Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer

Purpose Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population. Methods Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations. Results Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes. Conclusion Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of carrying mutations in genes other than BRCA1/2.

Download Full-text

Clinical Characteristics of Korean Breast Cancer Patients Who Carry Pathogenic Germline Mutations in Both BRCA1 and BRCA2: A Single-Center Experience

Cancers ◽

10.3390/cancers12051306 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1306

Author(s):

Joon Young Hur ◽

Ji-Yeon Kim ◽

Jin Seok Ahn ◽

Young-Hyuck Im ◽

Jiyun Lee ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Triple Negative ◽

Cancer Susceptibility ◽

Germline Mutations ◽

Breast Cancer Patients ◽

Single Center ◽

Brca1 And Brca2 ◽

Single Center Experience ◽

Cancer Susceptibility Genes

There are few reports of breast cancer patients who carry germline mutations in both germline breast cancer susceptibility genes 1 (gBRCA1) and 2 (gBRCA2). In this study, we analyzed the clinical, pathological, and genomic characteristics of Korean breast cancer patients with both gBRCA1 and gBRCA2 mutations. Medical records of patients who received gBRCA1 and gBRCA2 testing at Samsung Medical Center between January 2007 to October 2018 were retrospectively reviewed. Genomic DNA was isolated from peripheral blood leukocytes. Among a total of 2720 patients, four patients with both gBRCA1 and gBRCA2 mutations were identified (4/2720; 0.14%). Seven patients who had a gBRCA1 mutation and gBRCA2 variants of uncertain significance (VUS) were also identified. In those patients with both gBRCA1 and gBRCA2 mutations, the mean age at diagnosis for breast cancer was 36 years (range, 31–43 years). All four tumors were infiltrating ductal carcinomas and three of the tumors were estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative (triple-negative). All four patients who carried germline mutations in both BRCA1 and BRCA2 had a family history of breast/ovarian cancer. Pathologic stage was II in three patients and I in one patient. Breast cancer patients with both gBRCA1 and gBRCA2 mutations were rare, young at diagnosis, and all but one tumor was triple-negative based on our single-center experience.

Download Full-text

Absence of the CHEK2 c.1100delC mutation in familial breast and ovarian cancer in Colombia: a case-control study

F1000Research ◽

10.12688/f1000research.13368.1 ◽

2018 ◽

Vol 7 ◽

pp. 1032 ◽

Cited By ~ 1

Author(s):

Ana-Lucia Rivera-Herrera ◽

Laura Cifuentes-C ◽

JA Gil-Vera ◽

Guillermo Barreto

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Cancer Susceptibility ◽

Breast Cancer Susceptibility ◽

Brca1 And Brca2 ◽

Specific Pcr ◽

Breast Cancer Predisposition ◽

Predisposition Genes ◽

Allele Specific ◽

Allele Specific Pcr

Background: BRCA1 and BRCA2 have been identified as high-penetrance breast cancer predisposition genes, but they only account for a small fraction of the inherited component of breast cancer. To explain the remaining cases, a polygenic model with a large number of low- to moderate-penetrance genes have been proposed; one of these, is the CHEK2 gene (Checkpoint Kinase 2). The objective of this study was to determine the role of the CHEK2 gene, specifically the c.1100delC mutation in familial breast cancer susceptibility in Colombian patients. Methods: We screened 131 high-risk breast and/or ovarian cancer patients (negative for mutations in BRCA1 and BRCA2) and 131 controls for the germline mutation CHEK2 c.1100delC by allele-specific PCR. Results: None of the cases or controls showed the CHEK2 c.1100delC mutation, neither as a homozygote nor as a heterozygote. Conclusions: Our results suggest that the CHEK2 c.1100delC mutation is not a risk factor for genetic susceptibility to familial breast or ovarian cancer in the Colombian population. The absence of the CHEK2 c.1100delC mutation in our population show the importance of considering ethnic background before offering a genetic test.

Download Full-text

Racial and ethnic differences in the results of multigene panel testing of inherited cancer predisposition genes in breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1514 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1514-1514 ◽

Cited By ~ 1

Author(s):

Siddhartha Yadav ◽

Holly LaDuca ◽

Eric Polley ◽

Hermela Shimelis ◽

Nancy Niguidula ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Cancer Predisposition ◽

Ashkenazi Jewish ◽

Breast Cancer Predisposition ◽

Panel Testing ◽

Ethnic Populations ◽

Predisposition Genes ◽

Multigene Panel

1514 Background: The prevalence of germline mutations in non-white patients with breast cancer and the germline genetic drivers of breast cancer risk in non-white populations are largely unknown. Methods: The study population included 77,900 women with breast cancer (Non-Hispanic white: 57,003; Black: 6,722; Asian: 4,183; Hispanic: 5,194; Ashkenazi-Jewish: 4,798) who underwent germline multigene panel testing of cancer predisposition genes from March 2012 to December 2016. The prevalence of predisposition gene mutations in racial and ethnic populations relative to non-Hispanic Whites was assessed while accounting for age at diagnosis of breast cancer, family history of breast and ovarian cancer, and estrogen receptor status of breast tumors. Associations between mutations in each gene and breast cancer risk were evaluated using reference controls. Results: The overall frequency of pathogenic mutations in known breast cancer predisposition genes was 9.1% for non-Hispanic Whites, 9.8% for African Americans, 10.2% for Hispanics, 7.6% for Ashkenazi-Jewish, and 7.5% for Asians. BRCA1 mutations were enriched (p < 0.05) and CHEK2 mutations were under-represented in all racial and ethnic populations relative to non-Hispanic Whites. BRCA2 and BARD1 mutations were enriched in African Americans and Hispanics relative to non-Hispanic Whites, whereas PALB2 and RAD51C mutations were enriched in Hispanics. Among genes with mutation counts large enough for assessment, mutations in BARD1, BRCA1, BRCA2, PALB2 and TP53 were significantly associated with clinically relevant increased risks (odds ratio (OR) > 2) of breast cancer across all ethnicities and races. Rates of variants of uncertain significance were highest among Asians (29%), followed by blacks (27%), Hispanics (21%), non-Hispanic whites (16%) and Ashkenazi-Jews (14%). Conclusions: While there is some similarity across ethnic groups, substantial heterogeneity exists in the prevalence of mutations in breast cancer predisposition genes across major racial and ethnic groups in the US population. These findings contribute to our understanding of breast cancer risk and have significant implications for genetic testing, screening, and management of patients with an inherited predisposition to breast cancer, with a need for continued analysis with increased cohort size in ethnic minority groups.

Download Full-text

Detection of novel germline mutations in six breast cancer predisposition genes by targeted next-generation sequencing

Human Mutation ◽

10.1002/humu.23597 ◽

2018 ◽

Vol 39 (10) ◽

pp. 1442-1455 ◽

Cited By ~ 2

Author(s):

Li Dong ◽

Nan Wu ◽

Shaojing Wang ◽

Yanan Cheng ◽

Lei Han ◽

...

Keyword(s):

Breast Cancer ◽

Next Generation Sequencing ◽

Germline Mutations ◽

Cancer Predisposition ◽

Next Generation ◽

Targeted Next Generation Sequencing ◽

Breast Cancer Predisposition ◽

Predisposition Genes ◽

Generation Sequencing

Download Full-text

Abstract PD1-01: Triple negative breast cancer predisposition genes

10.1158/1538-7445.sabcs17-pd1-01 ◽

2018 ◽

Author(s):

FJ Couch ◽

H Shimelis ◽

H LaDuca ◽

C Hu ◽

SN Hart ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cancer Predisposition ◽

Breast Cancer Predisposition ◽

Predisposition Genes

Download Full-text

Discovery of structural deletions in breast cancer predisposition genes using whole genome sequencing data from > 2000 women of African-ancestry

Human Genetics ◽

10.1007/s00439-021-02342-8 ◽

2021 ◽

Author(s):

Zhishan Chen ◽

Xingyi Guo ◽

Jirong Long ◽

Jie Ping ◽

Bingshan Li ◽

...

Keyword(s):

Breast Cancer ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

African Ancestry ◽

Cancer Predisposition ◽

Whole Genome Sequencing Data ◽

Whole Genome ◽

Sequencing Data ◽

Breast Cancer Predisposition ◽

Predisposition Genes

Download Full-text

Primer on Hereditary Cancer Predisposition Genes Included Within Somatic Next-Generation Sequencing Panels

JCO Precision Oncology ◽

10.1200/po.18.00258 ◽

2019 ◽

pp. 1-11

Author(s):

Zade Akras ◽

Brandon Bungo ◽

Brandie H. Leach ◽

Jessica Marquard ◽

Manmeet Ahluwalia ◽

...

Keyword(s):

Hereditary Cancer ◽

Cancer Susceptibility ◽

Cancer Predisposition ◽

Comprehensive Overview ◽

Germline Variants ◽

Cancer Susceptibility Genes ◽

Germline Genes ◽

Number Of Genes ◽

Predisposition Genes ◽

Hereditary Cancer Predisposition

PURPOSE It has been estimated that 5% to 10% of cancers are due to hereditary causes. Recent data sets indicate that the incidence of hereditary cancer may be as high as 17.5% in patients with cancer, and a notable subset is missed if screening is solely by family history and current syndrome-based testing guidelines. Identification of germline variants has implications for both patients and their families. There is currently no comprehensive overview of cancer susceptibility genes or inclusion of these genes in commercially available somatic testing. We aimed to summarize genes linked to hereditary cancer and the somatic and germline panels that include such genes. METHODS Germline predisposition genes were chosen if commercially available for testing. Penetrance was defined as low, moderate, or high according to whether the gene conferred a 0% to 20%, 20% to 50%, or 50% to 100% lifetime risk of developing the cancer or, when percentages were not available, was estimated on the basis of existing literature descriptions. RESULTS We identified a total of 89 genes linked to hereditary cancer predisposition, and we summarized these genes alphabetically and by organ system. We considered four germline and six somatic commercially available panel tests and quantified the coverage of germline genes across them. Comparison between the number of genes that had germline importance and the number of genes included in somatic testing showed that many but not all germline genes are tested by frequently used somatic panels. CONCLUSION The inclusion of cancer-predisposing genes in somatic variant testing panels makes incidental germline findings likely. Although somatic testing can be used to screen for germline variants, this strategy is inadequate for comprehensive screening. Access to genetic counseling is essential for interpretation of germline implications of somatic testing and implementation of appropriate screening and follow-up.

Download Full-text

Clinical Implications of the Breast Cancer Susceptibility Genes BRCA1 and BRCA2

Women s Health ◽

10.1517/17455057.1.1.027 ◽

2005 ◽

Vol 1 (1) ◽

pp. 27-34

Author(s):

Steven A Narod

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Cancer Susceptibility ◽

Cancer Chemoprevention ◽

Breast Cancer Susceptibility ◽

High Risk Population ◽

Clinical Genetics ◽

Breast And Ovarian Cancer ◽

Brca1 And Brca2 ◽

Cancer Susceptibility Genes

Genetic testing for BRCA1 and BRCA2 mutations has become an important part of the practice of medical oncology and clinical genetics over the past decade. Increasing numbers of women are requesting a genetic test so that they may better understand their personal risks of breast and ovarian cancer, and so that they may take appropriate measures to reduce the risk. Several of the risk factors can be modified, including breastfeeding and the use of oral contraceptives. A significant number of women opt for preventive mastectomy or oophorectomy, which will dramatically reduce the risks of breast and ovarian cancer. Chemoprevention with tamoxifen is still uncommon, largely due to women's fears of the side effects of the drug. A number of studies have shown that magnetic resonance imaging is superior to conventional mammography in terms of the early detection of breast cancer in the high-risk population. This article explores what is known about assessing genetic risk and the evidence supporting a range of preventive strategies.

Download Full-text