title: Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities.
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.
authors.affiliation: Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.forename: Joyce A
authors.initials: JA
authors.lastname: O'Shaughnessy
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kiefer
authors.forename: Jessica
authors.initials: J
authors.lastname: Aldrich
authors.forename: Shripad
authors.initials: S
authors.lastname: Sinari
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Moses
authors.forename: Shukmei
authors.initials: S
authors.lastname: Wong
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dinh
authors.forename: Alexis
authors.initials: A
authors.lastname: Christoforides
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Blum
authors.forename: Cristi L
authors.initials: CL
authors.lastname: Aitelli
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Osborne
authors.forename: Tyler
authors.initials: T
authors.lastname: Izatt
authors.forename: Ahmet
authors.initials: A
authors.lastname: Kurdoglu
authors.forename: Angela
authors.initials: A
authors.lastname: Baker
authors.forename: Julie
authors.initials: J
authors.lastname: Koeman
authors.forename: Catalin
authors.initials: C
authors.lastname: Barbacioru
authors.forename: Onur
authors.initials: O
authors.lastname: Sakarya
authors.forename: Francisco M
authors.initials: FM
authors.lastname: De La Vega
authors.forename: Asim
authors.initials: A
authors.lastname: Siddiqui
authors.forename: Linh
authors.initials: L
authors.lastname: Hoang
authors.forename: Paul R
authors.initials: PR
authors.lastname: Billings
authors.forename: Bodour
authors.initials: B
authors.lastname: Salhia
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Trent
authors.forename: Spyro
authors.initials: S
authors.lastname: Mousses
authors.forename: Daniel
authors.initials: D
authors.lastname: Von Hoff
authors.forename: John D
authors.initials: JD
authors.lastname: Carpten
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002897:Chromosomes, Human, Pair 7; D004252:DNA Mutational Analysis; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D052138:Genes, Neoplasm; D015894:Genome, Human; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D017423:Sequence Analysis, RNA; D017384:Sequence Deletion; D015398:Signal Transduction; D059467:Transcriptome; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051178:alpha Catenin / Q000235:genetics
chemical_list: D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; D051178:alpha Catenin; C495273:CTNNA1 protein, human; C107585:FOXM1 protein, human; C495901:TP53 protein, human; C508053:ERBB2 protein, human