Comprehensive Cohort Analysis of Mutational Spectrum in Early Onset Breast Cancer Patients

Early onset breast cancer (EOBC), diagnosed at age ~40 or younger, is associated with a poorer prognosis and higher mortality rate compared to breast cancer diagnosed at age 50 or older. EOBC poses a serious threat to public health and requires in-depth investigation. We studied a cohort comprising 90 Taiwanese female patients, aiming to unravel the underlying mechanisms of EOBC etiopathogenesis. Sequence data generated by whole-exome sequencing (WES) and whole-genome sequencing (WGS) from white blood cell (WBC)–tumor pairs were analyzed to identify somatic missense mutations, copy number variations (CNVs) and germline missense mutations. Similar to regular breast cancer, the key somatic mutation-susceptibility genes of EOBC include TP53 (40% prevalence), PIK3CA (37%), GATA3 (17%) and KMT2C (17%), which are frequently reported in breast cancer; however, the structural protein-coding genes MUC17 (19%), FLG (16%) and NEBL (11%) show a significantly higher prevalence in EOBC. Furthermore, the top 2 genes harboring EOBC germline mutations, MUC16 (19%) and KRT18 (19%), encode structural proteins. Compared to conventional breast cancer, an unexpectedly higher number of EOBC susceptibility genes encode structural proteins. We suspect that mutations in structural proteins may increase physical permeability to environmental hormones and carcinogens and cause breast cancer to occur at a young age.

[1]  Sifeng Hu,et al.  KRT18 is correlated with the malignant status and acts as an oncogene in colorectal cancer , 2019, Bioscience reports.

[2]  G. Blanck,et al.  Matrix‐Metalloprotease Resistant Mucin‐16 (MUC16) Peptide Mutants Represent a Worse Lung Adenocarcinoma Outcome , 2019, Proteomics. Clinical applications.

[3]  Ji Ming Wang,et al.  Mucin 17 inhibits the progression of human gastric cancer by limiting inflammatory responses through a MYH9-p53-RhoA regulatory feedback loop , 2019, Journal of Experimental & Clinical Cancer Research.

[4]  Li Li,et al.  BRCA1/2 mutation spectrum in Chinese early-onset breast cancer , 2019, Translational cancer research.

[5]  B. Suktitipat,et al.  Tumor mutational profile of triple negative breast cancer patients in Thailand revealed distinctive genetic alteration in chromatin remodeling gene , 2019, PeerJ.

[6]  Wei Zhang,et al.  Association of MUC16 Mutation With Tumor Mutation Load and Outcomes in Patients With Gastric Cancer , 2018, JAMA oncology.

[7]  Joon Jeong,et al.  Low PR in ER(+)/HER2(−) breast cancer: high rates of TP53 mutation and high SUV , 2018, Endocrine-related cancer.

[8]  R. Trojanec,et al.  Genetic Markers in Triple‐Negative Breast Cancer , 2018, Clinical breast cancer.

[9]  S. Abdelhak,et al.  Family specific genetic predisposition to breast cancer: results from Tunisian whole exome sequenced breast cancer cases , 2018, Journal of Translational Medicine.

[10]  G. Petrushevska,et al.  Presentation of the Molecular Subtypes of Breast Cancer Detected By Immunohistochemistry in Surgically Treated Patients , 2018, Open access Macedonian journal of medical sciences.

[11]  Veronica Y. Sabelnykova,et al.  Somatic mutations in early onset luminal breast cancer , 2018, Oncotarget.

[12]  Guang-Biao Zhou,et al.  MUC16 overexpression induced by gene mutations promotes lung cancer cell growth and invasion , 2018, Oncotarget.

[13]  P. Fasching,et al.  Germline variation in ADAMTSL1 is associated with prognosis following breast cancer treatment in young women , 2017, Nature Communications.

[14]  P. Argüeso,et al.  N-Glycosylation affects the stability and barrier function of the MUC16 mucin , 2017, The Journal of Biological Chemistry.

[15]  J. Linke,et al.  The St. Gallen surrogate classification for breast cancer subtypes successfully predicts tumor presenting features, nodal involvement, recurrence patterns and disease free survival. , 2016, Breast.

[16]  David C. Jones,et al.  Landscape of somatic mutations in 560 breast cancer whole genome sequences , 2016, Nature.

[17]  N. Rosenfeld,et al.  The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes , 2016, Nature Communications.

[18]  C. Friedenreich,et al.  Breast cancer survival among young women: a review of the role of modifiable lifestyle factors , 2016, Cancer Causes & Control.

[19]  J. Long,et al.  Whole-Exome Sequencing Identifies Novel Somatic Mutations in Chinese Breast Cancer Patients , 2015, Journal of molecular and genetic medicine : an international journal of biomedical research.

[20]  Hua Tan,et al.  Genome-wide mutational spectra analysis reveals significant cancer-specific heterogeneity , 2015, Scientific Reports.

[21]  P. Brown,et al.  Epidemiology, biology, and treatment of triple-negative breast cancer in women of African ancestry. , 2014, The Lancet. Oncology.

[22]  Yoshiki Narimatsu,et al.  Characterization of binding epitopes of CA125 monoclonal antibodies. , 2014, Journal of proteome research.

[23]  L. Titus,et al.  Polymorphisms of MUC16 (CA125) and MUC1 (CA15.3) in Relation to Ovarian Cancer Risk and Survival , 2014, PloS one.

[24]  Jianxin Shi,et al.  A Genome-wide Association Study of Early-Onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age , 2014, Cancer Epidemiology, Biomarkers & Prevention.

[25]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[26]  S. Narod.  Breast cancer in young women , 2012, Nature Reviews Clinical Oncology.

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

[28]  A. Sivachenko,et al.  Sequence analysis of mutations and translocations across breast cancer subtypes , 2012, Nature.

[29]  A. Børresen-Dale,et al.  The landscape of cancer genes and mutational processes in breast cancer , 2012, Nature.

[30]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[31]  F. Markowetz,et al.  The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups , 2012, Nature.

[32]  F. Hsieh,et al.  Strategy for Breast Cancer Screening in Taiwan: Obstetrician–Gynecologists Should Actively Participate in Breast Cancer Screening , 2012 .

[33]  Mukesh Jain,et al.  NGS QC Toolkit: A Toolkit for Quality Control of Next Generation Sequencing Data , 2012, PloS one.

[34]  R. Gelber,et al.  Differential efficacy of three cycles of CMF followed by tamoxifen in patients with ER-positive and ER-negative tumors: long-term follow up on IBCSG Trial IX. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[35]  G. Getz,et al.  GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers , 2011, Genome Biology.

[36]  P. Walsh.  Re: Increased Cancer Risks for Relatives of Very Early-Onset Breast Cancer Cases With and Without BRCA1 and BRCA2 Mutations. , 2011, Journal of Urology.

[37]  M. DePristo,et al.  A framework for variation discovery and genotyping using next-generation DNA sequencing data , 2011, Nature Genetics.

[38]  A. Whittemore,et al.  Increased cancer risks for relatives of very early-onset breast cancer cases with and without BRCA1 and BRCA2 mutations , 2010, British Journal of Cancer.

[39]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[40]  D. Kufe,et al.  Mucins in cancer: function, prognosis and therapy , 2009, Nature Reviews Cancer.

[41]  A. Bleyer,et al.  Breast cancer before age 40 years. , 2009, Seminars in oncology.

[42]  A. Irvine,et al.  Filaggrin in atopic dermatitis. , 2008, The Journal of allergy and clinical immunology.

[43]  Peter Devilee,et al.  A family history of breast cancer will not predict female early onset breast cancer in a population-based setting , 2008, BMC Cancer.

[44]  A. Woodcock,et al.  Gene-Environment Interaction in the Onset of Eczema in Infancy: Filaggrin Loss-of-Function Mutations Enhanced by Neonatal Cat Exposure , 2008, PLoS medicine.

[45]  M. Pembrey,et al.  The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study. , 2008, The Journal of allergy and clinical immunology.

[46]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[47]  K. Kyriacou,et al.  Contribution of BRCA1 and BRCA2 germline mutations to the incidence of early‐onset breast cancer in Cyprus , 2007, Clinical genetics.

[48]  M. Sherman,et al.  Comparison of Age Distribution Patterns for Different Histopathologic Types of Breast Carcinoma , 2006, Cancer Epidemiology Biomarkers & Prevention.

[49]  Chiun Hsu,et al.  Significant Difference in the Trends of Female Breast Cancer Incidence Between Taiwanese and Caucasian Americans: Implications from Age-Period-Cohort Analysis , 2005, Cancer Epidemiology Biomarkers & Prevention.

[50]  S. Tan,et al.  Breast cancer in young Asian women: Study on survival , 2005, ANZ journal of surgery.

[51]  F. Bray,et al.  The changing global patterns of female breast cancer incidence and mortality , 2004, Breast Cancer Research.

[52]  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.

[53]  John L Hopper,et al.  Familial risks, early-onset breast cancer, and BRCA1 and BRCA2 germline mutations. , 2003, Journal of the National Cancer Institute.

[54]  Douglas F. Easton,et al.  Polygenic susceptibility to breast cancer and implications for prevention , 2002, Nature Genetics.

[55]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[56]  J. Hopper,et al.  Why are the majority of hereditary cases of early-onset breast cancer sporadic? A simulation study. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[57]  C. Sunkel,et al.  Human Autoantibodies Reveal Titin as a Chromosomal Protein , 1998, The Journal of cell biology.

[58]  L Piana,et al.  Age as a prognostic factor in breast cancer: Relationship to pathologic and biologic features , 1995, International journal of cancer.

[59]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[60]  Claude-Alain H. Roten,et al.  Fast and accurate short read alignment with Burrows–Wheeler transform , 2009, Bioinform..

[61]  B. Yankaskas.  Epidemiology of breast cancer in young women. , 2005, Breast disease.