Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes: ESMO Clinical Practice Guideline

Annals of Oncology, Год журнала: 2022, Номер 34(1), С. 33 - 47

Опубликована: Окт. 25, 2022

Язык: Английский

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Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond

Cancers, Год журнала: 2024, Номер 16(3), С. 579 - 579

Опубликована: Янв. 30, 2024

Among neoplastic diseases, breast cancer (BC) is one of the most influenced by gender. Despite common misconceptions associating BC as a women-only disease, can also occur in men. Additionally, transgender individuals may experience BC. Genetic risk factors play relevant role predisposition, with important implications precision prevention and treatment. The genetic architecture susceptibility similar women men, high-, moderate-, low-penetrance variants; however, some sex-specific features have emerged. Inherited high-penetrance pathogenic variants (PVs) BRCA1 BRCA2 genes are strongest factor. PVs more commonly associated increased female male BC, respectively. Notably, BRCA-associated BCs characterized pathologic features. Recently, next-generation sequencing technologies helped to provide insights on moderate-penetrance variants, particularly PALB2, CHEK2, ATM genes, while international collaborative genome-wide association studies contributed evidence their combined effect polygenic models, modulators BRCA1/2 PV carriers. Overall, all these suggested that basis although similar, differ from Evaluating component distinct entity first step improve both personalized assessment therapeutic choices patients sexes order reach gender equality care. In this review, we summarize latest research field predisposition particular focus similarities differences discuss implications, challenges, open issues surround establishment gender-oriented clinical management for

Язык: Английский

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The ATM Gene in Breast Cancer: Its Relevance in Clinical Practice

Genes, Год журнала: 2021, Номер 12(5), С. 727 - 727

Опубликована: Май 13, 2021

Molecular alterations of the Ataxia-telangiectasia (AT) gene are frequently detected in breast cancer (BC), with an incidence ranging up to 40%. The mutated form, (ATM) gene, is involved cell cycle control, apoptosis, oxidative stress, and telomere maintenance, its role as a risk factor for development well established. Recent studies have confirmed that some variants ATM associated increased BC worse prognosis. Thus, many patients harboring mutations develop intermediate- high-grade disease, there higher rate lymph node metastatic involvement. evidence concerning correlation efficacy therapeutic strategies management controversial. In fact, may sensitize cells platinum-derived drugs, BRCA1/2 do, whereas their implications objective responses hormonal therapy or target-based agents not defined. Herein, we conducted review development, prognosis, different treatment strategies.

Язык: Английский

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Moderate penetrance genes complicate genetic testing for breast cancer diagnosis: ATM, CHEK2, BARD1 and RAD51D

The Breast, Год журнала: 2022, Номер 65, С. 32 - 40

Опубликована: Июнь 18, 2022

Breast cancer risk associated with germline likely pathogenic/pathogenic variants (PV) varies by gene, often penetrance (high >50% or moderate 20–50%), and specific locus.Germline PVs in BRCA1 BRCA2 play important roles the development of breast ovarian particular, as well other cancers such pancreatic prostate melanoma. Recent studies suggest that susceptibility genes, including ATM, CHEK2, PALB2, RAD51C RAD51D confer differential risks cancers.In era multigene panel testing, advances next-generation sequencing technologies have notably reduced costs United States (US) enabled BRCA1/2 concomitantly additional genes. The use multigene-panel testing is beginning to expand Europe well.Further research into clinical implications particularly unaffected carriers, needed for appropriate counselling management data-driven plans surveillance and/or reduction. For individuals at high without any pathogenic variant genes some carriers moderate-risk ATM polygenic scores offer promise help stratify guide options.Cancer patients whose tumours are driven loss function both copies a predisposition gene may benefit from therapies targeting biological alterations induced dysfunctional e.g. poly ADP ribose polymerase (PARP) inhibitors novel pathway agents DNA repair deficiencies. A better understanding mechanisms which drive various malignancies lead improvements therapeutic preventive options.

Язык: Английский

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Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers

Annals of Oncology, Год журнала: 2022, Номер 33(11), С. 1186 - 1199

Опубликована: Авг. 18, 2022

•14.3% of patients with rare cancers and/or younger age onset carried a PGV.•PGVs were highly enriched in certain cancer entities, i.e. wild-type GISTs and leiomyosarcomas.•High PGV yields ATM, BRCA2, or PALB2 entities indicated potentially novel genotype–phenotype associations.•75% PGVs predisposition genes newly diagnosed due to study participation (118/157).•45% all supported molecularly informed therapeutic recommendations benefit 40% patients. BackgroundGermline variant evaluation precision oncology opens new paths toward the identification genetic tumor risk syndromes exploration relevance. Here, we present results germline analysis their clinical implications for predominantly cancers.Patients methodsMatched control genome/exome RNA sequencing was out 1485 (79%) young adults (77% than 51 years) National Center Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification Eradication Research (MASTER) trial, German multicenter, prospective, observational study. Clinical relevance prospective pathogenic (PGV) analyzed compared other studies.ResultsTen percent (n = 157) harbored 35 associated autosomal dominant predisposition, whereof up 75% unknown before participation. Another 5% 75) heterozygous carriers recessive syndromes. Particularly, high found gastrointestinal stromal tumors (GISTs) (28%, n 11/40), more specifically (50%, 10/20), leiomyosarcomas (21%, 19/89), hepatopancreaticobiliary (16%, 16/97). Forty-five 100/221) treatment recommendations, its implementation led 10/25). A comparison different studies revealed variable considerable differences workflows. We therefore propose detailed workflow evaluation.ConclusionsGenetic testing can identify very first patient hereditary family lead broad range entities. Its routine accompanied by harmonization workflows will increase boost research. Germline cancers. Matched studies. Ten evaluation. Genetic

Язык: Английский

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Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 7, 2023

Abstract Inflammation has long been recognized to contribute cancer development, particularly across the gastrointestinal tract. Patients with inflammatory bowel disease have an increased risk for cancers, and it posited that a field of genetic changes may underlie this risk. Here, we define clinical features, genomic landscape, germline alterations in 174 patients colitis-associated cancers sequenced 29 synchronous or isolated dysplasia. TP53 alterations, early highly recurrent event occur half dysplasia, largely as convergent evolution independent events. Wnt pathway are infrequent, our data suggest transcriptional rewiring away from Wnt. Sequencing multiple dysplasia/cancer lesions mouse models demonstrates rare shared between lesions. These findings neoplastic developing background inflammation experience lineage plasticity activation during tumorigenesis genetically

Язык: Английский

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Genetic Basis of Breast and Ovarian Cancer: Approaches and Lessons Learnt from Three Decades of Inherited Predisposition Testing

Genes, Год журнала: 2024, Номер 15(2), С. 219 - 219

Опубликована: Фев. 8, 2024

Germline variants occurring in BRCA1 and BRCA2 give rise to hereditary breast ovarian cancer (HBOC) syndrome, predisposing breast, ovarian, fallopian tube, peritoneal cancers marked by elevated incidences of genomic aberrations that correspond poor prognoses. These genes are fact involved genetic integrity, particularly the process homologous recombination (HR) DNA repair, a high-fidelity repair system for mending double-strand breaks. In addition its implication HBOC pathogenesis, impairment HR has become prime target therapeutic intervention utilizing poly (ADP-ribose) polymerase (PARP) inhibitors. present review, we introduce molecular roles orchestrated within framework sensitivity PARP We examine architecture underneath ranging from high- mid- low-penetrant taking into account both germline somatic variations. Finally, consider higher levels complexity landscape such as polygenic risk scores other approaches aiming optimize preventive strategies cancer.

Язык: Английский

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Hereditary Breast Cancer: Comprehensive Risk Assessment and Prevention Strategies

Genes, Год журнала: 2025, Номер 16(1), С. 82 - 82

Опубликована: Янв. 13, 2025

Women carrying pathogenic/likely pathogenic (P/LP) variants in moderate- or high-penetrance genes have an increased risk of developing breast cancer. However, most P/LP associated with cancer show incomplete penetrance. Age, gender, family history, polygenic risk, lifestyle, reproductive, hormonal, and environmental factors can affect the expressivity penetrance disease. there are gaps translating how individual genomic variation affects phenotypic presentation. The expansion criteria for genetic testing increasing utilization comprehensive panels may enhance identification individuals linked to hereditary Individualized assessment could facilitate implementation personalized risk-reduction strategies these individuals. Preventive interventions encompass lifestyle modifications, chemoprevention, enhanced surveillance through imaging, risk-reducing surgeries. This review addresses current literature’s inconsistencies limitations, particularly regarding intensity preventive women genes. In addition, it synthesizes latest evidence on primary secondary prevention at high

Язык: Английский

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Genetic Landscape of Male Breast Cancer

Cancers, Год журнала: 2021, Номер 13(14), С. 3535 - 3535

Опубликована: Июль 15, 2021

Male breast cancer (MBC) is now considered molecularly different from female (FBC). Evidence studies indicates that common genetic and epigenetic features of FBC are not shared with those diagnosed in men. Genetic predisposition likely to play a significant role the tumorigenesis this rare disease. Inherited germline variants

Язык: Английский

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ATM: Functions of ATM Kinase and Its Relevance to Hereditary Tumors

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(1), С. 523 - 523

Опубликована: Янв. 4, 2022

Ataxia–telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important processes, including repair, apoptosis, cell cycle arrest, oxidative sensing, proliferation. Over the past few decades, associations between germline pathogenic variants cancer risk have been reported, particularly for breast pancreatic cancers. In addition, given plays critical role in repairing double-strand breaks, inhibiting other repair could be synthetic lethal approach. Based on this rationale, several response inhibitors are currently being tested ATM-deficient review, we discuss current knowledge related to structure gene, function kinase, clinical significance patients with hereditary cancers, ongoing efforts target benefit patients.

Язык: Английский

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