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Causes for Frequent Pathogenic BRCA1 Variants Include Low Penetrance in Fertile Ages, Recurrent De-Novo Mutations and Genetic Drift

by Pål Møller, Mev Dominguez-Valentin, Einar Andreas Rødland and Eivind Hovig

Cancers 2019, 11(2), 132; https://doi.org/10.3390/cancers11020132 - 23 Jan 2019

Cited by 7 | Viewed by 4459 | Correction

Abstract

Background: We have previously demonstrated that the Norwegian frequent pathogenic BRCA1 (path_BRCA1) variants are caused by genetic drift and recurrent de-novo mutations. We here examined the penetrance of frequent path_BRCA1 variants in fertile ages as a surrogate marker for fitness. Material and [...] Read more.

Background: We have previously demonstrated that the Norwegian frequent pathogenic BRCA1 (path_BRCA1) variants are caused by genetic drift and recurrent de-novo mutations. We here examined the penetrance of frequent path_BRCA1 variants in fertile ages as a surrogate marker for fitness. Material and methods: We conducted an observational prospective study of penetrance for cancer in Norwegian female carriers of frequent path_BRCA1 variants, and compared our observed results to penetrance of infrequent path_BRCA1 variants and to average penetrance of path_BRCA1 variants reported by others. Results: The cumulative risk for breast cancer at 45 years in carriers of frequent path_BRCA1 variants was 20% (94% confidence interval 10–30%), compared to 35% (95% confidence interval 22–48%) in carriers of infrequent path_BRCA1 variants (p = 0.02), and to the 35% (confidence interval 32–39%) average for path_BRCA1 carriers reported by others (p = 0.0001). Discussion and conclusion: Carriers of the most frequent Norwegian path_BRCA1 variants had low incidence of cancer in fertile ages, indicating a low selective disadvantage. This, together with the variant locations being hotspots for de novo mutations and subject to genetic drift, as previously described, may have caused their high prevalence today. Besides being of theoretical interest to explain the phenomenon that a few path_BRCA1 variants are frequent, the later onset of breast cancer associated with the most frequent path_BRCA1 variants may be of interest for carriers who have to decide if and when to select prophylactic mastectomy. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

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13 pages, 670 KiB

Open AccessArticle

A Recurrent BRCA2 Mutation Explains the Majority of Hereditary Breast and Ovarian Cancer Syndrome Cases in Puerto Rico

by Hector J. Diaz-Zabala, Ana P. Ortiz, Lisa Garland, Kristine Jones, Cynthia M. Perez, Edna Mora, Nelly Arroyo, Taras K. Oleksyk, Miguel Echenique, Jaime L. Matta, Michael Dean and Julie Dutil

Cancers 2018, 10(11), 419; https://doi.org/10.3390/cancers10110419 - 2 Nov 2018

Cited by 19 | Viewed by 5847

Abstract

Breast cancer is the most common cause of cancer diagnosis in women and is responsible for considerable mortality among the women of Puerto Rico. However, there are few studies in Puerto Rico on the genetic factors influencing risk. To determine the contribution of [...] Read more.

Breast cancer is the most common cause of cancer diagnosis in women and is responsible for considerable mortality among the women of Puerto Rico. However, there are few studies in Puerto Rico on the genetic factors influencing risk. To determine the contribution of pathogenic mutations in BRCA1 and BRCA2, we sequenced these genes in 302 cases from two separate medical centers, who were not selected for age of onset or family history. We identified nine cases that are carriers of pathogenic germline mutation. This represents 2.9% of unselected cases and 5.6% of women meeting National Comprehensive Cancer Network (NCCN) criteria for BRCA testing. All of the identified pathogenic mutations were in the BRCA2 gene and the most common mutation is the p.Glu1308Ter (E1308X) mutation in BRCA2 found in eight out of nine cases, representing 89% of the pathogenic carriers. The E1308X mutation has been identified in breast and ovarian cancer families in Spain, and analysis of flanking DNA polymorphisms shows that all E1308X carriers occur on the same haplotype. This is consistent with BRCA2 E1308X being a founder mutation for the Puerto Rican population. These results will contribute to better inform genetic screening and counseling of breast and ovarian cancer cases in Puerto Rico and Puerto Rican populations in mainland United States. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

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Review

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14 pages, 953 KiB

Open AccessReview

Germline Missense Variants in BRCA1: New Trends and Challenges for Clinical Annotation

by Volha A. Golubeva, Thales C. Nepomuceno and Alvaro N. A. Monteiro

Cancers 2019, 11(4), 522; https://doi.org/10.3390/cancers11040522 - 12 Apr 2019

Cited by 19 | Viewed by 8002

Abstract

Genetic testing allows for the identification of germline DNA variations, which are associated with a significant increase in the risk of developing breast cancer (BC) and ovarian cancer (OC). Detection of a BRCA1 or BRCA2 pathogenic variant triggers several clinical management actions, which [...] Read more.

Genetic testing allows for the identification of germline DNA variations, which are associated with a significant increase in the risk of developing breast cancer (BC) and ovarian cancer (OC). Detection of a BRCA1 or BRCA2 pathogenic variant triggers several clinical management actions, which may include increased surveillance and prophylactic surgery for healthy carriers or treatment with the PARP inhibitor therapy for carriers diagnosed with cancer. Thus, standardized validated criteria for the annotation of BRCA1 and BRCA2 variants according to their pathogenicity are necessary to support clinical decision-making and ensure improved outcomes. Upon detection, variants whose pathogenicity can be inferred by the genetic code are typically classified as pathogenic, likely pathogenic, likely benign, or benign. Variants whose impact on function cannot be directly inferred by the genetic code are labeled as variants of uncertain clinical significance (VUS) and are evaluated by multifactorial likelihood models that use personal and family history of cancer, segregation data, prediction tools, and co-occurrence with a pathogenic BRCA variant. Missense variants, coding alterations that replace a single amino acid residue with another, are a class of variants for which determination of clinical relevance is particularly challenging. Here, we discuss current issues in the missense variant classification by following a typical life cycle of a BRCA1 missense variant through detection, annotation and information dissemination. Advances in massively parallel sequencing have led to a substantial increase in VUS findings. Although the comprehensive assessment and classification of missense variants according to their pathogenicity remains the bottleneck, new developments in functional analysis, high throughput assays, data sharing, and statistical models are rapidly changing this scenario. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

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32 pages, 874 KiB

Open AccessReview

Tailoring Ovarian Cancer Treatment: Implications of BRCA1/2 Mutations

by Ainhoa Madariaga, Stephanie Lheureux and Amit M. Oza

Cancers 2019, 11(3), 416; https://doi.org/10.3390/cancers11030416 - 23 Mar 2019

Cited by 59 | Viewed by 11468

Abstract

High grade serous ovarian cancer (HGSOC) is the most common epithelial ovarian cancer, harbouring more than 20% germline or somatic mutations in the tumour suppressor genes BRCA1 and BRCA2. These genes are involved in both DNA damage repair process via homologous recombination [...] Read more.

High grade serous ovarian cancer (HGSOC) is the most common epithelial ovarian cancer, harbouring more than 20% germline or somatic mutations in the tumour suppressor genes BRCA1 and BRCA2. These genes are involved in both DNA damage repair process via homologous recombination (HR) and transcriptional regulation. BRCA mutation confers distinct characteristics, including an increased response to DNA-damaging agents, such us platinum chemotherapy and poly-ADP ribose polymerase inhibitors (PARPi). However, several mechanisms of resistance to these agents have been described, including increased HR capacity through reverse BRCA mutations, non-homologous end-joint (NHEJ) repair alterations and drug efflux pumps. Current treatments of ovarian cancer including surgery, chemotherapy, targeted treatment and maintenance strategies, as well as resistance mechanisms will be reviewed, focusing on future trends with respect to BRCA mutation carriers. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

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15 pages, 253 KiB

Open AccessReview

BRCA2 and Other DDR Genes in Prostate Cancer

by Paz Nombela, Rebeca Lozano, Alvaro Aytes, Joaquin Mateo, David Olmos and Elena Castro

Cancers 2019, 11(3), 352; https://doi.org/10.3390/cancers11030352 - 12 Mar 2019

Cited by 78 | Viewed by 8747

Abstract

Germline and somatic aberrations in DNA damage repair (DDR) genes are more prevalent in prostate cancer than previously recognized, with BRCA2 as the most commonly altered gene. Germline mutations in BRCA2 have been linked to poor prognosis when patients are managed under the [...] Read more.

Germline and somatic aberrations in DNA damage repair (DDR) genes are more prevalent in prostate cancer than previously recognized, with BRCA2 as the most commonly altered gene. Germline mutations in BRCA2 have been linked to poor prognosis when patients are managed under the protocols currently approved for prostate cancer. The impact of germline mutations in other DDR genes beyond BRCA2 remain unclear. Importantly, a quarter of prostate cancer patients identified as germline mutation carriers lack a family history of cancer. The clinical implications of somatic DDR defects are yet to be elucidated. Poly ADP-ribose polymerase (PARP) inhibitors and platinum-based chemotherapy have proven to be effective in the treatment of other tumor types linked to BRCA1 and BRCA2 alterations and several trials are currently evaluating their efficacy in prostate cancer. Here, we summarize the available evidence regarding the prevalence of somatic and germline DDR defects in prostate cancer; their association with clinical outcomes; the trials assessing the efficacy of new therapies that exploit DDR defects in prostate cancer and briefly discuss some uncertainties about the most appropriate management for these patients. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

15 pages, 244 KiB

Open AccessFeature PaperReview

BRCA Mutations and Breast Cancer Prevention

by Joanne Kotsopoulos

Cancers 2018, 10(12), 524; https://doi.org/10.3390/cancers10120524 - 19 Dec 2018

Cited by 80 | Viewed by 14293

Abstract

Women who inherit a deleterious BRCA1 or BRCA2 mutation face substantially increased risks of developing breast cancer, which is estimated at 70%. Although annual screening with magnetic resonance imaging (MRI) and mammography promotes the earlier detection of the disease, the gold standard for [...] Read more.

Women who inherit a deleterious BRCA1 or BRCA2 mutation face substantially increased risks of developing breast cancer, which is estimated at 70%. Although annual screening with magnetic resonance imaging (MRI) and mammography promotes the earlier detection of the disease, the gold standard for the primary prevention of breast cancer remains bilateral mastectomy. In the current paper, I review the evidence regarding the management of healthy BRCA mutation carriers, including key risk factors and protective factors, and also discuss potential chemoprevention options. I also provide an overview of the key findings from the literature published to date, with a focus on data from studies that are well-powered, and preferably prospective in nature. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

16 pages, 980 KiB

Open AccessReview

BRCA1-Dependent Transcriptional Regulation: Implication in Tissue-Specific Tumor Suppression

by Xiaowen Zhang and Rong Li

Cancers 2018, 10(12), 513; https://doi.org/10.3390/cancers10120513 - 14 Dec 2018

Cited by 17 | Viewed by 6297

Abstract

Germ-line mutations in breast cancer susceptibility gene 1 (BRCA1) predominantly predispose women to breast and ovarian cancers. BRCA1 is best known for its functions in maintenance of genomic integrity including repairing DNA double-strand breaks through homologous recombination and suppressing DNA replication [...] Read more.

Germ-line mutations in breast cancer susceptibility gene 1 (BRCA1) predominantly predispose women to breast and ovarian cancers. BRCA1 is best known for its functions in maintenance of genomic integrity including repairing DNA double-strand breaks through homologous recombination and suppressing DNA replication stress. However, whether these universally important BRCA1 functions in maintenance of genomic stability are sufficient to account for its tissue-specific tumor-suppressing function remains unclear. Accumulating evidence indicates that there are previously underappreciated roles of BRCA1 in transcriptional regulation and chromatin remodeling. In this review, we discuss the functional significance of interactions between BRCA1 and various transcription factors, its role in epigenetic regulation and chromatin dynamics, and BRCA1-dependent crosstalk between the machineries of transcription and genome integrity. Furthermore, we propose a model of how transcriptional regulation could contribute to tissue-dependent tumor-suppressing function of BRCA1. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

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22 pages, 643 KiB

Open AccessFeature PaperReview

Targeting BRCA Deficiency in Breast Cancer: What are the Clinical Evidences and the Next Perspectives?

by Emanuel Nicolas, François Bertucci, Renaud Sabatier and Anthony Gonçalves

Cancers 2018, 10(12), 506; https://doi.org/10.3390/cancers10120506 - 11 Dec 2018

Cited by 39 | Viewed by 5156

Abstract

Breast cancers (BC) associated with germline mutations of BRCA1/2 represent 3–5% of cases. BRCA1/2-associated BC have biological features leading to genomic instability and potential sensitivity to DNA damaging agents, including poly(ADP-ribose) polymerase (PARP) and platinum agents. In this review, we will summarize [...] Read more.

Breast cancers (BC) associated with germline mutations of BRCA1/2 represent 3–5% of cases. BRCA1/2-associated BC have biological features leading to genomic instability and potential sensitivity to DNA damaging agents, including poly(ADP-ribose) polymerase (PARP) and platinum agents. In this review, we will summarize clinical trials of chemotherapy and PARP inhibitors (PARPi), alone or in combination, at the early or late stage of BRCA1/2-associated BC. We will also present the mechanisms of resistance to PARPi as well as the new therapeutic strategies of association with PARPi. Finally, we will discuss under which conditions the use of DNA damaging agents can be extended to the BRCA1/2-wild type population, the BRCAness concept. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

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11 pages, 271 KiB

Open AccessReview

Screening BRCA1 and BRCA2 Mutation Carriers for Breast Cancer

by Ellen Warner

Cancers 2018, 10(12), 477; https://doi.org/10.3390/cancers10120477 - 30 Nov 2018

Cited by 40 | Viewed by 6320

Abstract

Women with BRCA mutations, who choose to decline or defer risk-reducing mastectomy, require a highly sensitive breast screening regimen they can begin by age 25 or 30. Meta-analysis of multiple observational studies, in which both mammography and magnetic resonance imaging (MRI) were performed [...] Read more.

Women with BRCA mutations, who choose to decline or defer risk-reducing mastectomy, require a highly sensitive breast screening regimen they can begin by age 25 or 30. Meta-analysis of multiple observational studies, in which both mammography and magnetic resonance imaging (MRI) were performed annually, demonstrated a combined sensitivity of 94% for MRI plus mammography compared to 39% for mammography alone. There was negligible benefit from adding screening ultrasound or clinical breast examination to the other two modalities. The great majority of cancers detected were non-invasive or stage I. While the addition of MRI to mammography lowered the specificity from 95% to 77%, the specificity improved significantly after the first round of screening. The median follow-up of women with screen-detected breast cancer in the above observational studies now exceeds 10 years, and the long-term breast cancer-free survival in most of these studies is 90% to 95%. However, ongoing follow-up of these study patients, as well of women screened and treated more recently, is necessary. Advances in imaging technology will make highly sensitive screening accessible to a greater number of high-risk women. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

21 pages, 545 KiB

Open AccessReview

Non-Coding Variants in BRCA1 and BRCA2 Genes: Potential Impact on Breast and Ovarian Cancer Predisposition

by Elizabeth Santana dos Santos, François Lallemand, Leslie Burke, Dominique Stoppa-Lyonnet, Melissa Brown, Sandrine M. Caputo and Etienne Rouleau

Cancers 2018, 10(11), 453; https://doi.org/10.3390/cancers10110453 - 16 Nov 2018

Cited by 21 | Viewed by 7904

Abstract

BRCA1 and BRCA2 are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to BRCA1/2 exons and intron/exon boundaries. Most identified pathogenic [...] Read more.

BRCA1 and BRCA2 are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to BRCA1/2 exons and intron/exon boundaries. Most identified pathogenic variants cause the partial or complete loss of function of the protein. However, it is becoming increasingly clear that variants in these regions only account for a small proportion of cancer risk. The role of variants in non-coding regions beyond splice donor and acceptor sites, including those that have no qualitative effect on the protein, has not been thoroughly investigated. The key transcriptional regulatory elements of BRCA1 and BRCA2 are housed in gene promoters, untranslated regions, introns, and long-range elements. Within these sequences, germline and somatic variants have been described, but the clinical significance of the majority is currently unknown and it remains a significant clinical challenge. This review summarizes the available data on the impact of variants on non-coding regions of BRCA1/2 genes and their role on breast and ovarian cancer predisposition. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

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36 pages, 607 KiB

Open AccessReview

Next-Generation Service Delivery: A Scoping Review of Patient Outcomes Associated with Alternative Models of Genetic Counseling and Genetic Testing for Hereditary Cancer

by Jeanna M. McCuaig, Susan Randall Armel, Melanie Care, Alexandra Volenik, Raymond H. Kim and Kelly A. Metcalfe

Cancers 2018, 10(11), 435; https://doi.org/10.3390/cancers10110435 - 13 Nov 2018

Cited by 79 | Viewed by 6934

Abstract

The combination of increased referral for genetic testing and the current shortage of genetic counselors has necessitated the development and implementation of alternative models of genetic counseling and testing for hereditary cancer assessment. The purpose of this scoping review is to provide an [...] Read more.

The combination of increased referral for genetic testing and the current shortage of genetic counselors has necessitated the development and implementation of alternative models of genetic counseling and testing for hereditary cancer assessment. The purpose of this scoping review is to provide an overview of the patient outcomes that are associated with alternative models of genetic testing and genetic counseling for hereditary cancer, including germline-only and tumor testing models. Seven databases were searched, selecting studies that were: (1) full-text articles published ≥2007 or conference abstracts published ≥2015, and (2) assessing patient outcomes of an alternative model of genetic counseling or testing. A total of 79 publications were included for review and synthesis. Data-charting was completed using a data-charting form that was developed by the study team for this review. Seven alternative models were identified, including four models that involved a genetic counselor: telephone, telegenic, group, and embedded genetic counseling models; and three models that did not: mainstreaming, direct, and tumor-first genetic testing models. Overall, these models may be an acceptable alternative to traditional models on knowledge, patient satisfaction, psychosocial measures, and the uptake of genetic testing; however, particular populations may be better served by traditional in-person genetic counseling. As precision medicine initiatives continue to advance, institutions should consider the implementation of new models of genetic service delivery, utilizing a model that will best serve the needs of their unique patient populations. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

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22 pages, 442 KiB

Open AccessReview

Population Based Testing for Primary Prevention: A Systematic Review

by Ranjit Manchanda and Faiza Gaba

Cancers 2018, 10(11), 424; https://doi.org/10.3390/cancers10110424 - 5 Nov 2018

Cited by 38 | Viewed by 5260

Abstract

The current clinical model for genetic testing is based on clinical-criteria/family-history (FH) and a pre-defined mutation probability threshold. It requires people to develop cancer before identifying unaffected individuals in the family to target prevention. This process is inefficient, resource intensive and misses >50% [...] Read more.

The current clinical model for genetic testing is based on clinical-criteria/family-history (FH) and a pre-defined mutation probability threshold. It requires people to develop cancer before identifying unaffected individuals in the family to target prevention. This process is inefficient, resource intensive and misses >50% of individuals or mutation carriers at risk. Population genetic-testing can overcome these limitations. It is technically feasible to test populations on a large scale; genetic-testing costs are falling and acceptability and awareness are rising. MEDLINE, EMBASE, Pubmed, CINAHL and PsychINFO databases were searched using free-text and MeSH terms; retrieved reference lists of publications were screened; additionally, web-based platforms, Google, and clinical-trial registries were searched. Quality of studies was evaluated using appropriate check-lists. A number of studies have evaluated population-based BRCA-testing in the Jewish population. This has been found to be acceptable, feasible, clinically-effective, safe, associated with high satisfaction rates and extremely cost-effective. Data support change in guidelines for population-based BRCA-testing in the Jewish population. Population panel testing for BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 gene mutations is the most cost-effective genetic-testing strategy in general-population women and can prevent thousands more breast and ovarian cancers than current clinical-criteria based approaches. A few ongoing studies are evaluating population-based genetic-testing for multiple cancer susceptibility genes in the general population but more implementation studies are needed. A future population-testing programme could also target other chronic diseases. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

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Other

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5 pages, 169 KiB

Open AccessCorrection

Correction: Møller, P.; et al. Causes for Frequent Pathogenic BRCA1 Variants Include Low Penetrance in Fertile Ages, Recurrent De-Novo Mutations and Genetic Drift. Cancers 2019, 11, 132

by Pål Møller, Mev Dominguez-Valentin, Einar Andreas Rødland and Eivind Hovig

Cancers 2020, 12(2), 410; https://doi.org/10.3390/cancers12020410 - 10 Feb 2020

Cited by 1 | Viewed by 2018

Abstract

The authors wish to make the following corrections to this paper [1]: The authors would like to replace Table 3 in [1]. The corrections are correcting typographical errors when translating our database in BIC format to HGVS nomenclature, and removing four carriers which [...] Read more.

The authors wish to make the following corrections to this paper [1]: The authors would like to replace Table 3 in [1]. The corrections are correcting typographical errors when translating our database in BIC format to HGVS nomenclature, and removing four carriers which had zero follow-up time. [...] Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

9 pages, 1186 KiB

Open AccessPerspective

Back to the Future? The Fallopian Tube, Precursor Escape and a Dualistic Model of High-Grade Serous Carcinogenesis

by T. Rinda Soong, David L. Kolin, Nathan J. Teschan and Christopher P. Crum

Cancers 2018, 10(12), 468; https://doi.org/10.3390/cancers10120468 - 28 Nov 2018

Cited by 33 | Viewed by 5392

Abstract

Beginning with the discovery of the BRCA-associated ovarian cancer susceptibility genes and subsequent detailed examination of risk-reducing salpingo-oophorectomy (RRSO) specimens, a new paradigm of ovarian carcinogenesis has unfolded with attention to the distal fallopian tube. The primary focus has been an early [...] Read more.

Beginning with the discovery of the BRCA-associated ovarian cancer susceptibility genes and subsequent detailed examination of risk-reducing salpingo-oophorectomy (RRSO) specimens, a new paradigm of ovarian carcinogenesis has unfolded with attention to the distal fallopian tube. The primary focus has been an early cancer or neoplasm in the fallopian tube which is seen in virtually all incidentally discovered high-grade serous cancers in asymptomatic women. This high-frequency of tubal involvement in early serous neoplasm (usually in the form of serous tubal intraepithelial carcinoma—STIC) has galvanized attention to this organ as a primary source of this disease. However, an enduring mystery has been the relatively low frequency of STIC in the fallopian tubes of women with advanced malignancy. This paradox, a high frequency of tubal involvement early on and a low frequency of involvement later in the disease process, has spurred interest in other potential sources, such as the ovarian surface epithelium or cortical inclusions and the secondary Mullerian system. However, because essentially all high-grade serous carcinomas are linked by TP53 mutations, and because fallopian tubes frequently contain early serous proliferations (ESPs) with these mutations, attention has turned to the possibility that the nonmalignant but TP53 mutated tubal epithelium could be responsible for an eventual malignancy. Recent data have shown evidence of a lineage continuity between ESPs and concurrent serous carcinomas prompting the concept of “precursor escape”. This creates a second component of the paradigm by which cells from early precursors are shed from the tube and undergo subsequent malignant transformation, emerging suddenly as widespread intraperitoneal malignancy. This dualistic model thus provides a unique pathway by which the future outcome (wide spread high-grade serous carcinomas—HGSC) is ultimately explained by going back in time to an early serous proliferation. This paradigm also brings the peritoneal cavity into focus, raising new questions about the potential co-variables or exposures that might facilitate the occasional malignant transformation of an ESP in the peritoneal cavity or on the peritoneal surface. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

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