylvie Mazoyer, Inès Schultz, Nicolas Sevenet, Nancy Uhrhammer, Céline Bonnet, Anne-Françoise Tilkin-Mariamé, Claude Houdayer, Virginie Moncoutier, Catherine Andrieu, French COVAR Group Collaborators, Ivan Bièche, Marc-Henri Stern, Dominique Stoppa-Lyonnet, Rosette Lidereau, Christine Toulas and Etienne Rouleau Show full author list Hide full author list

Cancers 2021, 13(13), 3171; https://doi.org/10.3390/cancers13133171 - 25 Jun 2021

Cited by 5 | Viewed by 4406

Abstract

Background: Large genomic rearrangements (LGR) in BRCA1 consisting of deletions/duplications of one or several exons have been found throughout the gene with a large proportion occurring in the 5′ region from the promoter to exon 2. The aim of this study was to better characterize those LGR in French high-risk breast/ovarian cancer families. Methods: DNA from 20 families with one apparent duplication and nine deletions was analyzed with a dedicated comparative genomic hybridization (CGH) array, high-resolution BRCA1 Genomic Morse Codes analysis and Sanger sequencing. Results: The apparent duplication was in fact a tandem triplication of exons 1 and 2 and part of intron 2 of BRCA1, fully characterized here for the first time. We calculated a causality score with the multifactorial model from data obtained from six families, classifying this variant as benign. Among the nine deletions detected in this region, eight have never been identified. The breakpoints fell in six recurrent regions and could confirm some specific conformation of the chromatin. Conclusions: Taken together, our results firmly establish that the BRCA1 5′ region is a frequent site of different LGRs and highlight the importance of the segmental duplication and Alu sequences, particularly the very high homologous region, in the mechanism of a recombination event. This also confirmed that those events are not systematically deleterious. Full article

(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)

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20 pages, 1808 KiB

Open AccessArticle

RAD51D Aberrant Splicing in Breast Cancer: Identification of Splicing Regulatory Elements and Minigene-Based Evaluation of 53 DNA Variants

by Elena Bueno-Martínez, Lara Sanoguera-Miralles, Alberto Valenzuela-Palomo, Víctor Lorca, Alicia Gómez-Sanz, Sara Carvalho, Jamie Allen, Mar Infante, Pedro Pérez-Segura, Conxi Lázaro, Douglas F. Easton, Peter Devilee, Maaike P. G. Vreeswijk, Miguel de la Hoya and Eladio A. Velasco

Cancers 2021, 13(11), 2845; https://doi.org/10.3390/cancers13112845 - 07 Jun 2021

Cited by 10 | Viewed by 3228

Abstract

RAD51D loss-of-function variants increase lifetime risk of breast and ovarian cancer. Splicing disruption is a frequent pathogenic mechanism associated with variants in susceptibility genes. Herein, we have assessed the splicing and clinical impact of splice-site and exonic splicing enhancer (ESE) variants identified through the study of ~113,000 women of the BRIDGES cohort. A RAD51D minigene with exons 2–9 was constructed in splicing vector pSAD. Eleven BRIDGES splice-site variants (selected by MaxEntScan) were introduced into the minigene by site-directed mutagenesis and tested in MCF-7 cells. The 11 variants disrupted splicing, collectively generating 25 different aberrant transcripts. All variants but one produced negligible levels (<3.4%) of the full-length (FL) transcript. In addition, ESE elements of the alternative exon 3 were mapped by testing four overlapping exonic microdeletions (≥30-bp), revealing an ESE-rich interval (c.202_235del) with critical sequences for exon 3 recognition that might have been affected by germline variants. Next, 26 BRIDGES variants and 16 artificial exon 3 single-nucleotide substitutions were also assayed. Thirty variants impaired splicing with variable amounts (0–65.1%) of the FL transcript, although only c.202G>A demonstrated a complete aberrant splicing pattern without the FL transcript. On the other hand, c.214T>C increased efficiency of exon 3 recognition, so only the FL transcript was detected (100%). In conclusion, 41 RAD51D spliceogenic variants (28 of which were from the BRIDGES cohort) were identified by minigene assays. We show that minigene-based mapping of ESEs is a powerful approach for identifying ESE hotspots and ESE-disrupting variants. Finally, we have classified nine variants as likely pathogenic according to ACMG/AMP-based guidelines, highlighting the complex relationship between splicing alterations and variant interpretation. Full article

(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)

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13 pages, 265 KiB

Open AccessArticle

Study of the Genetic Variants in BRCA1/2 and Non-BRCA Genes in a Population-Based Cohort of 2155 Breast/Ovary Cancer Patients, Including 443 Triple-Negative Breast Cancer Patients, in Argentina

by Angela R. Solano, Pablo G. Mele, Fernanda S. Jalil, Natalia C. Liria, Ernesto J. Podesta and Leandro G. Gutiérrez

Cancers 2021, 13(11), 2711; https://doi.org/10.3390/cancers13112711 - 31 May 2021

Cited by 7 | Viewed by 2387

Abstract

Gene/s sequencing in hereditary breast/ovary cancer (HBOC) in routine diagnosis is challenged by the analysis of panels. We aim to report a retrospective analysis of BRCA1/2 and non-BRCA gene sequencing in patients with breast/ovary cancer (BOC), including triple-negative breast cancer (TNBC), in our population. In total 2155 BOC patients (1900 analyzed in BRCA1/2 and 255 by multigenic panels) gave 372 (17.2.6%) and 107 (24.1%) likely pathogenic/pathogenic variants (LPVs/PVs), including BRCA and non-BRCA genes, for the total and TNBC patients, respectively. When BOC was present in the same proband, a 51.3% rate was found for LPVs/PVs in BRCA1/2. Most of the LPVs/PVs in the panels were in BRCA1/2; non-BRCA gene LPVs/PVs were in CDH1, CHEK2, CDKN2A, MUTYH, NBN, RAD51D, and TP53. TNBC is associated with BRCA1/2 at a higher rate than the rest of the breast cancer types. The more prevalent PVs in BRCA1/2 genes (mostly in BRCA1) do not rule out the importance to panels of genes, although they are certainly far from shedding light on the gap of the 85% predicted linkage association of BOC with BRCA1/2 and are still not elucidated. Full article

(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)

15 pages, 1903 KiB

Open AccessArticle

A Population-Based Analysis of BRCA1/2 Genes and Associated Breast and Ovarian Cancer Risk in Korean Patients: A Multicenter Cohort Study

by Kyung-Sun Park, Woochang Lee, Moon-Woo Seong, Sun-Young Kong, Kyung-A Lee, Jung-Sook Ha, Eun-Hae Cho, Sung-Hee Han, Inho Park and Jong-Won Kim

Cancers 2021, 13(9), 2192; https://doi.org/10.3390/cancers13092192 - 02 May 2021

Cited by 6 | Viewed by 3135

Abstract

In this study, we performed a comprehensive analysis of BRCA1/2 variants and associated cancer risk in Korean patients considering two aspects: variants of uncertain significance (VUS) and pathogenic or likely pathogenic variants (PLPVs) in BRCA1 and BRCA2. This study included 5433 Korean participants who were tested for BRCA1/2 genes. The BRCA1/2 variants were classified following the standards/guidelines for interpretation of genetic variants and using a multifactorial probability-based approach. In Korea, 15.8% of participants had BRCA1 or BRCA2 PLPVs. To estimate the additional sample numbers needed to resolve unclassified status, we applied a simulation analysis. The simulation study for VUS showed that the smaller the number of samples, the more the posterior probability was affected by the prior probability; in addition, more samples for BRCA2 VUS than those of BRCA1 VUS were required to resolve the unclassified status, and the presence of clinical information associated with their VUS was an important factor. The cumulative lifetime breast cancer risk was 59.1% (95% CI: 44.1–73.6%) for BRCA1 and 58.3% (95% CI: 43.2–73.0%) for BRCA2 carriers. The cumulative lifetime ovarian cancer risk was estimated to be 36.9% (95% CI: 23.4–53.9%) for BRCA1 and 14.9% (95% CI: 7.4–28.5%) for BRCA2 carriers. Full article

(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)

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11 pages, 501 KiB

Open AccessArticle

Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in CHEK2: Findings from the Australian Breast Cancer Family Registry

by Tú Nguyen-Dumont, James G. Dowty, Jason A. Steen, Anne-Laure Renault, Fleur Hammet, Maryam Mahmoodi, Derrick Theys, Amanda Rewse, Helen Tsimiklis, Ingrid M. Winship, Graham G. Giles, Roger L. Milne, John L. Hopper and Melissa C. Southey

Cancers 2021, 13(6), 1378; https://doi.org/10.3390/cancers13061378 - 18 Mar 2021

Cited by 10 | Viewed by 2395

Abstract

Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant CHEK2 c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic CHEK2 variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5–9.5) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02–11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5–12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11–30%) and 33% (95% CI 21–48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2. Full article

(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)

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12 pages, 2015 KiB

Open AccessArticle

Performance of In Silico Prediction Tools for the Detection of Germline Copy Number Variations in Cancer Predisposition Genes in 4208 Female Index Patients with Familial Breast and Ovarian Cancer

by Louisa Lepkes, Mohamad Kayali, Britta Blümcke, Jonas Weber, Malwina Suszynska, Sandra Schmidt, Julika Borde, Katarzyna Klonowska, Barbara Wappenschmidt, Jan Hauke, Piotr Kozlowski, Rita K. Schmutzler, Eric Hahnen and Corinna Ernst

Cancers 2021, 13(1), 118; https://doi.org/10.3390/cancers13010118 - 01 Jan 2021

Cited by 7 | Viewed by 3534

Abstract

The identification of germline copy number variants (CNVs) by targeted next-generation sequencing (NGS) frequently relies on in silico CNV prediction tools with unknown sensitivities. We investigated the performances of four in silico CNV prediction tools, including one commercial (Sophia Genetics DDM) and three non-commercial tools (ExomeDepth, GATK gCNV, panelcn.MOPS) in 17 cancer predisposition genes in 4208 female index patients with familial breast and/or ovarian cancer (BC/OC). CNV predictions were verified via multiplex ligation-dependent probe amplification. We identified 77 CNVs in 76 out of 4208 patients (1.81%); 33 CNVs were identified in genes other than BRCA1/2, mostly in ATM, CHEK2, and RAD51C and less frequently in BARD1, MLH1, MSH2, PALB2, PMS2, RAD51D, and TP53. The Sophia Genetics DDM software showed the highest sensitivity; six CNVs were missed by at least one of the non-commercial tools. The positive predictive values ranged from 5.9% (74/1249) for panelcn.MOPS to 79.1% (72/91) for ExomeDepth. Verification of in silico predicted CNVs is required due to high frequencies of false positive predictions, particularly affecting target regions at the extremes of the GC content or target length distributions. CNV detection should not be restricted to BRCA1/2 due to the relevant proportion of CNVs in further BC/OC predisposition genes. Full article

(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)

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21 pages, 1857 KiB

Open AccessArticle

Comprehensive Functional Characterization and Clinical Interpretation of 20 Splice-Site Variants of the RAD51C Gene

by Lara Sanoguera-Miralles, Alberto Valenzuela-Palomo, Elena Bueno-Martínez, Patricia Llovet, Beatriz Díez-Gómez, María José Caloca, Pedro Pérez-Segura, Eugenia Fraile-Bethencourt, Marta Colmena, Sara Carvalho, Jamie Allen, Douglas F. Easton, Peter Devilee, Maaike P. G. Vreeswijk, Miguel de la Hoya and Eladio A. Velasco

Cancers 2020, 12(12), 3771; https://doi.org/10.3390/cancers12123771 - 15 Dec 2020

Cited by 11 | Viewed by 4109

Abstract

Hereditary breast and/or ovarian cancer is a highly heterogeneous disease with more than 10 known disease-associated genes. In the framework of the BRIDGES project (Breast Cancer Risk after Diagnostic Gene Sequencing), the RAD51C gene has been sequenced in 60,466 breast cancer patients and 53,461 controls. We aimed at functionally characterizing all the identified genetic variants that are predicted to disrupt the splicing process. Forty RAD51C variants of the intron-exon boundaries were bioinformatically analyzed, 20 of which were selected for splicing functional assays. To test them, a splicing reporter minigene with exons 2 to 8 was designed and constructed. This minigene generated a full-length transcript of the expected size (1062 nucleotides), sequence, and structure (Vector exon V1- RAD51C exons_2-8- Vector exon V2). The 20 candidate variants were genetically engineered into the wild type minigene and functionally assayed in MCF-7 cells. Nineteen variants (95%) impaired splicing, while 18 of them produced severe splicing anomalies. At least 35 transcripts were generated by the mutant minigenes: 16 protein-truncating, 6 in-frame, and 13 minor uncharacterized isoforms. According to ACMG/AMP-based standards, 15 variants could be classified as pathogenic or likely pathogenic variants: c.404G > A, c.405-6T > A, c.571 + 4A > G, c.571 + 5G > A, c.572-1G > T, c.705G > T, c.706-2A > C, c.706-2A > G, c.837 + 2T > C, c.905-3C > G, c.905-2A > C, c.905-2_905-1del, c.965 + 5G > A, c.1026 + 5_1026 + 7del, and c.1026 + 5G > T. Full article

(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)

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17 pages, 1604 KiB

Open AccessArticle

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

by Carolina Velázquez, De Leeneer K., Eva M. Esteban-Cardeñosa, Francisco Avila Cobos, Enrique Lastra, Luis E. Abella, Virginia de la Cruz, Carmen D. Lobatón, Kathleen B. Claes, Mercedes Durán and Mar Infante

Cancers 2020, 12(8), 2151; https://doi.org/10.3390/cancers12082151 - 03 Aug 2020

Cited by 4 | Viewed by 3635

Abstract

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). Full article

(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)

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Review

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10 pages, 889 KiB

Open AccessReview

Missense Variants of Uncertain Significance: A Powerful Genetic Tool for Function Discovery with Clinical Implications

by Gaetana Sessa, Åsa Ehlén, Catharina von Nicolai and Aura Carreira

Cancers 2021, 13(15), 3719; https://doi.org/10.3390/cancers13153719 - 23 Jul 2021

Cited by 2 | Viewed by 2284

Abstract

The breast cancer susceptibility gene BRCA2 encodes a multifunctional protein required for the accurate repair of DNA double-strand breaks and replicative DNA lesions. In addition, BRCA2 exhibits emerging important roles in mitosis. As a result, mutations in BRCA2 may affect chromosomal integrity in multiple ways. However, many of the BRCA2 mutations found in breast cancer patients and their families are single amino acid substitutions, sometimes unique, and their relevance in cancer risk remains difficult to assess. In this review, we focus on three recent reports that investigated variants of uncertain significance (VUS) located in the N-terminal region of BRCA2. In this framework, we make the case for how the functional evaluation of VUS can be a powerful genetic tool not only for revealing novel aspects of BRCA2 function but also for re-evaluating cancer risk. We argue that other functions beyond homologous recombination deficiency or “BRCAness” may influence cancer risk. We hope our discussion will help the reader appreciate the potential of these functional studies in the prevention and diagnostics of inherited breast and ovarian cancer. Moreover, these novel aspects in BRCA2 function might help find new therapeutic strategies. Full article

(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)

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24 pages, 826 KiB

Open AccessReview

Genetic Landscape of Male Breast Cancer

by Fernando Augusto Batista Campos, Etienne Rouleau, Giovana Tardin Torrezan, Dirce Maria Carraro, José Claudio Casali da Rocha, Higor Kassouf Mantovani, Leonardo Roberto da Silva, Cynthia Aparecida Bueno de Toledo Osório, Solange Moraes Sanches, Sandrine M. Caputo and Elizabeth Santana dos Santos

Cancers 2021, 13(14), 3535; https://doi.org/10.3390/cancers13143535 - 15 Jul 2021

Cited by 19 | Viewed by 4812

Abstract

Male breast cancer (MBC) is now considered molecularly different from female breast cancer (FBC). Evidence from studies indicates that common genetic and epigenetic features of FBC are not shared with those diagnosed in men. Genetic predisposition is likely to play a significant role in the tumorigenesis of this rare disease. Inherited germline variants in BRCA1 and BRCA2 account for around 2% and 10% of MBC cases, respectively, and the lifetime risk of breast cancer for men harboring BRCA1 and BRCA2 mutations is 1.2% and 6.8%. As for FBC, pathogenic mutations in other breast cancer genes have also been recently associated with an increased risk of MBC, such as PALB2 and CHEK2 mutations. However, while multigene germline panels have been extensively performed for BC female patients, the rarity of MBC has resulted in limited data to allow the understanding of the magnitude of risk and the contribution of recently identified moderate penetrance genes of FBC for MBC predisposition. This review gathers available data about the germline genetic landscape of men affected by breast cancer, estimated risk associated with these genetic variants, and current guidelines for clinical management. Full article

(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)

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14 pages, 302 KiB

Open AccessReview

Germline TP53 Testing in Breast Cancers: Why, When and How?

by D. Gareth Evans, Emma R. Woodward, Svetlana Bajalica-Lagercrantz, Carla Oliveira and Thierry Frebourg

Cancers 2020, 12(12), 3762; https://doi.org/10.3390/cancers12123762 - 14 Dec 2020

Cited by 16 | Viewed by 3158

Abstract

Germline TP53 variants represent a main genetic cause of breast cancers before 31 years of age. Development of cancer multi-gene panels has resulted in an exponential increase of germline TP53 testing in breast cancer patients. Interpretation of TP53 variants, which are mostly missense, is complex and requires excluding clonal haematopoiesis and circulating tumour DNA. In breast cancer patients harbouring germline disease-causing TP53 variants, radiotherapy contributing to the development of subsequent tumours should be, if possible, avoided and, within families, annual follow-up including whole-body MRI should be offered to carriers. We consider that, in breast cancer patients, germline TP53 testing should be performed before treatment and offered systematically only to patients with: (i) invasive breast carcinoma or ductal carcinoma in situ (DCIS) before 31; or (ii) bilateral or multifocal or HER2+ invasive breast carcinoma/DCIS or phyllode tumour before 36; or (iii) invasive breast carcinoma before 46 and another TP53 core tumour (breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumour, adrenocortical carcinoma); or (iv) invasive breast carcinoma before 46 and one first- or second-degree relative with a TP53 core tumour before 56. In contrast, women presenting with breast cancer after 46, without suggestive personal or familial history, should not be tested for TP53. Full article

(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)

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