title: Whole exome sequencing of rare aggressive breast cancer histologies.
abstract: Little is known about mutational landscape of rare breast cancer (BC) subtypes. The aim of the study was to apply next generation sequencing to three different subtypes of rare BCs in order to identify new genes related to cancer progression. We performed whole exome and targeted sequencing of 29 micropapillary, 23 metaplastic, and 27 pleomorphic lobular BCs. Micropapillary BCs exhibit a profile comparable to common BCs: PIK3CA, TP53, GATA3, and MAP2K4 were the most frequently mutated genes. Metaplastic BCs presented a high frequency of TP53 (78 %) and PIK3CA (48 %) mutations and were recurrently mutated on KDM6A (13 %), a gene involved in histone demethylation. Pleomorphic lobular carcinoma exhibited high mutation rate of PIK3CA (30 %), TP53 (22 %), and CDH1 (41 %) and also presented mutations in PYGM, a gene involved in glycogen metabolism, in 8 out of 27 samples (30 %). Further analyses of publicly available datasets showed that PYGM is dramatically underexpressed in common cancers as compared to normal tissues and that low expression in tumors is correlated with poor relapse-free survival. Immunohistochemical staining on formalin-fixed paraffin-embedded tissues available in our cohort of patients confirmed higher PYGM expression in normal breast tissue compared to equivalent tumoral zone. Next generation sequencing methods applied on rare cancer subtypes can serve as a useful tool in order to uncover new potential therapeutic targets. Sequencing of pleomorphic lobular carcinoma identified a high rate of alterations in PYGM. These findings emphasize the role of glycogen metabolism in cancer progression.
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35121, Padua, Italy.|Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128, Padua, Italy.
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Dieci
authors.affiliation: INSERM Unit U981, 114 rue E Vaillant, 94805, Villejuif, France.|Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.|Univ. Paris Sud, 63 rue Gabriel Péri, 94270, Le Kremlin-Bicêtre, France.
authors.forename: Veronika
authors.initials: V
authors.lastname: Smutná
authors.affiliation: INSERM Unit U981, 114 rue E Vaillant, 94805, Villejuif, France.|Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Scott
authors.affiliation: BGI-Shenzhen, Shenzhen, 518083, China.
authors.forename: Guangliang
authors.initials: G
authors.lastname: Yin
authors.affiliation: BGI-Shenzhen, Shenzhen, 518083, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Medical Biology and Pathology, Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.|Laboratory of Translational Research and Biobank, Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vielh
authors.affiliation: Department of Medical Biology and Pathology, Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Mathieu
authors.affiliation: INSERM Unit U981, 114 rue E Vaillant, 94805, Villejuif, France.|Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.|Univ. Paris Sud, 63 rue Gabriel Péri, 94270, Le Kremlin-Bicêtre, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Vicier
authors.affiliation: Laboratory of Translational Research and Biobank, Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Laporte
authors.affiliation: Laboratory of Translational Research and Biobank, Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Drusch
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35121, Padua, Italy.|Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128, Padua, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Guarneri
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35121, Padua, Italy.|Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128, Padua, Italy.
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Conte
authors.affiliation: Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.|Department of Medical Oncology, Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.
authors.forename: Suzette
authors.initials: S
authors.lastname: Delaloge
authors.affiliation: Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.|Laboratory of Translational Research and Biobank, Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.affiliation: INSERM Unit U981, 114 rue E Vaillant, 94805, Villejuif, France.|Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Fromigué
authors.affiliation: INSERM Unit U981, 114 rue E Vaillant, 94805, Villejuif, France.|Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.|Univ. Paris Sud, 63 rue Gabriel Péri, 94270, Le Kremlin-Bicêtre, France.|Department of Medical Oncology, Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.affiliation: INSERM Unit U981, 114 rue E Vaillant, 94805, Villejuif, France. celine.lefebvre@gustaveroussy.fr.|Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France. celine.lefebvre@gustaveroussy.fr.
authors.forename: Celine
authors.initials: C
authors.lastname: Lefebvre
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D059472:Exome; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human
keywords: Glycogen metabolism; Metaplastic breast cancer; Micropapillary breast cancer; PYGM; Pleomorphic lobular breast cancer; Sequencing