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30 pages, 944 KiB

Open AccessArticle

Combining Breast Cancer Risk Prediction Models

by Zoe Guan, Theodore Huang, Anne Marie McCarthy, Kevin Hughes, Alan Semine, Hajime Uno, Lorenzo Trippa, Giovanni Parmigiani and Danielle Braun

Cancers 2023, 15(4), 1090; https://doi.org/10.3390/cancers15041090 - 8 Feb 2023

Cited by 5 | Viewed by 3472

Abstract

Accurate risk stratification is key to reducing cancer morbidity through targeted screening and preventative interventions. Multiple breast cancer risk prediction models are used in clinical practice, and often provide a range of different predictions for the same patient. Integrating information from different models [...] Read more.

Accurate risk stratification is key to reducing cancer morbidity through targeted screening and preventative interventions. Multiple breast cancer risk prediction models are used in clinical practice, and often provide a range of different predictions for the same patient. Integrating information from different models may improve the accuracy of predictions, which would be valuable for both clinicians and patients. BRCAPRO is a widely used model that predicts breast cancer risk based on detailed family history information. A major limitation of this model is that it does not consider non-genetic risk factors. To address this limitation, we expand BRCAPRO by combining it with another popular existing model, BCRAT (i.e., Gail), which uses a largely complementary set of risk factors, most of them non-genetic. We consider two approaches for combining BRCAPRO and BCRAT: (1) modifying the penetrance (age-specific probability of developing cancer given genotype) functions in BRCAPRO using relative hazard estimates from BCRAT, and (2) training an ensemble model that takes BRCAPRO and BCRAT predictions as input. Using both simulated data and data from Newton-Wellesley Hospital and the Cancer Genetics Network, we show that the combination models are able to achieve performance gains over both BRCAPRO and BCRAT. In the Cancer Genetics Network cohort, we show that the proposed BRCAPRO + BCRAT penetrance modification model performs comparably to IBIS, an existing model that combines detailed family history with non-genetic risk factors. Full article

(This article belongs to the Special Issue Hereditary Breast Cancer in Men and Women: Genetic Mutations, Cancer Risk and Treatment)

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11 pages, 292 KiB

Open AccessArticle

Pathogenic Variant Spectrum in Breast Cancer Risk Genes in Finnish Patients

by Anna K. Nurmi, Maija Suvanto, Joe Dennis, Kristiina Aittomäki, Carl Blomqvist and Heli Nevanlinna

Cancers 2022, 14(24), 6158; https://doi.org/10.3390/cancers14246158 - 14 Dec 2022

Cited by 3 | Viewed by 2306

Abstract

Recurrent pathogenic variants have been detected in several breast and ovarian cancer (BC/OC) risk genes in the Finnish population. We conducted a gene-panel sequencing and copy number variant (CNV) analysis to define a more comprehensive spectrum of pathogenic variants in BRCA1, BRCA2 [...] Read more.

Recurrent pathogenic variants have been detected in several breast and ovarian cancer (BC/OC) risk genes in the Finnish population. We conducted a gene-panel sequencing and copy number variant (CNV) analysis to define a more comprehensive spectrum of pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, ATM, BARD1, RAD51C, RAD51D, BRIP1, and FANCM genes in Finnish BC patients. The combined frequency of pathogenic variants in the BRCA1/2 genes was 1.8% in 1356 unselected patients, whereas variants in the other genes were detected altogether in 8.3% of 1356 unselected patients and in 12.9% of 699 familial patients. CNVs were detected in 0.3% of both 1137 unselected and 612 familial patients. A few variants covered most of the pathogenic burden in the studied genes. Of the BRCA1/2 carriers, 70.8% had 1 of 10 recurrent variants. In the other genes combined, 92.1% of the carrier patients had at least 1 of 11 recurrent variants. In particular, PALB2 c.1592delT and CHEK2 c.1100delC accounted for 88.9% and 82.9%, respectively, of the pathogenic variation in each gene. Our results highlight the importance of founder variants in the BC risk genes in the Finnish population and could be used in the designing of population screening for the risk variants. Full article

(This article belongs to the Special Issue Hereditary Breast Cancer in Men and Women: Genetic Mutations, Cancer Risk and Treatment)

12 pages, 529 KiB

Open AccessArticle

A Large Case-Control Study Performed in Spanish Population Suggests That RECQL5 Is the Only RECQ Helicase Involved in Breast Cancer Susceptibility

by Erik Michel Marchena-Perea, Milton Eduardo Salazar-Hidalgo, Alicia Gómez-Sanz, Mónica Arranz-Ledo, Alicia Barroso, Victoria Fernández, Hugo Tejera-Pérez, Guillermo Pita, Rocío Núñez-Torres, Luz Pombo, Rafael Morales-Chamorro, Juana María Cano-Cano, Maria del Carmen Soriano, Pilar Garre, Mercedes Durán, María Currás-Freixes, Miguel de la Hoya and Ana Osorio

Cancers 2022, 14(19), 4738; https://doi.org/10.3390/cancers14194738 - 28 Sep 2022

Cited by 3 | Viewed by 3065

Abstract

Around 50% of the familial breast cancer (BC) cases are estimated to be caused by germline variants in known low-, moderate-, and high-risk susceptibility genes, while the other half is of unknown genetic origin. In the present study, we wanted to evaluate the [...] Read more.

Around 50% of the familial breast cancer (BC) cases are estimated to be caused by germline variants in known low-, moderate-, and high-risk susceptibility genes, while the other half is of unknown genetic origin. In the present study, we wanted to evaluate the role of the RECQ helicases, some of which have been studied in the past as candidates, with unclear results about their role in the disease. Using next-generation sequencing (NGS) technology, we analyzed the whole coding sequence of BLM, RECQL1, RECQL4, RECQL5, and WRN in almost 2000 index cases from BC Spanish families that had previously tested negative for the known BC susceptibility genes (BRCAX) and compared the results with the controls extracted from gnomAD. Our results suggest that BLM, RECQL1, RECQL4, and WRN do not play a major role in BC susceptibility. However, in the combined analysis, joining the present results with those previously reported in a series of 1334 BC Spanish patients and controls, we found a statistically significant association between Loss of Function (LoF) variants in RECQL5 and BC risk, with an OR of 2.56 (p = 0.009; 95% CI, 1.18–4.98). Our findings support our previous work and places the RECQL5 gene as a new moderate-risk BC gene. Full article

(This article belongs to the Special Issue Hereditary Breast Cancer in Men and Women: Genetic Mutations, Cancer Risk and Treatment)

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9 pages, 969 KiB

Open AccessArticle

Contraception and Hormone Replacement Therapy in Healthy Carriers of Germline BRCA1/2 Genes Pathogenic Variants: Results from an Italian Survey

by Claudia Massarotti, Barbara Buonomo, Miriam Dellino, Maria Campanella, Cristofaro De Stefano, Alberta Ferrari, Paola Anserini, Matteo Lambertini and Fedro A. Peccatori

Cancers 2022, 14(14), 3457; https://doi.org/10.3390/cancers14143457 - 15 Jul 2022

Cited by 7 | Viewed by 2879

Abstract

Several myths and misconceptions exist about hormones in women with familial predisposition to cancer, and there are few real-life data on their prescription and uptake. To better understand how they are prescribed and accepted in healthy carriers of a BRCA1/2 pathogenetic variant, an [...] Read more.

Several myths and misconceptions exist about hormones in women with familial predisposition to cancer, and there are few real-life data on their prescription and uptake. To better understand how they are prescribed and accepted in healthy carriers of a BRCA1/2 pathogenetic variant, an online survey was uploaded on Google Forms and shared through social media closed groups of patients’ associations, aBRCAcadabra and ACTO Campania. A total of 241 questionnaires were collected. Sexual quality of life was considered of the utmost importance by most of the respondents (mean score of 7 ± 2.8/10), but they felt the counseling they received by healthcare professionals on the topic was insufficient (4.9 ± 3.2/10). Only 57 women out of 233 (24.5%) had used hormonal contraception after being diagnosed as carriers of a BRCA pathogenetic variant, and 42 out of 148 (28.4%) underwent menopause hormonal therapy. The majority of women (53.6% for contraception and 61.5% for menopause) reported being dissatisfied with the counseling received, and 58.2% were not aware of the protective effect of hormonal contraception on the risk of ovarian cancer. An educational effort is desirable to guarantee healthy BRCA carriers reliable contraception and evidence-based menopause counseling. Full article

(This article belongs to the Special Issue Hereditary Breast Cancer in Men and Women: Genetic Mutations, Cancer Risk and Treatment)

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23 pages, 967 KiB

Open AccessArticle

Uncovering the Contribution of Moderate-Penetrance Susceptibility Genes to Breast Cancer by Whole-Exome Sequencing and Targeted Enrichment Sequencing of Candidate Genes in Women of European Ancestry

by Martine Dumont, Nana Weber-Lassalle, Charles Joly-Beauparlant, Corinna Ernst, Arnaud Droit, Bing-Jian Feng, Stéphane Dubois, Annie-Claude Collin-Deschesnes, Penny Soucy, Maxime Vallée, Frédéric Fournier, Audrey Lemaçon, Muriel A. Adank, Jamie Allen, Janine Altmüller, Norbert Arnold, Margreet G. E. M. Ausems, Riccardo Berutti, Manjeet K. Bolla, Shelley Bull, Sara Carvalho, Sten Cornelissen, Michael R. Dufault, Alison M. Dunning, Christoph Engel, Andrea Gehrig, Willemina R. R. Geurts-Giele, Christian Gieger, Jessica Green, Karl Hackmann, Mohamed Helmy, Julia Hentschel, Frans B. L. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, Judit Horváth, M. Arfan Ikram, Silke Kaulfuß, Renske Keeman, Da Kuang, Craig Luccarini, Wolfgang Maier, John W. M. Martens, Dieter Niederacher, Peter Nürnberg, Claus-Eric Ott, Annette Peters, Paul D. P. Pharoah, Alfredo Ramirez, Juliane Ramser, Steffi Riedel-Heller, Gunnar Schmidt, Mitul Shah, Martin Scherer, Antje Stäbler, Tim M. Strom, Christian Sutter, Holger Thiele, Christi J. van Asperen, Lizet van der Kolk, Rob B. van der Luijt, Alexander E. Volk, Michael Wagner, Quinten Waisfisz, Qin Wang, Shan Wang-Gohrke, Bernhard H. F. Weber, Genome of the Netherlands Project, GHS Study Group, Peter Devilee, Sean Tavtigian, Gary D. Bader, Alfons Meindl, David E. Goldgar, Irene L. Andrulis, Rita K. Schmutzler, Douglas F. Easton, Marjanka K. Schmidt, Eric Hahnen and Jacques Simard Show full author list Hide full author list

Cancers 2022, 14(14), 3363; https://doi.org/10.3390/cancers14143363 - 11 Jul 2022

Cited by 3 | Viewed by 7928

Abstract

Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the [...] Read more.

Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes. Full article

(This article belongs to the Special Issue Hereditary Breast Cancer in Men and Women: Genetic Mutations, Cancer Risk and Treatment)

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Review

Jump to: Research

20 pages, 920 KiB

Open AccessReview

Prognostic and Predictive Biomarkers in Familial Breast Cancer

by Siddhartha Deb, Anannya Chakrabarti and Stephen B. Fox

Cancers 2023, 15(4), 1346; https://doi.org/10.3390/cancers15041346 - 20 Feb 2023

Cited by 1 | Viewed by 3186

Abstract

Large numbers of breast cancers arise within a familial context, either with known inherited germline mutations largely within DNA repair genes, or with a strong family history of breast and/or ovarian cancer, with unknown genetic underlying mechanisms. These cancers appear to be different [...] Read more.

Large numbers of breast cancers arise within a familial context, either with known inherited germline mutations largely within DNA repair genes, or with a strong family history of breast and/or ovarian cancer, with unknown genetic underlying mechanisms. These cancers appear to be different to sporadic cases, with earlier age of onset, increased multifocality and with association with specific breast cancer histological and phenotypic subtypes. Furthermore, tumours showing homologous recombination deficiency, due to loss of BRCA1, BRCA2, PALB2 and CHEK2 function, have been shown to be especially sensitive to platinum-based chemotherapeutics and PARP inhibition. While there is extensive research and data accrued on risk stratification and genetic predisposition, there are few data pertaining to relevant prognostic and predictive biomarkers within this breast cancer subgroup. The following is a review of such biomarkers in male and female familial breast cancer, although the data for the former are particularly sparse. Full article

(This article belongs to the Special Issue Hereditary Breast Cancer in Men and Women: Genetic Mutations, Cancer Risk and Treatment)

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17 pages, 379 KiB

Open AccessReview

Analysis of the Clinical Advancements for BRCA-Related Malignancies Highlights the Lack of Treatment Evidence for BRCA-Positive Male Breast Cancer

by Dylan P. McClurg, Gordan Urquhart, Trevor McGoldrick, Subarnarekha Chatterji, Zosia Miedzybrodzka, Valerie Speirs and Beatrix Elsberger

Cancers 2022, 14(13), 3175; https://doi.org/10.3390/cancers14133175 - 28 Jun 2022

Cited by 6 | Viewed by 3308

Abstract

Male breast cancer (MBC) is a rare disease that accounts for less than 1% of all breast cancers and male malignancies. Despite recognised clinico-pathological and molecular differences to female breast cancer (FBC), the clinical management of MBC follows established FBC treatment strategies. Loss [...] Read more.

Male breast cancer (MBC) is a rare disease that accounts for less than 1% of all breast cancers and male malignancies. Despite recognised clinico-pathological and molecular differences to female breast cancer (FBC), the clinical management of MBC follows established FBC treatment strategies. Loss of function mutations in the DNA damage response genes BRCA1 and BRCA2, have been strongly implicated in the pathogenesis of MBC. While there have been extensive clinical advancements in other BRCA-related malignancies, including FBC, improvements in MBC remain stagnant. Here we present a review that highlights the lack of treatment evidence for BRCA-related MBC and the required national and global collaborative effort to address this unmet need. In doing so, we summarise the transformative clinical advancements with poly(ADP-ribose) polymerase (PARP) inhibitors in other BRCA-related cancers namely, FBC and prostate cancer. Full article

(This article belongs to the Special Issue Hereditary Breast Cancer in Men and Women: Genetic Mutations, Cancer Risk and Treatment)

15 pages, 593 KiB

Open AccessReview

Male Breast Cancer: From Molecular Genetics to Clinical Management

by Matilde Pensabene, Claudia Von Arx and Michelino De Laurentiis

Cancers 2022, 14(8), 2006; https://doi.org/10.3390/cancers14082006 - 15 Apr 2022

Cited by 13 | Viewed by 3782

Abstract

MBC is a rare disease accounting for almost 1% of all cancers in men and less than 1% of breast cancer. Emerging data on the genetic drivers of predisposition for MBC are available and different risk factors have been associated with its pathogenesis. [...] Read more.

MBC is a rare disease accounting for almost 1% of all cancers in men and less than 1% of breast cancer. Emerging data on the genetic drivers of predisposition for MBC are available and different risk factors have been associated with its pathogenesis. Genetic alterations, such as pathogenetic variants in BRCA1/2 and other moderate-/low-penetrance genes, along with non-genetic risk factors, have been recognized as pathogenic factors for MBC. Preventive and therapeutic implications could be related to the detection of alterations in predisposing genes, especially BRCA1/2, and to the identification of oncogenic drivers different from FBC. However, approved treatments for MBC remain the same as FBC. Cancer genetic counseling has to be considered in the diagnostic work-up of MBC with or without positive oncological family history. Here, we review the literature, reporting recent data about this malignancy with a specific focus on epidemiology, and genetic and non-genetic risk factors. We introduce the perspective of cancer genetic counseling for MBC patients and their healthy at-risk family members, with a focus on different hereditary cancer syndromes. Full article

(This article belongs to the Special Issue Hereditary Breast Cancer in Men and Women: Genetic Mutations, Cancer Risk and Treatment)

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