title: A Molecular Portrait of High-Grade Ductal Carcinoma In Situ.
abstract: Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2(+)) displayed signatures characteristic of activated Treg cells (CD4(+)/CD25(+)/FOXP3(+)) and CTLA4(+)/CD86(+) complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.
authors.affiliation: CINIBA, School of Medical Sciences, National University of La Plata, La Plata, Argentina.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Abba
authors.affiliation: The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Ting
authors.initials: T
authors.lastname: Gong
authors.affiliation: The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Jaeho
authors.initials: J
authors.lastname: Lee
authors.affiliation: The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: CINIBA, School of Medical Sciences, National University of La Plata, La Plata, Argentina.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Lacunza
authors.affiliation: CINIBA, School of Medical Sciences, National University of La Plata, La Plata, Argentina.
authors.forename: Matias
authors.initials: M
authors.lastname: Butti
authors.affiliation: The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takata
authors.affiliation: The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Sally
authors.initials: S
authors.lastname: Gaddis
authors.affiliation: The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Shen
authors.affiliation: The University of Texas MD Anderson Cancer Center, Smithville, Texas. The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Marcos R
authors.initials: MR
authors.lastname: Estecio
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.affiliation: The University of Texas MD Anderson Cancer Center, Smithville, Texas. maaldaz@mdanderson.org.
authors.forename: C Marcelo
authors.initials: CM
authors.lastname: Aldaz
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D001940:Breast / Q000737:chemistry; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D060908:CTLA-4 Antigen / Q000032:analysis; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000276:immunology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000737:chemistry / Q000276:immunology; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D059467:Transcriptome
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D022661:RNA, Untranslated