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

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.

Now, whole genome sequencing has revealed previously unreported mutations in metastatic triple-negative breast cancer (TNBC), according to a study published by the journal Molecular Cancer Therapeutics.

The study, “Genome and transcriptome sequencing in prospective triple negative breast cancer uncovers therapeutic vulnerabilities,” was sponsored by the Translational Genomics Research Institute (TGen) and US Oncology Research with support from Life Technologies Corporation and is currently available online.

In this paper, the researchers present initial analyses of whole genome and transcriptome sequencing data from 14 prospective metastatic mTNBC. The team has cataloged the collection of somatic genomic alterations in these advanced tumors; particularly those that might 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 to nonmalignant breast samples. Using an outlier analysis of gene expression comparing one cancer to 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.

  • 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 DD, Carpten JD. (2012) Genome and transcriptome sequencing in prospective refractory metastatic triple negative breast cancer uncovers therapeutic vulnerabilities. Mol Cancer Ther [Epub ahead of print]. [abstract]

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