scholarly journals Prevalence and Clinicopathological Characteristics of Moderate and High-Penetrance Genes in Non-BRCA1/2 Breast Cancer High-Risk Spanish Families

2021 ◽  
Vol 11 (6) ◽  
pp. 548
Author(s):  
Maria Fonfria ◽  
Inmaculada de Juan Jiménez ◽  
Isabel Tena ◽  
Isabel Chirivella ◽  
Paula Richart-Aznar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Clinical Characteristics ◽  
Single Gene ◽  
Clinicopathological Characteristics ◽  
Loss Of Function ◽  
Moderate Risk ◽  
Risk Genes ◽  
Pathogenic Variants ◽  
Index Cases

(1) Background: Over the last decade, genetic counseling clinics have moved from single-gene sequencing to multigene panel sequencing. Multiple genes related to a moderate risk of breast cancer (BC) have emerged, although many questions remain regarding the risks and clinical features associated with these genes. (2) Methods: Ninety-six BC index cases (ICs) with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for BRCA1/2 were tested with a panel of 41 genes associated with BC risk. The frequency of pathogenic variants (PVs) was related to the clinical characteristics of BC. (3) Results: We detected a PV rate of 13.5% (excluding two cases each of BRCA1 and MUTYH). Among the 95 assessed cases, 17 PVs were identified in 16 ICs, as follows: BRCA1 (n = 2), CHEK2 (n = 3), ATM (n = 5), MUTYH (n = 2), TP53 (n = 2), BRIP1 (n = 1), CASP8 (n = 1), and MSH2 (n = 1). We also identified a novel loss-of-function variant in CASP8, a candidate gene for increased BC risk. There was no evidence that the clinical characteristics of BC might be related to a higher chance of identifying a PV. (4) Conclusions: In our cohort, which was enriched with families with a high number of BC cases, a high proportion of mutations in ATM and CHEK2 were identified. The clinical characteristics of BC associated with moderate-risk genes were different from those related to BRCA1/2 genes.

scholarly journals Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Na Li ◽  
Belle W. X. Lim ◽  
Ella R. Thompson ◽  
Simone McInerny ◽  
Magnus Zethoven ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Candidate Genes ◽  
Familial Aggregation ◽  
Loss Of Function ◽  
Cancer Data ◽  
Pathogenic Variants ◽  
New Genes ◽  
Predisposing Genes ◽  
Predisposition Genes

AbstractBreast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10−9) and missense (OR 1.27, p = 3.96 × 10−73) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.

scholarly journals Sequencing for germline mutations in Swedish breast cancer families reveals novel breast cancer risk genes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hafdis T. Helgadottir ◽  
Jessada Thutkawkorapin ◽  
Kristina Lagerstedt-Robinson ◽  
Annika Lindblom
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Cancer Risk ◽  
Dna Recombination ◽  
Strand Break ◽  
Risk Genes ◽  
Cancer Risk Factors ◽  
Pathogenic Variants ◽  
Risk Variants ◽  
History Of

AbstractIdentifying genetic cancer risk factors will lead to improved genetic counseling, cancer prevention and cancer care. Analyzing families with a strong history of breast cancer (BC) has been a successful method to identify genes that contribute to the disease. This has led to discoveries of high-risk genes like the BRCA-genes. Nevertheless, many BC incidences are of unknown causes. In this study, exome sequencing on 59 BC patients from 24 Swedish families with a strong history of BC was performed to identify variants in known and novel BC predisposing genes. First, we screened known BC genes and identified two pathogenic variants in the BRIP1 and PALB2 genes. Secondly, to identify novel BC genes, rare and high impact variants and segregating in families were analyzed to identify 544 variants in novel BC candidate genes. Of those, 22 variants were defined as high-risk variants. Several interesting genes, either previously linked with BC or in pathways that when flawed could contribute to BC, were among the detected genes. The strongest candidates identified are the FANCM gene, involved in DNA double-strand break repair, and the RAD54L gene, involved in DNA recombination. Our study shows identifying pathogenic variants is challenging despite a strong family history of BC. Several interesting candidates were observed here that need to be further studied.

scholarly journals From BRCA1 to Polygenic Risk Scores: Mutation-Associated Risks in Breast Cancer-Related Genes

Breast Care ◽  
2021 ◽  
pp. 1-12
Author(s):  
Emma R. Woodward ◽  
Elke M. van Veen ◽  
D. Gareth Evans
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Reproductive Factors ◽  
Risk Scores ◽  
Clinical Indication ◽  
Nucleotide Polymorphisms ◽  
Moderate Risk ◽  
Risk Genes ◽  
Increased Risk ◽  
Gene Panels

<b><i>Background:</i></b> There has been huge progress over the last 30 years in identifying the familial component of breast cancer. <b><i>Summary:</i></b> Currently around 20% is explained by the high-risk genes <i>BRCA1</i> and <i>BRCA2</i>, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes <i>ATM</i> and<i> CHEK2</i>. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40–90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace. <b><i>Key-Messages:</i></b> There is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as <i>CDH1</i> and <i>TP53</i>, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.

scholarly journals Prevalence of deleterious mutations among patients with breast cancer referred for multigene panel testing in a Romanian population

2018 ◽  
Vol 91 (2) ◽  
pp. 157-165 ◽  
Author(s):  
Iulian Gabriel Goidescu ◽  
Gabriela Caracostea ◽  
Dan Tudor Eniu ◽  
Florin Vasile Stamatian
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Risk Group ◽  
Deleterious Mutations ◽  
Cancer Genes ◽  
Moderate Risk ◽  
Risk Genes ◽  
Panel Testing ◽  
Pathogenic Mutations ◽  
Multigene Panel

Aim. Multigene panel testing for Hereditary Breast and Ovarian Cancer (HBOC) using next generation sequencing is becoming more common in medical care.We report our experience regarding deleterious mutations of high and moderate-risk breast cancer genes (BRCA1/2, TP53, STK11, CDH1, PTEN, PALB2, CHEK2, ATM), as well as more recently identified cancer genes, many of which have increased risk but less well-defined penetrance.Methods. Genetic testing was performed in 130 consecutive cases with breast cancer referred to our clinic for surgical evaluation and who met the 2016 National Comprehensive Cancer Network (NCCN) criteria for genetic testing.Results. 82 patients had pathogenic/likely pathogenic mutations and VUS mutations, and 48 were negative; 36 of the pathogenic mutations were in the high-risk genes and 16 were in the moderate risk genes and only 5 cases in the intermediary risk group.From the VUS mutation group 21 cases were in the intermediary risk group, 9 cases were in the moderate risk group and only 7 cases in high risk group.The most frequent BRCA1 variant was c.3607C>T (7 cases) followed by c.5266dupC and c.4035delA (each in 4 cases). Regarding BRCA-2 mutations we identified c.9371A>T and c.8755-1G>A in 6 cases and we diagnosed VUS mutations in 3 cases.Conclusion. Our study identified 2 mutations in the BRCA1 gene that are less common in the Romanian population, c.3607C>T and c.4035delA. Both variants had particular molecular phenotypes, c.3607C>T variant respecting the triple negative pattern of BRCA1 breast cancer while c.4035delA were Luminal B HER positive.

scholarly journals Gene Panel Sequencing in a Chinese High-risk Breast Cancer Cohort

2019 ◽  
Author(s):  
Xianyu Zhang ◽  
Xiaohong Wang ◽  
Bingbing Song ◽  
Kang Shao ◽  
Guibo Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Gene Sequencing ◽  
Multiple Gene ◽  
Brca Gene ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
High Risk Breast Cancer ◽  
High Risk Breast ◽  
Risk Breast Cancer

AbstractCurrently, over 20 genes have been defined that can confer susceptibility for high-risk breast cancer. Although research has proved the utility of multiple-gene sequencing in the assessment of breast cancer risk, there is little data from China patients. Here, we use a multiple-gene sequencing panel to identify the variant spectrum in Chinese high-risk breast cancer subjects.A total of 829 Chinese high-risk breast cancer patients participated in the research. The coding regions of 115 hereditary cancer susceptibility genes were sequenced using a next generation sequencing platform. In total, 193 pathogenic variants were identified in 45 genes from 177 patients. The pathogenic variant carrier rate is 21.4%: with 10.5% patients carrying a BRCA1 or BRCA2 mutation only, 10.0% of patients carried non-BRCA gene mutations only, while 1.0% of patients carried both a BRCA1/2 and a non-BRCA gene mutation. Variants of uncertain significance (VUS) totaling 2632 were identified in 115 genes from 787 of 829 patients: 82.5% patients carried more than one VUS, and only 5.1% patients did not carry any VUS. Families carrying pathogenic variants were tracked and adenoma was founded in three of them. Our data provide a comprehensive analysis of potential susceptibility variations of high-risk for breast cancer in a Chinese population. This data will be useful for the comparison of the susceptibility variation spectrum between different populations and to discover potential pathogenic variants to improve the prevention and treatment of high-risk breast cancer.

scholarly journals Integrating de novo and inherited variants in over 42,607 autism cases identifies mutations in new moderate risk genes

2021 ◽  
Author(s):  
Xueya Zhou ◽  
Pamela Feliciano ◽  
Tianyun Wang ◽  
Irina Astrovskaya ◽  
Chang Shu ◽  
...  
Keyword(s):  
Genetic Risk ◽  
De Novo ◽  
Meta Analysis ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Moderate Risk ◽  
Full Spectrum ◽  
Risk Genes ◽  
Biological Parents

AbstractDespite the known heritable nature of autism spectrum disorder (ASD), studies have primarily identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 19,843 cases with one or both biological parents and found that known ASD or neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of-function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive impairment compared to 129 ASD individuals with LoF variants in well-established, highly penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06). These findings will guide future gene discovery efforts and suggest that much larger numbers of ASD cases and controls are needed to identify additional genes that confer moderate risk of ASD through rare, inherited variants.

scholarly journals Clustering of known low and moderate risk alleles rather than a novel recessive high‐risk gene in non‐ BRCA1 /2 sib trios affected with breast cancer

2020 ◽  
Vol 147 (10) ◽  
pp. 2708-2716
Author(s):  
Florentine S. Hilbers ◽  
Peter J. Hof ◽  
Caro M. Meijers ◽  
Hailiang Mei ◽  
Kyriaki Michailidou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Moderate Risk ◽  
Risk Gene ◽  
Risk Alleles

scholarly journals BRCA1/2 Variants and Metabolic Factors: Results From a Cohort of Italian Female Carriers

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3584
Author(s):  
Andreina Oliverio ◽  
Eleonora Bruno ◽  
Mara Colombo ◽  
Angelo Paradiso ◽  
Stefania Tommasi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Logistic Regression Model ◽  
Serum Insulin ◽  
Loss Of Function ◽  
Nonsynonymous Variant ◽  
Metabolic Factors ◽  
Pathogenic Variants ◽  
Previous Diagnosis ◽  
Risk Effect ◽  
Female Carriers

Women carriers of pathogenic variants (mutations) in the BRCA1/2 genes face a high lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). However, metabolic factors may influence BRCA penetrance. We studied the association of metabolic factors with BRCA1/2 variants and the risk effect of metabolic exposures in relation to the position of the mutations within the BRCA1/2. Overall, 438 women carriers of BRCA1/2 mutations, aged 18–70, with or without a previous diagnosis of BC/OC and without metastases, who joined our randomized dietary trial, were included in the study. The pathogenic variants were divided, according to their predicted effect, into loss of function (LOF) and nonsynonymous variants. The association between metabolic exposures and variants were analyzed by a logistic regression model. LOF variant carriers showed higher levels of metabolic parameters compared to carriers of nonsynonymous variants. LOF variant carriers had significantly higher levels of plasma glucose and serum insulin than nonsynonymous variant carriers (p = 0.03 and p < 0.001, respectively). This study suggests that higher insulin levels are significantly associated with LOF variants. Further investigations are required to explore the association of metabolic factors with LOF variants and the mechanisms by which these factors may affect BRCA-related cancer risk.

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