Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities

David W. Craig, Joyce A. O'Shaughnessy, Jeffrey A. Kiefer, Jessica Aldrich, Shripad Sinari, Tracy M. Moses, Shukmei Wong, Jennifer Dinh, Alexis Christoforides, Joanne L. Blum, Cristi L. Aitelli, Cynthia R. Osborne, Tyler Izatt, Ahmet Kurdoglu, Angela Baker, Julie Koeman, Catalin Barbacioru, Onur Sakarya, Francisco M. De La Vega, Asim SiddiquiLinh Hoang, Paul R. Billings, Bodour Salhia, Anthony W. Tolcher, Jeffrey M. Trent, Spyro Mousses, Daniel Von Hoff, John D. Carpten

Research output: Contribution to journalArticle

Abstract

Triple-negative breast cancer (TNBC) is characterized by the absence of expression of estrogen receptor, progesterone receptor, and HER-2. Thirty percent of patients recur after first-line treatment, and metastatic TNBC (mTNBC) has a poor prognosis with median survival of one year. Here, we present initial analyses of whole genome and transcriptome sequencing data from 14 prospective mTNBC. We have cataloged the collection of somatic genomic alterations in these advanced tumors, particularly those that may inform targeted therapies. Genes mutated in multiple tumors included TP53, LRP1B, HERC1, CDH5, RB1, and NF1. Notable genes involved in focal structural events were CTNNA1, PTEN, FBXW7, BRCA2, WT1, FGFR1, KRAS, HRAS, ARAF, BRAF, and PGCP. Homozygous deletion of CTNNA1 was detected in 2 of 6 African Americans. RNA sequencing revealed consistent overexpression of the FOXM1 gene when tumor gene expression was compared with nonmalignant breast samples. Using an outlier analysis of gene expression comparing one cancer with all the others, we detected expression patterns unique to each patient's tumor. Integrative DNA/ RNA analysis provided evidence for deregulation of mutated genes, including the monoallelic expression of TP53 mutations. Finally, molecular alterations in several cancers supported targeted therapeutic intervention on clinical trials with known inhibitors, particularly for alterations in the RAS/RAF/MEK/ERK and PI3K/ AKT/mTOR pathways. In conclusion, whole genome and transcriptome profiling of mTNBC have provided insights into somatic events occurring in this difficult to treat cancer. These genomic data have guided patients to investigational treatment trials and provide hypotheses for future trials in this irremediable cancer.

Original languageEnglish (US)
Pages (from-to)104-116
Number of pages13
JournalMolecular Cancer Therapeutics
Volume12
Issue number1
DOIs
StatePublished - Jan 2013
Externally publishedYes

Fingerprint

Triple Negative Breast Neoplasms
Transcriptome
Genome
Neoplasms
Therapeutics
Genes
RNA Sequence Analysis
Gene Expression
Investigational Therapies
Mitogen-Activated Protein Kinase Kinases
Gene Expression Profiling
Progesterone Receptors
Phosphatidylinositol 3-Kinases
Estrogen Receptors
African Americans
Breast
Clinical Trials
RNA
Mutation
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Craig, D. W., O'Shaughnessy, J. A., Kiefer, J. A., Aldrich, J., Sinari, S., Moses, T. M., ... Carpten, J. D. (2013). Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities. Molecular Cancer Therapeutics, 12(1), 104-116. https://doi.org/10.1158/1535-7163.MCT-12-0781

Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities. / Craig, David W.; O'Shaughnessy, Joyce A.; Kiefer, Jeffrey A.; Aldrich, Jessica; Sinari, Shripad; Moses, Tracy M.; Wong, Shukmei; Dinh, Jennifer; Christoforides, Alexis; Blum, Joanne L.; Aitelli, Cristi L.; Osborne, Cynthia R.; Izatt, Tyler; Kurdoglu, Ahmet; Baker, Angela; Koeman, Julie; Barbacioru, Catalin; Sakarya, Onur; De La Vega, Francisco M.; Siddiqui, Asim; Hoang, Linh; Billings, Paul R.; Salhia, Bodour; Tolcher, Anthony W.; Trent, Jeffrey M.; Mousses, Spyro; Von Hoff, Daniel; Carpten, John D.

In: Molecular Cancer Therapeutics, Vol. 12, No. 1, 01.2013, p. 104-116.

Research output: Contribution to journalArticle

Craig, DW, O'Shaughnessy, JA, Kiefer, JA, Aldrich, J, Sinari, S, Moses, TM, Wong, S, Dinh, J, Christoforides, A, Blum, JL, Aitelli, CL, Osborne, CR, Izatt, T, Kurdoglu, A, Baker, A, Koeman, J, Barbacioru, C, Sakarya, O, De La Vega, FM, Siddiqui, A, Hoang, L, Billings, PR, Salhia, B, Tolcher, AW, Trent, JM, Mousses, S, Von Hoff, D & Carpten, JD 2013, 'Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities', Molecular Cancer Therapeutics, vol. 12, no. 1, pp. 104-116. https://doi.org/10.1158/1535-7163.MCT-12-0781
Craig, David W. ; O'Shaughnessy, Joyce A. ; Kiefer, Jeffrey A. ; Aldrich, Jessica ; Sinari, Shripad ; Moses, Tracy M. ; Wong, Shukmei ; Dinh, Jennifer ; Christoforides, Alexis ; Blum, Joanne L. ; Aitelli, Cristi L. ; Osborne, Cynthia R. ; Izatt, Tyler ; Kurdoglu, Ahmet ; Baker, Angela ; Koeman, Julie ; Barbacioru, Catalin ; Sakarya, Onur ; De La Vega, Francisco M. ; Siddiqui, Asim ; Hoang, Linh ; Billings, Paul R. ; Salhia, Bodour ; Tolcher, Anthony W. ; Trent, Jeffrey M. ; Mousses, Spyro ; Von Hoff, Daniel ; Carpten, John D. / Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 1. pp. 104-116.
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AU - Sinari, Shripad

AU - Moses, Tracy M.

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AU - Dinh, Jennifer

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AU - Izatt, Tyler

AU - Kurdoglu, Ahmet

AU - Baker, Angela

AU - Koeman, Julie

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AU - Sakarya, Onur

AU - De La Vega, Francisco M.

AU - Siddiqui, Asim

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AU - Mousses, Spyro

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