scholarly journals Penetrance of breast cancer genes from the eMERGE III Network

2021 ◽  
Author(s):  
Xiao Fan ◽  
Julia Wynn ◽  
Shang Ning ◽  
Cong Liu ◽  
Alexander Fedotov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Population Based ◽  
Cancer Genes ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Potential Clinical Impact ◽  
Brca1 Brca2 ◽  
Genetic Results

We studied the penetrance and clinical outcomes of seven breast cancer susceptibility genes (BRCA1, BRCA2, TP53, CHEK2, ATM, PALB2 and PTEN) in almost 25,000 participants unselected for personal or family history of breast cancer. We identified 420 participants with pathogenic or likely pathogenic variants, and 147 were women who did not previously know their genetic results. Out of these 147 women, 32 women were diagnosed with breast cancer at an average age of 52.8 years. Estimated penetrance by age 60 years ranged from 18-44%, depending on the gene. Within the first twelve months after genetic results disclosure, 42% of women had taken actions related to their genetic results and two new breast cancer cases were identified. Our study provides population-based penetrance estimates for the understudied genes, CHEK2, ATM, and PALB2, and highlights the importance of using unselected populations for penetrance studies. It also demonstrates the potential clinical impact of genetic testing to improve healthcare through early diagnosis and preventative screening.

Evidence for further breast cancer susceptibility genes in addition toBRCA1 andBRCA2 in a population-based study

2001 ◽  
Vol 21 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Antonis C. Antoniou ◽  
Paul D.P. Pharoah ◽  
Greg McMullan ◽  
Nickolas E. Day ◽  
Bruce A.J. Ponder ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Population Based ◽  
Susceptibility Genes ◽  
Population Based Study ◽  
Cancer Susceptibility Genes ◽  
Breast Cancer Susceptibility Genes

scholarly journals Breast cancer risks associated with missense variants in breast cancer susceptibility genes

2021 ◽  
Author(s):  
Leila Dorling ◽  
Sara Carvalho ◽  
Jamie Allen ◽  
Michael Parsons ◽  
Cristina Fortuno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
In Silico ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Cancer Risks ◽  
Functional Protein ◽  
Missense Variants ◽  
Cancer Susceptibility Genes ◽  
Gene Panel Testing ◽  
Brca1 Brca2

BACKGROUND Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2 and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS Combining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), CHEK2 (325) and PALB2 (472). We evaluated breast cancer risks according to five in-silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS The most predictive in-silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1 and BRCA2, data were compatible with small subsets (approximately 7%, 2% and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS These results will inform risk prediction models and the selection of candidate variants for functional assays, and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.

scholarly journals A novel high-throughput assay using mixed genomic DNA for fast screening germline pathogenic variants in breast cancer susceptibility genes

2021 ◽  
Author(s):  
Qiting Wan ◽  
Li Hu ◽  
Lu Yao ◽  
Jiuan Chen ◽  
Jie Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Throughput ◽  
Genomic Dna ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Breast Cancer Susceptibility Genes ◽  
High Throughput Assay

The demand for genetic testing for breast cancer susceptibility genes is increasing for both breast cancer patients and healthy individuals. Here we established a novel high-throughput assay to detect germline pathogenic variants in breast cancer susceptibility genes. In general, up 10 to 50 individual genomic DNA samples were mixed together to create a mixed DNA sample and the mixed DNA sample was subjected to a next-generation multigene panel. Germline pathogenic variants in breast cancer susceptibility genes could be found in the mixed DNA sample; next, site-specific Sanger sequencing was performed to identify individuals who carried he pathogenic variant in the mixed samples. We found that the recall and precision rates were 89.9% and 92.9% when twenty individual genomic samples were mixed. Therefore, our new assay can increase an approximately 20-fold of efficacy to identify the pathogenic variants in breast cancer susceptibility genes in individuals when compared with current assay.

scholarly journals Mutational Spectrum of Breast Cancer Susceptibility Genes among Women in Northeast Brazil

2021 ◽  
Author(s):  
Gabriela ES Felix ◽  
Rodrigo Santa Cruz Guindalini ◽  
Yonglan Zheng ◽  
Tom Walsh ◽  
Elisabeth Sveen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Assessment ◽  
Cancer Susceptibility ◽  
African Ancestry ◽  
Breast Cancer Susceptibility ◽  
Cancer Risk Assessment ◽  
Northeast Brazil ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Breast Cancer Susceptibility Genes

Abstract Purpose: There is a paucity of data on the spectrum and prevalence of pathogenic variants among women of African ancestry in the Northeast region of Brazil. Methods: We performed BROCA panel sequencing to identify inherited loss-of-function variants in breast cancer susceptibility genes among 292 Brazilian women referred to a single institution cancer risk assessment program. Results: The study included a convenient cohort of 173 women with invasive breast cancer and 119 women who were cancer-free at the time of ascertainment. The majority of the women self-reported as African-descended (67% for cases and 90.8% for controls). Thirty-seven pathogenic variants were found in 36 (20.8%) patients. While the spectrum of pathogenic variants was heterogeneous, the majority (70.3%) of the pathogenic variants were detected in high-risk genes BRCA1 , BRCA2 , PALB2 , and TP53 . Pathogenic variants were also found in the ATM , BARD1 , BRIP1 , FAM175A , FANCM , NBN , and SLX4 genes in 6.4% of the affected women. Four recurrent pathogenic variants were detected in 11 patients of African ancestry. Only one unaffected woman had a pathogenic variant in the RAD51C gene. Conclusion: The high prevalence and heterogenous spectrum of pathogenic variants identified among self-reported African descendants in Northeast Brazil is consistent with studies in other African populations with a high burden of aggressive young onset breast cancer. It underscores the need to integrate comprehensive cancer risk assessment and genomic testing in the management of newly diagnosed Black women with breast cancer across the African Diaspora, enabling improved cancer control in admixed underserved and understudied populations.

Breast cancer treatment according to pathogenic variants in cancer susceptibility genes in a population-based cohort.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 560-560 ◽  
Author(s):  
Allison W. Kurian ◽  
Kevin C. Ward ◽  
Paul Abrahamse ◽  
Ann S Hamilton ◽  
Dennis Deapen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Genetic Test ◽  
Cancer Susceptibility ◽  
Population Based ◽  
Susceptibility Genes ◽  
Breast Cancer Treatment ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
To Receive

560 Background: Increasing use of germline genetic testing may have unintended consequences on breast cancer treatment. We do not know whether treatment deviates from guidelines for women with pathogenic variants (PV) in cancer susceptibility genes. Methods: SEER data for all women aged ≥20 years, diagnosed with breast cancer in 2014-15 and reported to Georgia and California registries (N = 77,588) by December 1, 2016 were linked to germline genetic testing results from 4 laboratories that did nearly all clinical testing. We examined first course of therapy (before recurrence or progression) of stage < IV patients who linked to a genetic test: bilateral mastectomy (BLM) in candidates for surgery (unilateral, stages 0-III); post-lumpectomy radiation in those with an indication (all but age ≥70, stage I, hormone receptor (HR)-positive and HER2-negative); and chemotherapy in those without a definitive indication (stage I-II, HR-positive, HER2-negative and 21-gene recurrence score < 30). We report the percent treated based on multivariable modeling, adjusted for age, race, stage, grade, insurance and socioeconomic status. Results: The table shows that 9% of patients who linked to a genetic test result had a PV (N = 1,283). Compared to women with negative results,women with BRCA1/2 PVs were more likely to receive BLM, more likely to receive chemotherapy without definitive indication, and less likely to receive indicated radiation in their first course of therapy. Lower-magnitude effects were seen with other PVs but not variants of uncertain significance (VUS). Conclusions: In a population-based setting, women with PVs in BRCA1/2 or other cancer susceptibility genes may have a higher risk of receiving locoregional and systemic treatment that does not follow guidelines. [Table: see text]

scholarly journals Development and Validation of a Clinical Polygenic Risk Score to Predict Breast Cancer Risk

2020 ◽  
pp. 585-592 ◽  
Author(s):  
Elisha Hughes ◽  
Placede Tshiaba ◽  
Shannon Gallagher ◽  
Susanne Wagner ◽  
Thaddeus Judkins ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Cancer History ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Breast Cancer Susceptibility Genes

PURPOSE Women with a family history of breast cancer are frequently referred for hereditary cancer genetic testing, yet < 10% are found to have pathogenic variants in known breast cancer susceptibility genes. Large-scale genotyping studies have identified common variants (primarily single-nucleotide polymorphisms [SNPs]) with individually modest breast cancer risk that, in aggregate, account for considerable breast cancer susceptibility. Here, we describe the development and empirical validation of an SNP-based polygenic breast cancer risk score. METHODS A panel of 94 SNPs was examined for association with breast cancer in women of European ancestry undergoing hereditary cancer genetic testing and negative for pathogenic variants in breast cancer susceptibility genes. Candidate polygenic risk scores (PRSs) as predictors of personal breast cancer history were developed through multivariable logistic regression models adjusted for age, cancer history, and ancestry. An optimized PRS was validated in 2 independent cohorts (n = 13,174; n = 141,160). RESULTS Within the training cohort (n = 24,259), 4,291 women (18%) had a personal history of breast cancer and 8,725 women (36%) reported breast cancer in a first-degree relative. The optimized PRS included 86 variants and was highly predictive of breast cancer status in both validation cohorts ( P = 6.4 × 10−66; P < 10−325). The odds ratio (OR) per unit standard deviation was consistent between validations (OR, 1.45 [95% CI, 1.39 to 1.52]; OR 1.47 [95% CI, 1.45 to 1.49]). In a direct comparison, the 86-SNP PRS outperformed a previously described PRS of 77 SNPs. CONCLUSION The validation and implementation of a PRS for women without pathogenic variants in known breast cancer susceptibility genes offers potential for risk stratification to guide surveillance recommendations.

Sign in / Sign up

Export Citation Format

Share Document