Non-BRCA1/2 Variants Detected in a High-Risk Chilean Cohort With a History of Breast and/or Ovarian Cancer

PURPOSE Little is known about the genetic predisposition to breast and ovarian cancer among the Chilean population, in particular genetic predisposition beyond BRCA1 and BRCA2 mutations. In the current study, we aim to describe the germline variants detected in individuals who were referred to a hereditary cancer program in Santiago, Chile. METHODS Data were retrospectively collected from the registry of the High-Risk Breast and Ovarian Cancer Program at Clínica Las Condes, Santiago, Chile. Data captured included index case diagnosis, ancestry, family history, and genetic test results. RESULTS Three hundred fifteen individuals underwent genetic testing during the study period. The frequency of germline pathogenic and likely pathogenic variants in a breast or ovarian cancer predisposition gene was 20.3%. Of those patients who underwent testing with a panel of both high- and moderate-penetrance genes, 10.5% were found to have pathogenic or likely pathogenic variants in non-BRCA1/2 genes. CONCLUSION Testing for non-BRCA1 and -2 mutations may be clinically relevant for individuals who are suspected to have a hereditary breast or ovarian cancer syndrome in Chile. Comprehensive genetic testing of individuals who are at high risk is necessary to further characterize the genetic susceptibility to cancer in Chile.

[1]  Tom Walsh,et al.  Genomic analysis of inherited breast cancer among Palestinian women: Genetic heterogeneity and a founder mutation in TP53 , 2017, International journal of cancer.

[2]  Adrina Zhong,et al.  Ethical, social, and cultural issues related to clinical genetic testing and counseling in low- and middle-income countries: protocol for a systematic review , 2017, Systematic Reviews.

[3]  L. Carvajal-Carmona,et al.  BRCA1 and BRCA2 founder mutations account for 78% of germline carriers among hereditary breast cancer families in Chile. , 2017, Oncotarget.

[4]  A. Meindl,et al.  The RAD51C exonic splice-site mutations c.404G>C and c.404G>T are associated with familial breast and ovarian cancer , 2017, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[5]  J. Weitzel,et al.  Genetic Cancer Risk Assessment for Breast Cancer in Latin America. , 2017, Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion.

[6]  E. Podesta,et al.  Spectrum of BRCA1/2 variants in 940 patients from Argentina including novel, deleterious and recurrent germline mutations: impact on healthcare and clinical practice , 2016, Oncotarget.

[7]  Georgia Vasileiou,et al.  Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2 , 2017, International journal of cancer.

[8]  C. Ossa,et al.  A multi-gene panel study in hereditary breast and ovarian cancer in Colombia , 2017, Familial Cancer.

[9]  J. L. Costa,et al.  Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry , 2016, Oncotarget.

[10]  P. Ashton-Prolla,et al.  Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations. , 2016, Cancer genetics.

[11]  H. LaDuca,et al.  Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers. , 2016, Cancer genetics.

[12]  U. Hamann,et al.  High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients , 2016, BMC Cancer.

[13]  M. Teixeira,et al.  Implementation of next-generation sequencing for molecular diagnosis of hereditary breast and ovarian cancer highlights its genetic heterogeneity , 2016, Breast Cancer Research and Treatment.

[14]  D. Torres,et al.  Founder and Recurrent Mutations in BRCA1 and BRCA2 Genes in Latin American Countries: State of the Art and Literature Review. , 2016, The oncologist.

[15]  Liying Zhang,et al.  Prevalence and Prognostic Role of BRCA1/2 Variants in Unselected Chinese Breast Cancer Patients , 2016, PloS one.

[16]  Raymond M. Moore,et al.  Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. , 2016, American journal of human genetics.

[17]  Kenneth Offit,et al.  Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015. , 2016, Journal of the National Comprehensive Cancer Network : JNCCN.

[18]  James Y. Zou.  Analysis of protein-coding genetic variation in 60,706 humans , 2015, Nature.

[19]  L. Mæhle,et al.  Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort , 2016, Familial Cancer.

[20]  S. Narod,et al.  Revisiting breast cancer patients who previously tested negative for BRCA mutations using a 12-gene panel , 2016, Breast Cancer Research and Treatment.

[21]  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.

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

[23]  M. Teixeira,et al.  The role of targeted BRCA1/BRCA2 mutation analysis in hereditary breast/ovarian cancer families of Portuguese ancestry , 2015, Clinical genetics.

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

[25]  Jane E. Carpenter,et al.  Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer , 2015, Breast Cancer Research and Treatment.

[26]  C. Pérez-Plasencia,et al.  Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico , 2015, Cancer.

[27]  J. Tapia,et al.  Association of PALB2 sequence variants with the risk of familial and early-onset breast cancer in a South-American population , 2015, BMC Cancer.

[28]  E. Friedman,et al.  Screening for germline mutations in breast/ovarian cancer susceptibility genes in high-risk families in Israel , 2015, Breast Cancer Research and Treatment.

[29]  B. Fridley,et al.  The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. , 2014, Human molecular genetics.

[30]  Nancy R. Zhang,et al.  Metastatic tumor evolution and organoid modeling implicate TGFBR2 as a cancer driver in diffuse gastric cancer , 2014, Genome Biology.

[31]  P. Andreassen,et al.  PALB2: the hub of a network of tumor suppressors involved in DNA damage responses. , 2014, Biochimica et biophysica acta.

[32]  Lincoln D. Stein,et al.  Exome sequencing identifies nonsegregating nonsense ATM and PALB2 variants in familial pancreatic cancer , 2013, Human Genomics.

[33]  C. G. Ponce,et al.  Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence , 2013, Familial Cancer.

[34]  M. Brentani,et al.  Comprehensive Analysis of BRCA1, BRCA2 and TP53 Germline Mutation and Tumor Characterization: A Portrait of Early-Onset Breast Cancer in Brazil , 2013, PloS one.

[35]  E. Podesta,et al.  BRCA1 And BRCA2 analysis of Argentinean breast/ovarian cancer patients selected for age and family history highlights a role for novel mutations of putative south-American origin , 2012, SpringerPlus.

[36]  D. West,et al.  Identification of BRCA1/2 Founder Mutations in Southern Chinese Breast Cancer Patients Using Gene Sequencing and High Resolution DNA Melting Analysis , 2012, PloS one.

[37]  D. de Jong,et al.  CDH1‐related hereditary diffuse gastric cancer syndrome: Clinical variations and implications for counseling , 2012, International journal of cancer.

[38]  R. Lidereau,et al.  Variation in breast cancer risk associated with factors related to pregnancies according to truncating mutation location, in the French National BRCA1 and BRCA2 mutations carrier cohort (GENEPSO) , 2012, Breast Cancer Research.

[39]  M. King,et al.  Response to DNA damage of CHEK2 missense mutations in familial breast cancer. , 2012, Human molecular genetics.

[40]  J. Santos,et al.  The BARD1 Cys557Ser variant and risk of familial breast cancer in a South-American population , 2012, Molecular Biology Reports.

[41]  J. Benítez,et al.  Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. , 2012, Human molecular genetics.

[42]  Sue Healey,et al.  ENIGMA—Evidence‐based network for the interpretation of germline mutant alleles: An international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes , 2012, Human mutation.

[43]  Etienne Rouleau,et al.  Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases , 2011, Nucleic Acids Res..

[44]  Gladys Ibanez,et al.  Genetic variants in FGFR2 and MAP3K1 are associated with the risk of familial and early-onset breast cancer in a South-American population , 2012, Breast Cancer Research and Treatment.

[45]  M. Shoukier,et al.  Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families , 2011, Familial Cancer.

[46]  C. Greenwood,et al.  On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations , 2011, European Journal of Human Genetics.

[47]  D. Stoppa-Lyonnet,et al.  EMMA, a cost‐ and time‐effective diagnostic method for simultaneous detection of point mutations and large‐scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients , 2011, Human mutation.

[48]  P. Faúndez,et al.  Genomic rearrangements of the BRCA1 gene in Chilean breast cancer families: an MLPA analysis , 2011, Breast Cancer Research and Treatment.

[49]  O. Díez,et al.  Spectrum of BRCA1/2 point mutations and genomic rearrangements in high-risk breast/ovarian cancer Chilean families , 2011, Breast Cancer Research and Treatment.

[50]  R. Janavicius.  Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control , 2010, EPMA Journal.

[51]  T. Frebourg,et al.  The BRCA1 c.5434C→G (p.Pro1812Ala) variant induces a deleterious exon 23 skipping by affecting exonic splicing regulatory elements , 2010, Journal of Medical Genetics.

[52]  C. G. Ponce,et al.  Broad BRCA1 and BRCA2 mutational spectrum and high incidence of recurrent and novel mutations in the eastern Spain population , 2010, Breast Cancer Research and Treatment.

[53]  Alison P. Klein,et al.  Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene , 2009, Science.

[54]  R. Jeffrey,et al.  Risk-reducing Total Gastrectomy for Germline Mutations in E-cadherin (CDH1): Pathologic Findings With Clinical Implications , 2008, The American journal of surgical pathology.

[55]  O. Peralta,et al.  Association of common ATM variants with familial breast cancer in a South American population , 2008, BMC Cancer.

[56]  D. Yannoukakos,et al.  Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast/ovarian cancer patients , 2008, Breast Cancer Research and Treatment.

[57]  G. Hortobagyi,et al.  BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[58]  S. Ampuero,et al.  RAD51 135G>C polymorphism and risk of familial breast cancer in a South American population. , 2007, Cancer genetics and cytogenetics.

[59]  M. Moraga,et al.  ATM allelic variants associated to hereditary breast cancer in 94 Chilean women: susceptibility or ethnic influences? , 2007, Breast Cancer Research and Treatment.

[60]  A. Monteiro,et al.  Prevalence of BRCA1 and BRCA2 mutations in breast cancer patients from Brazil , 2007, Breast Cancer Research and Treatment.

[61]  K.‐R. Lee,et al.  Mutation analysis of BRCA1 and BRCA2 from 793 Korean patients with sporadic breast cancer , 2006, Clinical genetics.

[62]  S. Seal,et al.  A Multicenter Study of Cancer Incidence in CHEK2 1100delC Mutation Carriers , 2006, Cancer Epidemiology Biomarkers & Prevention.

[63]  A. Monteiro,et al.  The P1812A and P25T BRCA1 and the 5164del4 BRCA2 mutations: occurrence in high-risk non-Ashkenazi Jews. , 2006, Genetic testing.

[64]  S. Ampuero,et al.  BRCA1 and BRCA2 mutations in a South American population. , 2006, Cancer genetics and cytogenetics.

[65]  J. García-Foncillas,et al.  Structure-based assessment of BRCA1 and BRCA2 mutations in a small Spanish population. , 2005, Oncology reports.

[66]  Kenneth Offit,et al.  Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. , 2005, Human molecular genetics.

[67]  M. King,et al.  Incidence of BRCA1 and BRCA2 mutations in 54 Chilean families with breast/ovarian cancer, genotype–phenotype correlations , 2005, Breast Cancer Research and Treatment.

[68]  M. Gallardo,et al.  [Determination of a BRCA1 gene mutation in a family with hereditary breast cancer]. , 2004, Revista medica de Chile.

[69]  C. Alonso,et al.  [Haplotype of the BRCA2 6857delAA mutation in 4 families with breast/ovarian cancer]. , 2004, Medicina clinica.

[70]  J. Benítez,et al.  Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: A high proportion of mutations unique to Spain and evidence of founder effects , 2003, Human mutation.

[71]  G. Llort,et al.  Low frequency of recurrent BRCA1 and BRCA2 mutations in Spain , 2002, Human mutation.

[72]  J. Olsen,et al.  BRCA1 andBRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age , 2001, Journal of medical genetics.

[73]  M. Ausems,et al.  De novo recurrent germline mutation of theBRCA2 gene in a patient with early onset breast cancer , 2001, Journal of medical genetics.

[74]  P. Pérez-Segura,et al.  Spanish family study on hereditary breast and/or ovarian cancer: Analysis of the BRCA1 gene , 2001, International journal of cancer.

[75]  C. Adebamowo,et al.  Protein truncating BRCA1 and BRCA2 mutations in African women with pre-menopausal breast cancer , 2000, Human Genetics.

[76]  Olufunmilayo I. Olopade,et al.  Prevalence of BRCA1 and BRCA2 mutations among clinic-based African American families with breast cancer , 2000, Human Genetics.

[77]  Sara G. Becker-Catania,et al.  Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences. , 1999, American journal of human genetics.

[78]  M. King,et al.  Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study. , 1998, American journal of human genetics.

[79]  C. Mathew,et al.  Identification of missense and truncating mutations in the BRCA1 gene in sporadic and familial breast and ovarian cancer , 1998, Genes, chromosomes & cancer.

[80]  G. Pals,et al.  A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. , 1997, American journal of human genetics.

[81]  F. Couch,et al.  Mutations and Polymorphisms in the familial early‐onset breast cancer (BRCA1) gene , 1996, Human mutation.

[82]  J. Rommens,et al.  Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families , 1994, Nature Genetics.