Mutational profiles in triple-negative breast cancer defined by ultradeep multigene sequencing show high rates of PI3K pathway alterations and clinically relevant entity subgroup specific differences

作者：Kriegsmann Mark^*; Endris Volker; Wolf Thomas; Pfarr Nicole; Stenzinger Albrecht; Loibl Sibylle; Denkert Carsten; Schneeweiss Andreas; Budczies Jan; Sinn Peter; Weichert Wilko

来源：Oncotarget, 2014, 5(20): 9952-9965.

DOI：10.18632/oncotarget.2481

• triple-negative breast cancer
• next generation sequencing
• immunohistochemistry
• mutation profiling

Mutational profiling of triple-negative breast cancer (TNBC) by whole exome sequencing (WES) yielded a landscape of genomic alterations in this tumor entity. However, the clinical significance of these findings remains enigmatic. Further, integration of WES in routine diagnostics using formalin-fixed paraffin-embedded (FFPE) material is currently not feasible.
Therefore, we designed and validated a breast cancer specific gene panel for semiconductor-based sequencing comprising 137 amplicons covering mutational hotspots in 44 genes and applied this panel on a cohort of 104 well-characterized FFPE TNBC with complete clinical follow-up.
TP53 mutations were present in more than 80% of cases. PI3K pathway alterations (29.8%) comprising mainly PIK3CA mutations (22.1%) but also mutations and/or amplifications/deletions in other PI3K-associated genes (7.7%) were far more frequently observed, when compared to WES data. Alterations in MAPK signaling genes (8.7%) and cell-cycle regulators (14.4%) were also frequent. Mutational profiles were linked to TNBC subgroups defined by morphology and immunohistochemistry. Alterations in cell-cycle pathway regulators were linked with better overall (p=0.053) but not disease free survival.
Taken together, we could demonstrate that breast cancer targeted hotspot sequencing is feasible in a routine setting and yields reliable and clinically meaningful results. Mutational spectra were linked to clinical and immunohistochemically defined parameters.

• 出版日期2014-10-30