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.

[1]  C. Begg,et al.  Rare germline mutations in PALB2 and breast cancer risk: A population‐based study , 2012, Human mutation.

[2]  Lara E Sucheston-Campbell,et al.  Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. , 2015, Journal of the National Cancer Institute.

[3]  C. Eng,et al.  Lifetime Cancer Risks in Individuals with Germline PTEN Mutations , 2012, Clinical Cancer Research.

[4]  D. Pruss,et al.  A comprehensive laboratory‐based program for classification of variants of uncertain significance in hereditary cancer genes , 2014, Clinical genetics.

[5]  Willy Lissens,et al.  Cancer predisposing missense and protein truncating BARD1 mutations in non‐BRCA1 or BRCA2 breast cancer families , 2010, Human mutation.

[6]  Dieter Niederacher,et al.  Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene , 2010, Nature Genetics.

[7]  J. Manola,et al.  PrECOG 0105: Final efficacy results from a phase II study of gemcitabine (G) and carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer. , 2013 .

[8]  M. Rezai,et al.  Pathological complete response (pCR) rates after carboplatin-containing neoadjuvant chemotherapy in patients with germline BRCA (gBRCA) mutation and triple-negative breast cancer (TNBC): Results from GeparSixto. , 2014 .

[9]  William D. Foulkes,et al.  Re: Germline BRCA1 Mutations and a Basal Epithelial Phenotype in Breast Cancer , 2004 .

[10]  Brigitte Rack,et al.  Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  Yuya Kobayashi,et al.  Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  J. Schleutker,et al.  RAD51C is a susceptibility gene for ovarian cancer. , 2011, Human molecular genetics.

[13]  Barry Rosen,et al.  Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. , 2006, Journal of the National Cancer Institute.

[14]  Nazneen Rahman,et al.  Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles , 2006, Nature Genetics.

[15]  D. Pruss,et al.  Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes , 2014, Breast Cancer Research and Treatment.

[16]  S. Gruber,et al.  Frequency and Spectrum of Cancers in the Peutz-Jeghers Syndrome , 2006, Clinical Cancer Research.

[17]  J. Oosterwijk,et al.  Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age , 2010, Breast Cancer Research and Treatment.

[18]  Lara E Sucheston-Campbell,et al.  Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  Karla Bowles,et al.  Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next‐generation sequencing with a 25‐gene panel , 2015, Cancer.

[20]  S. Seal,et al.  Germline RAD51C mutations confer susceptibility to ovarian cancer , 2012, Nature Genetics.

[21]  B. Karlan,et al.  Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  T. Rebbeck,et al.  Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. , 2002, Journal of the National Cancer Institute.

[23]  S. Cross,et al.  CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  C. Begg,et al.  Variation of breast cancer risk among BRCA1/2 carriers. , 2008, JAMA.

[25]  A. Whittemore,et al.  BRCA2 Mutation-associated Breast Cancers Exhibit a Distinguishing Phenotype Based on Morphology and Molecular Profiles From Tissue Microarrays , 2007, The American journal of surgical pathology.

[26]  T. Frebourg,et al.  Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes , 2014, European Journal of Human Genetics.

[27]  Christopher I Amos,et al.  Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  L. Bégin,et al.  Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. , 2004, Journal of the National Cancer Institute.

[29]  Sean V Tavtigian,et al.  Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  Deborah Hughes,et al.  Germline mutations in RAD51D confer susceptibility to ovarian cancer , 2011, Nature Genetics.

[31]  Angela DeMichele,et al.  Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2 negative patients with early onset breast cancer , 2014, Genetics in Medicine.

[32]  A. Oza,et al.  Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer. , 2010 .

[33]  A. Gylfason,et al.  Mutations in BRIP1 confer high risk of ovarian cancer , 2011, Nature Genetics.

[34]  A. Jakubowska,et al.  Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. , 2015, The Lancet. Oncology.

[35]  A Hollestelle,et al.  Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: impact of adjuvant chemotherapy , 2014, British Journal of Cancer.

[36]  Thomas J. Smith,et al.  American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  M. Akbari,et al.  Genetic testing for RAD51C mutations: in the clinic and community , 2015, Clinical genetics.

[38]  Preclinical S Tudy.  Inherited predisposition to breast cancer among African American women , 2015 .

[39]  Yuya Kobayashi,et al.  Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment. , 2015, JAMA oncology.

[40]  R. Tibshirani,et al.  Repeated observation of breast tumor subtypes in independent gene expression data sets , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Mark Robson,et al.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial , 2010, The Lancet.

[42]  Giovanni Parmigiani,et al.  Meta-analysis of BRCA1 and BRCA2 penetrance. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  W. Foulkes,et al.  Breast-cancer risk in families with mutations in PALB2. , 2014, The New England journal of medicine.

[44]  Cancer predisposing BARD1 mutations in breast–ovarian cancer families , 2011, Breast Cancer Research and Treatment.

[45]  Nazneen Rahman,et al.  Gene-panel sequencing and the prediction of breast-cancer risk. , 2015, The New England journal of medicine.

[46]  S. Miller,et al.  Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers With Cancer Risk and Mortality , 2012 .

[47]  C Caldas,et al.  Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. , 2001, Gastroenterology.

[48]  Satish Bhatnagar,et al.  T E C H N I C a L a D V a N C E Open Access , 2022 .

[49]  K. A. Gelmon.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial , 2011 .

[50]  S. Gruber,et al.  Relative frequency and morphology of cancers in STK11 mutation carriers. , 2004, Gastroenterology.

[51]  C. Pilarsky,et al.  Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data. , 2004, Neoplasia.

[52]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[53]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[54]  A. Tutt,et al.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial , 2010, The Lancet.