Dataset Information

Penetrance of Breast Cancer Susceptibility Genes From the eMERGE III Network.

ABSTRACT: Unbiased estimates of penetrance are challenging but critically important to make informed choices about strategies for risk management through increased surveillance and risk-reducing interventions. We studied the penetrance and clinical outcomes of 7 breast cancer susceptibility genes (BRCA1, BRCA2, TP53, CHEK2, ATM, PALB2, and PTEN) in almost 13 458 participants unselected for personal or family history of breast cancer. We identified 242 female participants with pathogenic or likely pathogenic variants in 1 of the 7 genes for penetrance analyses, and 147 women did not previously know their genetic results. Out of the 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 17.8% to 43.8%, depending on the gene. In clinical-impact analysis, 42.3% (95% confidence interval = 31.3% to 53.3%) of women had taken actions related to their genetic results, and 2 new breast cancer cases were identified within the first 12 months after genetic results disclosure. 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 health care through early diagnosis and preventative screening.

SUBMITTER: Fan X

PROVIDER: S-EPMC8346699 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Penetrance of Breast Cancer Susceptibility Genes From the eMERGE III Network.

Fan Xiao X Wynn Julia J Shang Ning N Liu Cong C Fedotov Alexander A Hallquist Miranda L G MLG Buchanan Adam H AH Williams Marc S MS Smith Maureen E ME Hoell Christin C Rasmussen-Torvik Laura J LJ Peterson Josh F JF Wiesner Georgia L GL Murad Andrea M AM Jarvik Gail P GP Gordon Adam S AS Rosenthal Elisabeth A EA Stanaway Ian B IB Crosslin David R DR Larson Eric B EB Leppig Kathleen A KA Henrikson Nora B NB Williams Janet L JL Li Rongling R Hebbring Scott S Weng Chunhua C Shen Yufeng Y Crew Katherine D KD Chung Wendy K WK

JNCI cancer spectrum 20210508 4

<h4>Background</h4>Unbiased estimates of penetrance are challenging but critically important to make informed choices about strategies for risk management through increased surveillance and risk-reducing interventions.<h4>Methods</h4>We studied the penetrance and clinical outcomes of 7 breast cancer susceptibility genes (<i>BRCA1</i>, <i>BRCA2</i>, <i>TP53</i>, <i>CHEK2</i>, <i>ATM</i>, <i>PALB2</i>, and <i>PTEN</i>) in almost 13 458 participants unselected for personal or family history of brea ...[more]

PMID: 34377931

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Project description:BackgroundRecent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined.MethodsWe applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence.ResultsFirst, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the "omic" properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk.ConclusionThis study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common omic properties, molecular interactions and possible functional effects of candidate genes and proteins.

Project description:Significant advances have been made to understand the genetic basis of breast cancer. High, moderate and low penetrance variants have been identified with inter-ethnic variability in mutation frequency and spectrum. Genome wide association studies (GWAS) are widely used to identify disease-associated SNPs. Understanding the functional impact of these risk-SNPs will help the translation of GWAS findings into clinical interventions. Here we aim to characterize the genetic patterns of high and moderate penetrance breast cancer susceptibility genes and to assess the functional impact of non-coding SNPs. We analyzed BRCA1/2, PTEN, STK11, TP53, ATM, BRIP1, CHEK2 and PALB2 genotype data obtained from 135 healthy participants genotyped using Affymetrix Genome-Wide Human SNP-Array 6.0. Haplotype analysis was performed using Haploview.V4.2 and PHASE.V2.1. Population structure and genetic differentiation were assessed using principal component analysis (PCA) and fixation index (FST). Functional annotation was performed using In Silico web-based tools including RegulomeDB and VARAdb. Haplotype analysis showed distinct LD patterns with high levels of recombination and haplotype blocks of moderate to small size. Our findings revealed also that the Tunisian population tends to have a mixed origin with European, South Asian and Mexican footprints. Functional annotation allowed the selection of 28 putative regulatory variants. Of special interest were BRCA1_ rs8176318 predicted to alter the binding sites of a tumor suppressor miRNA hsa-miR-149 and PALB2_ rs120963 located in tumorigenesis-associated enhancer and predicted to strongly affect the binding of P53. Significant differences in allele frequencies were observed with populations of African and European ancestries for rs8176318 and rs120963 respectively. Our findings will help to better understand the genetic basis of breast cancer by guiding upcoming genome wide studies in the Tunisian population. Putative functional SNPs may be used to develop an efficient polygenic risk score to predict breast cancer risk leading to better disease prevention and management.

Dataset Information

Penetrance of Breast Cancer Susceptibility Genes From the eMERGE III Network.

Publications

Penetrance of Breast Cancer Susceptibility Genes From the eMERGE III Network.

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