title: Revealing the Molecular Portrait of Triple Negative Breast Tumors in an Understudied Population through Omics Analysis of Formalin-Fixed and Paraffin-Embedded Tissues.
abstract: Triple negative breast cancer (TNBC), defined by the lack of expression of the estrogen receptor, progesterone receptor and human epidermal receptor 2, is an aggressive form of breast cancer that is more prevalent in certain populations, in particular in low- and middle-income regions. The detailed molecular features of TNBC in these regions remain unexplored as samples are mostly accessible as formalin-fixed paraffin embedded (FFPE) archived tissues, a challenging material for advanced genomic and transcriptomic studies. Using dedicated reagents and analysis pipelines, we performed whole exome sequencing and miRNA and mRNA profiling of 12 FFPE tumor tissues collected from pathological archives in Mexico. Sequencing analyses of the tumor tissues and their blood pairs identified TP53 and RB1 genes as the most frequently mutated genes, with a somatic mutation load of 1.7 mutations/exome Mb on average. Transcriptional analyses revealed an overexpression of growth-promoting signals (EGFR, PDGFR, VEGF, PIK3CA, FOXM1), a repression of cell cycle control pathways (TP53, RB1), a deregulation of DNA-repair pathways, and alterations in epigenetic modifiers through miRNA:mRNA network de-regulation. The molecular programs identified were typical of those described in basal-like tumors in other populations. This work demonstrates the feasibility of using archived clinical samples for advanced integrated genomics analyses. It thus opens up opportunities for investigating molecular features of tumors from regions where only FFPE tissues are available, allowing retrospective studies on the search for treatment strategies or on the exploration of the geographic diversity of breast cancer.
authors.affiliation: Group of Molecular Mechanisms and Biomarkers, International Agency for Research on Cancer, Lyon, France; Subdirección de Investigación Básica, Instituto Nacional de Cancerología, México D.F., México; Unidad de Biomedicina, FES-Iztacala, Universidad Nacional Autónoma de México (UNAM), México D.F., México.
authors.forename: Felipe
authors.initials: F
authors.lastname: Vaca-Paniagua
authors.affiliation: Unidad de Genómica y Secuenciación Masiva (UGESEM), Instituto Nacional de Cancerología, México D.F., México.
authors.forename: Rosa María
authors.initials: RM
authors.lastname: Alvarez-Gomez
authors.affiliation: Departamento de Patología Molecular, Instituto Nacional de Cancerología, México D.F., México.
authors.forename: Hector Aquiles
authors.initials: HA
authors.lastname: Maldonado-Martínez
authors.affiliation: Subdirección de Investigación Básica, Instituto Nacional de Cancerología, México D.F., México; Unidad de Biomedicina, FES-Iztacala, Universidad Nacional Autónoma de México (UNAM), México D.F., México; Unidad de Genómica y Secuenciación Masiva (UGESEM), Instituto Nacional de Cancerología, México D.F., México.
authors.forename: Carlos
authors.initials: C
authors.lastname: Pérez-Plasencia
authors.affiliation: Subdirección de Investigación Básica, Instituto Nacional de Cancerología, México D.F., México; Unidad de Genómica y Secuenciación Masiva (UGESEM), Instituto Nacional de Cancerología, México D.F., México.
authors.forename: Veronica
authors.initials: V
authors.lastname: Fragoso-Ontiveros
authors.affiliation: Departamento de Epidemiología, Instituto Nacional de Cancerología, México D.F., México.
authors.forename: Federico
authors.initials: F
authors.lastname: Lasa-Gonsebatt
authors.affiliation: Unidad de Investigaciones Biomédicas en Cáncer, Instituto Nacional de Cancerología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), México D.F., México.
authors.forename: Luis Alonso
authors.initials: LA
authors.lastname: Herrera
authors.affiliation: Unidad de Investigaciones Biomédicas en Cáncer, Instituto Nacional de Cancerología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), México D.F., México.
authors.forename: David
authors.initials: D
authors.lastname: Cantú
authors.affiliation: Departamento de Tumores Mamarios, Instituto Nacional de Cancerología, México D.F., México.
authors.forename: Enrique
authors.initials: E
authors.lastname: Bargallo-Rocha
authors.affiliation: Departamento de Epidemiología, Instituto Nacional de Cancerología, México D.F., México.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Mohar
authors.affiliation: Group of Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Durand
authors.affiliation: Group of Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Forey
authors.affiliation: Group of Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Voegele
authors.affiliation: Group of Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Vallée
authors.affiliation: Group of Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Le Calvez-Kelm
authors.affiliation: Group of Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
authors.forename: James
authors.initials: J
authors.lastname: McKay
authors.affiliation: Group of Molecular Mechanisms and Biomarkers, International Agency for Research on Cancer, Lyon, France.
authors.forename: Maude
authors.initials: M
authors.lastname: Ardin
authors.affiliation: Group of Molecular Mechanisms and Biomarkers, International Agency for Research on Cancer, Lyon, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Villar
authors.affiliation: Group of Molecular Mechanisms and Biomarkers, International Agency for Research on Cancer, Lyon, France.
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.affiliation: Group of Molecular Mechanisms and Biomarkers, International Agency for Research on Cancer, Lyon, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Olivier
mesh_terms: D000328:Adult; D005260:Female; D005557:Formaldehyde / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D008875:Middle Aged; D010232:Paraffin / Q000737:chemistry*; D012189:Retrospective Studies; D016707:Tissue Fixation; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D005557:Formaldehyde; D010232:Paraffin