Triple-negative breast cancer and PTEN ( phosphatase and tensin homologue ) loss are predictors of BRCA 1 germline mutations in women with early-onset and familial breast cancer , but not in women with isolated late-onset breast cancer

Introduction: Given that breast cancers in germline BRCA1 carriers are predominantly estrogen-negative and triplenegative, it has been suggested that women diagnosed with triple-negative breast cancer (TNBC) younger than 50 years should be offered BRCA1 testing, regardless of family cancer characteristics. However, the predictive value of triple-negative breast cancer, when taken in the context of personal and family cancer characteristics, is unknown. The aim of this study was to determine whether TNBC is a predictor of germline BRCA1 mutations, in the context of multiple predictive factors. Methods: Germline mutations in BRCA1 and BRCA2 were analyzed by Sanger sequencing and multiple ligationdependent probe amplification (MLPA) analysis in 431 women from the Malaysian Breast Cancer Genetic Study, including 110 women with TNBC. Logistic regression was used to identify and to estimate the predictive strength of major determinants. Estrogen receptor (ER) and phosphatase and tensin homologue (PTEN) status were assessed and included in a modified Manchester scoring method. Results: Our study in an Asian series of TNBC patients demonstrated that 27 (24.5%) of 110 patients have germline mutations in BRCA1 (23 of 110) and BRCA2 (four of 110). We found that among women diagnosed with breast cancer aged 36 to 50 years but with no family history of breast or ovarian cancer, the prevalence of BRCA1 and BRCA2 mutations was similar in TNBC (8.5%) and non-TNBC patients (6.7%). By contrast, in women diagnosed with breast cancer, younger than 35 years, with no family history of these cancers, and in women with a family history of breast cancer, the prevalence of mutations was higher in TNBC compared with non-TNBC (28.0% and 9.9%; P = 0.045; and 42.1% and 14.2%; P < 0.0001, respectively]. Finally, we found that incorporation of estrogen-receptor and TNBC status improves the sensitivity of the Manchester Scoring method (42.9% to 64.3%), and furthermore, incorporation of PTEN status further improves sensitivity (42.9% to 85.7%). Conclusions: We found that TNBC is an important criterion for highlighting women who may benefit from genetic testing, but that this may be most useful for women with early-onset breast cancer (35 years or younger) or with a family history of cancers. Furthermore, addition of TNBC and PTEN status improves the sensitivity of the Manchester scoring method and may be particularly important in the Asian context, where risk-assessment models underestimate the number of mutation carriers. * Correspondence: soohwang.teo@carif.com.my Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, Subang Jaya, 47500 Selangor, Malaysia Full list of author information is available at the end of the article Phuah et al. Breast Cancer Research 2012, 14:R142 http://breast-cancer-research.com/content/14/6/R142 © 2012 Phuah et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

[1]  C. Deng,et al.  Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155 , 2011, Nature Medicine.

[2]  Diane D. Liu,et al.  Outcome of triple-negative breast cancer in patients with or without deleterious BRCA mutations , 2011, Breast Cancer Research and Treatment.

[3]  A. Howell,et al.  Prevalence of BRCA1 and BRCA2 mutations in triple negative breast cancer , 2011, Journal of Medical Genetics.

[4]  C. Hudis,et al.  Relative contributions of BRCA1 and BRCA2 mutations to “triple-negative” breast cancer in Ashkenazi Women , 2011, Breast Cancer Research and Treatment.

[5]  S. Teo,et al.  Genetic counseling for patients and families with hereditary breast and ovarian cancer in a developing Asian country: an observational descriptive study , 2011, Familial Cancer.

[6]  G. Mills,et al.  Incidence and Outcome of BRCA Mutations in Unselected Patients with Triple Receptor-Negative Breast Cancer , 2011, Clinical Cancer Research.

[7]  Alan Ashworth,et al.  Synthetic lethal approaches to breast cancer therapy , 2010, Nature Reviews Clinical Oncology.

[8]  J. Kwon,et al.  Expanding the criteria for BRCA mutation testing in breast cancer survivors. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  T. Rebbeck,et al.  Incorporating tumour pathology information into breast cancer risk prediction algorithms , 2010, Breast Cancer Research.

[10]  A. Kurian BRCA1 and BRCA2 mutations across race and ethnicity: distribution and clinical implications , 2010, Current opinion in obstetrics & gynecology.

[11]  S. Fox,et al.  Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers , 2009, Nature Medicine.

[12]  E A Jones,et al.  Addition of pathology and biomarker information significantly improves the performance of the Manchester scoring system for BRCA1 and BRCA2 testing , 2009, Journal of Medical Genetics.

[13]  Stephanie A Cohen,et al.  The prevalence of BRCA1 mutations among young women with triple-negative breast cancer , 2009, BMC Cancer.

[14]  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.

[15]  C. Yip,et al.  Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer , 2008, Breast Cancer Research.

[16]  S. Teo,et al.  BRCA1 and BRCA2 Germline Mutations in Malaysian Women with Early-Onset Breast Cancer without a Family History , 2008, PloS one.

[17]  L. Saal,et al.  Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair , 2008, Nature Genetics.

[18]  B. Mukesh,et al.  Optimal selection of individuals for BRCA mutation testing: a comparison of available methods. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  Julian Peto,et al.  Prediction of BRCA1 Status in Patients with Breast Cancer Using Estrogen Receptor and Basal Phenotype , 2005, Clinical Cancer Research.

[20]  N. Rahman,et al.  Update on the Manchester Scoring System for BRCA1 and BRCA2 testing , 2005, Journal of Medical Genetics.

[21]  B. Haffty,et al.  Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women , 2005, Journal of Medical Genetics.

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

[23]  S. Fisher,et al.  Log odds of carrying an Ancestral Mutation in BRCA1 or BRCA2 for a Defined personal and family history in an Ashkenazi Jewish woman (LAMBDA) , 2003, Breast Cancer Research.

[24]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Sng,et al.  Pathological features and BRCA1 mutation screening in premenopausal breast cancer patients. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  D. Birnbaum,et al.  Major improvement in the efficacy of BRCA1 mutation screening using morphoclinical features of breast cancer. , 2000, Cancer research.

[27]  M. Stratton,et al.  Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. , 1998, Journal of the National Cancer Institute.

[28]  M N Pollak,et al.  Influence of BRCA1 mutations on nuclear grade and estrogen receptor status of breast carcinoma in Ashkenazi Jewish women , 1997, Cancer.