Somatic mutations in early onset luminal breast cancer

Abstract

Breast cancer arising in very young patients may be biologically distinct; however, these tumors have been less well studied. We characterized a group of very young patients (≤ 35 years) for BRCA germline mutation and for somatic mutations in luminal (<i>HER2</i> negative) breast cancer. Thirteen of 79 unselected very young patients were <i>BRCA</i>1/2 germline mutation carriers. Of the non-<i>BRCA</i> tumors, eight with luminal subtype (<i>HER2</i> negative) were submitted for whole exome sequencing and integrated with 29 luminal samples from the COSMIC database or previous literature for analysis. We identified C to T single nucleotide variants (SNVs) as the most common base-change. A median of six candidate driver genes was mutated by SNVs in each sample and the most frequently mutated genes were <i>PIK3CA, GATA3, TP53</i> and <i>MAP2K4</i>. Potential cancer drivers affected in the present non-<i>BRCA</i> tumors include <i>GRHL2, PIK3AP1, CACNA1E</i>, <i>SEMA6D</i>, <i>SMURF2</i>, <i>RSBN1</i> and <i>MTHFD2.</i> Sixteen out of 37 luminal tumors (43%) harbored SNVs in DNA repair genes, such as <i>ATR, BAP1, ERCC6, FANCD2, FANCL, MLH1</i>, <i>MUTYH, PALB2, POLD1, POLE</i>, <i>RAD9A, RAD51 and TP53</i>, and 54% presented pathogenic mutations (frameshift or nonsense) in at least one gene involved in gene transcription. The differential biology of luminal early-age onset breast cancer needs a deeper genomic investigation.