Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency.
Triple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2. Currently, apart from poly ADP-ribose polymerase inhibitors, there are few effective therapeutic options for this type of cancer. Here, we present compre...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-06-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC5500377?pdf=render |
| _version_ | 1811230559209259008 |
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| author | Masahito Kawazu Shinya Kojima Toshihide Ueno Yasushi Totoki Hiromi Nakamura Akiko Kunita Wei Qu Jun Yoshimura Manabu Soda Takahiko Yasuda Natsuko Hama Mihoko Saito-Adachi Kazuhito Sato Shinji Kohsaka Eirin Sai Masako Ikemura Shigeru Yamamoto Tomoko Ogawa Masashi Fukayama Keiichiro Tada Yasuyuki Seto Shinichi Morishita Shoichi Hazama Tatsuhiro Shibata Yoshihiro Yamashita Hiroyuki Mano |
| author_facet | Masahito Kawazu Shinya Kojima Toshihide Ueno Yasushi Totoki Hiromi Nakamura Akiko Kunita Wei Qu Jun Yoshimura Manabu Soda Takahiko Yasuda Natsuko Hama Mihoko Saito-Adachi Kazuhito Sato Shinji Kohsaka Eirin Sai Masako Ikemura Shigeru Yamamoto Tomoko Ogawa Masashi Fukayama Keiichiro Tada Yasuyuki Seto Shinichi Morishita Shoichi Hazama Tatsuhiro Shibata Yoshihiro Yamashita Hiroyuki Mano |
| author_sort | Masahito Kawazu |
| collection | DOAJ |
| description | Triple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2. Currently, apart from poly ADP-ribose polymerase inhibitors, there are few effective therapeutic options for this type of cancer. Here, we present comprehensive characterization of the genetic alterations in TNBC performed by high coverage whole genome sequencing together with transcriptome and whole exome sequencing. Silencing of the BRCA1 gene impaired the homologous recombination pathway in a subset of TNBCs, which exhibited similar phenotypes to tumors with BRCA1 mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication. Clonal analysis suggested that TP53 mutations and methylation of CpG dinucleotides in the BRCA1 promoter were early events of carcinogenesis. SVs were associated with driver oncogenic events such as amplification of MYC, NOTCH2, or NOTCH3 and affected tumor suppressor genes including RB1, PTEN, and KMT2C. Furthermore, we identified putative TGFA enhancer regions. Recurrent SVs that affected the TGFA enhancer region led to enhanced expression of the TGFA oncogene that encodes one of the high affinity ligands for epidermal growth factor receptor. We also identified a variety of oncogenes that could transform 3T3 mouse fibroblasts, suggesting that individual TNBC tumors may undergo a unique driver event that can be targetable. Thus, we revealed several features of TNBC with clinically important implications. |
| first_indexed | 2024-04-12T10:30:27Z |
| format | Article |
| id | doaj.art-6a162a70df7847e08883bac287297886 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-12T10:30:27Z |
| publishDate | 2017-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-6a162a70df7847e08883bac2872978862022-12-22T03:36:51ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042017-06-01136e100685310.1371/journal.pgen.1006853Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency.Masahito KawazuShinya KojimaToshihide UenoYasushi TotokiHiromi NakamuraAkiko KunitaWei QuJun YoshimuraManabu SodaTakahiko YasudaNatsuko HamaMihoko Saito-AdachiKazuhito SatoShinji KohsakaEirin SaiMasako IkemuraShigeru YamamotoTomoko OgawaMasashi FukayamaKeiichiro TadaYasuyuki SetoShinichi MorishitaShoichi HazamaTatsuhiro ShibataYoshihiro YamashitaHiroyuki ManoTriple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2. Currently, apart from poly ADP-ribose polymerase inhibitors, there are few effective therapeutic options for this type of cancer. Here, we present comprehensive characterization of the genetic alterations in TNBC performed by high coverage whole genome sequencing together with transcriptome and whole exome sequencing. Silencing of the BRCA1 gene impaired the homologous recombination pathway in a subset of TNBCs, which exhibited similar phenotypes to tumors with BRCA1 mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication. Clonal analysis suggested that TP53 mutations and methylation of CpG dinucleotides in the BRCA1 promoter were early events of carcinogenesis. SVs were associated with driver oncogenic events such as amplification of MYC, NOTCH2, or NOTCH3 and affected tumor suppressor genes including RB1, PTEN, and KMT2C. Furthermore, we identified putative TGFA enhancer regions. Recurrent SVs that affected the TGFA enhancer region led to enhanced expression of the TGFA oncogene that encodes one of the high affinity ligands for epidermal growth factor receptor. We also identified a variety of oncogenes that could transform 3T3 mouse fibroblasts, suggesting that individual TNBC tumors may undergo a unique driver event that can be targetable. Thus, we revealed several features of TNBC with clinically important implications.http://europepmc.org/articles/PMC5500377?pdf=render |
| spellingShingle | Masahito Kawazu Shinya Kojima Toshihide Ueno Yasushi Totoki Hiromi Nakamura Akiko Kunita Wei Qu Jun Yoshimura Manabu Soda Takahiko Yasuda Natsuko Hama Mihoko Saito-Adachi Kazuhito Sato Shinji Kohsaka Eirin Sai Masako Ikemura Shigeru Yamamoto Tomoko Ogawa Masashi Fukayama Keiichiro Tada Yasuyuki Seto Shinichi Morishita Shoichi Hazama Tatsuhiro Shibata Yoshihiro Yamashita Hiroyuki Mano Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency. PLoS Genetics |
| title | Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency. |
| title_full | Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency. |
| title_fullStr | Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency. |
| title_full_unstemmed | Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency. |
| title_short | Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency. |
| title_sort | integrative analysis of genomic alterations in triple negative breast cancer in association with homologous recombination deficiency |
| url | http://europepmc.org/articles/PMC5500377?pdf=render |
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