Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families

Castéra, Laurent; Harter, Valentin; Müller, Etienne; Krieger, Sophie; Goardon, Nicolas; Ricou, Agathe; Rousselin, Antoine; Paimparay, Germain; Legros, Angélina; Bruet, Olivia; Quesnelle, Céline; Domin, Florian; San, Chankannira; Brault, Baptiste; Fouillet, Robin; Abadie, Caroline; Béra, Odile; Berthet, Pascaline; Frébourg, Thierry; Vaur, Dominique

doi:10.1038/s41436-018-0005-9

Cited by 62 publications

(70 citation statements)

References 41 publications

(51 reference statements)

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“…While the highest prevalence of BRCA1/2 mutation carriers was in patients diagnosed with double primary OC and BC, mutations in RAD51C/RAD51D/BRIP1 prevailed in patients diagnosed with OC only ( Figure 2B); nevertheless, their distribution among histological subtypes was similar to that in BRCA1/2 mutation carriers ( Figure 2E). In contrast to Castera et al who found mutations in RAD51C/RAD51D/BRIP1 dominantly in French OC patients with a positive family OC history [32], we identified mutations in these genes in 1/116 (0.9%) and 22/587 (3.7%) carriers in HOC patients and in patients with a negative family cancer history, respectively. Further, we have noticed a surprisingly high frequency of OC-predisposing mutations in older patients.…”

Section: Discussioncontrasting

confidence: 99%

Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

Lhotová

Zemánková

Vočka

et al. 2020

Cancers

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Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates treatment and preventive strategies reducing OC mortality in mutation carriers. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We aimed to analyze 219 genes in 1333 Czech OC patients and 2278 population-matched controls using next-generation sequencing. We revealed germline mutations in 18 OC/BC predisposition genes in 32.0% of patients and in 2.5% of controls. Mutations in BRCA1/BRCA2, RAD51C/RAD51D, BARD1, and mismatch repair genes conferred high OC risk (OR > 5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR = 3.5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Our findings demonstrate the high proportion of patients with hereditary OC in Slavic population justifying genetic testing in all patients with OC, including BTO.

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Section: Discussioncontrasting

confidence: 99%

Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

Lhotová

Zemánková

Vočka

et al. 2020

Cancers

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“…PALB2 is a crucial regulator in maintaining genome integrity, while its dysfunction leads to breast cancer predisposition. The clinical relevance of PALB2 has been partially described, and PALB2 is reported to be a highrisk breast cancer susceptibility gene comparable to BRCA2 (16). With the identification of deleterious PALB2 recurrent mutations and PARPi, individualized risk assessment and precision medicine for PALB2 mutation-associated breast cancer become possible.…”

Section: Discussionmentioning

confidence: 99%

“…However, the high-penetrance BRCA1 and BRCA2 are responsible for only ∼20% of the familial aggregation of breast cancer (12,13), and syndromic breast cancer susceptibility genes such as TP53, PTEN, and CDH1 are estimated to explain just 5% of familial breast cancers (14). Large-scale analyses of multigene panel testing recently confirmed PALB2 as a high-risk breast cancer susceptibility gene (15), and the odds ratio (OR) of PALB2 mutations for breast cancer was comparable to that of BRCA2 mutations (16). Hence, a comprehensive understanding of the biological functions of PALB2 is vital for breast cancer management and precision medicine.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management

Zhou

Zhang

et al. 2020

Front. Oncol.

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Partner and localizer of BRCA2 (PALB2) is vital for homologous recombination (HR) repair in response to DNA double-strand breaks (DSBs). PALB2 functions as a tumor suppressor and participates in the maintenance of genome integrity. In this review, we summarize the current knowledge of the biological roles of the multifaceted PALB2 protein and of its regulation. Moreover, we describe the link between PALB2 pathogenic variants (PVs) and breast cancer predisposition, aggressive clinicopathological features, and adverse clinical prognosis. We also refer to both the opportunities and challenges that the identification of PALB2 PVs provides in breast cancer genetic counseling and precision medicine.

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“…Early studies of cases selected for a family history of breast or ovarian cancer found that 24–76% had deleterious variants in BRCA1 and 1–17% had deleterious variants in BRCA2 [ 17 ]. Recent studies using clinical testing laboratory data have reported the prevalence of BRCA1/2 pathogenic variants in 5020 and 7489 cases from the USA [ 26 , 27 ], 4409 cases from France [ 28 ], and 3230 cases from a meta-analysis of 48 multi-gene panel testing-based studies [ 29 ]. In these studies, the frequency of germline pathogenic variants in BRCA1 in ovarian cancer cases were 5.1%, 3.6%, 3.7%, and 8.6%, respectively, and 3.9%, 3.3%, 4.0%, and 4.5% in BRCA2 [ 26 , 27 , 28 , 29 ].…”

Section: Protein Truncating Variants In Confirmed Susceptibility Gmentioning

confidence: 99%

Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer

Pavanello

Chan

Ariff

et al. 2020

Cancers

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A family history of ovarian or breast cancer is the strongest risk factor for epithelial ovarian cancer (EOC). Germline deleterious variants in the BRCA1 and BRCA2 genes confer EOC risks by age 80, of 44% and 17% respectively. The mismatch repair genes, particularly MSH2 and MSH6, are also EOC susceptibility genes. Several other DNA repair genes, BRIP1, RAD51C, RAD51D, and PALB2, have been identified as moderate risk EOC genes. EOC has five main histotypes; high-grade serous (HGS), low-grade serous (LGS), clear cell (CCC), endometrioid (END), and mucinous (MUC). This review examines the current understanding of the contribution of rare genetic variants to EOC, focussing on providing frequency data for each histotype. We provide an overview of frequency and risk for pathogenic variants in the known susceptibility genes as well as other proposed genes. We also describe the progress to-date to understand the role of missense variants and the different breast and ovarian cancer risks for each gene. Identification of susceptibility genes have clinical impact by reducing disease-associated mortality through improving risk prediction, with the possibility of prevention strategies, and developing new targeted treatments and these clinical implications are also discussed.

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Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families

Abstract: Our results validate the integration of PALB2, RAD51C, and RAD51D in the diagnosis of HBOC and suggest that the other genes are involved in an oligogenic determinism.

Cited by 62 publications

References 41 publications

Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management

Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer

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