102IN - Whole genome sequencing for luminal-type breast cancer

Date 01 October 2012
Event ESMO Congress 2012
Session ESMO-ASCO Joint symposium: Genomics in breast cancer: Opening new doors
Topics Breast Cancer
Personalised Medicine
Translational Research
Presenter Matthew Ellis
Authors M.J. Ellis
  • Siteman Cancer Center Breast Cancer Program, Washington University School of Medicine, 63110 - St Louis/US

Abstract

Whole genome sequencing is an unbiased approach to detect all classes of somatic mutation in a cancer. To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we applied this technique to pre-treatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. These findings suggest that breast cancer, like leukaemia, can be viewed as a stem-cell disorder that produces indolent or aggressive tumours that display varying phenotypes depending on differentiation blocks generated by different mutation repertoires. Mutant MAP3K1 was associated with luminal A status, low grade histology and low proliferation rates, whereas mutant TP53 associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. These analyses also identified transcriptional associations to Ki67 response reside in a connected network under the control of several key ‘hub’ genes including MYC, FYN and MAP kinases, among others. Targeting these hubs in resistant tumours could produce therapeutic advances. Aside from the common PIK3CA mutations, druggable mutations were relatively uncommon, but were observed in HER2, KIT, PDGFA, DDR1/2, MET, JAK1, CSFR1, LTK, BRAF and AKT1/2. If these mutations are activating and drug sensitive these are significant findings since breast cancer is so common that drug sensitizing mutations with a 1% prevalence represents a population with a similar magnitude to CML and PML, diseases in which a randomized trials are feasible. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing and large mutation screening programs.

Disclosure

The author has declared no conflicts of interest.