Polarity gene alterations in pure invasive micropapillary carcinomas of the breast
Menée à partir d'échantillons tumoraux prélevés sur 50 patientes atteintes d'un cancer micropapillaire invasif pur (CMIP) du sein et sur 27 patientes atteintes d'un carcinome canalaire invasif, cette étude française identifie un ensemble de mutations somatiques et d'autres anomalies biologiques (modifications épigénétiques, altérations du stroma) spécifiques du CMIP
INTRODUCTION:Pure invasive micropapillary carcinoma (IMPC) is a special type of breast carcinoma characterized by clusters of cells presenting polarity abnormalities. The biological alterations underlying this pattern remain unknown. METHODS:Pangenomic analysis (SNP6.0 Affymetrix, n = 39), TP53 (n = 43) and PIK3CA (n = 41) sequencing in a series of IMPC were performed. A subset of cases was also analysed with whole-exome (n = 4) and RNA sequencing (n = 6). Copy number alteration profiles were compared to those of estrogen-receptors and grade-matched invasive ductal carcinomas (IDC) of no special type. RESULTS:Unsupervised analysis of genomic data distinguished two IMPC subsets: one (Sawtooth/8/16) exhibited a significant increase in 16p gains (71%) and the other (Firestorm/Amplifier) was characterized by a high frequency of 8q (35%), 17q (20 to 46%) and 20q (23 to 30%) amplifications and 17p loss (74%). TP53 mutations (10%) were more frequently identified in the amplifier subset, while PIK3CA mutations (4%) were detected in both subsets. When compared to IDC, IMPC exhibited specific loss of the 6q16-q22 region (45%), associated with downregulation of FOXO3 and SEC63 gene expression. SEC63 and FOXO3 missense mutations were each identified in one case, respectively (2%). Whole-exome sequencing combined with RNA sequencing of IMPC identified somatic mutations in genes involved in polarity, DNAH9 and FMN2 (8 and 2%, respectively) or ciliogenesis, BBS12 and BBS9, (2% each) or genes coding for endoplasmic reticulum protein, HSP90B1 and SPTLC3, (2% each) and cytoskeleton, UBR4 and PTPN21, (2% each), regardless of the genomic subset. The intracellular biological function of the mutated genes identified by gene ontology analysis suggests a driving role in the clinicopathological characteristics of IMPC. CONCLUSION:Our comprehensive molecular analysis of IMPC identified numerous genomic alterations without any recurrent fusion genes. Recurrent somatic mutations of genes participating in cell polarity and shape suggest that they, together with other biological alterations (epigenetic modifications, stromal alterations), could contribute to the morphological pattern of IMPC. Though none of the individual abnormalities demonstrated specificity for IMPC, it remains to be examined whether their combination in IMPC may have a cumulative effect to drive the abnormal polarity of IMPC that should be further demonstrated with in vitro experiments.