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Pure invasive micropapillary carcinoma (IMPC) is a special type of breast carcinoma characterised by clusters of cells presenting polarity abnormalities. The biological alterations underlying this pattern remain unknown.    Methods  Pangenomic analysis ( n  = 39),  TP53  ( n  = 43) and  PIK3CA  ( n  = 41) sequencing in a series of IMPCs were performed. A subset of cases was also analysed with whole-exome sequencing ( n  = 4) and RNA sequencing ( n  = 6). Copy number variation profiles were compared with those of oestrogen receptors and grade-matched invasive ductal carcinomas (IDCs) 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 characterised 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, and  PIK3CA  mutations (4%) were detected in both subsets. Compared to IDC, IMPC exhibited specific loss of the 6q16-q22 region (45%), which is associated with downregulation of  FOXO3  and  SEC63  gene expression.  SEC63  and  FOXO3  missense mutations were identified in one case each (2%). Whole-exome sequencing combined with RNA sequencing of IMPC allowed us to identify 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  In our comprehensive molecular analysis of IMPC, we identified numerous genomic alterations without any recurrent fusion genes. Recurrent somatic mutations of genes participating in cellular polarity and shape suggest that they, together with other biological alterations (such as epigenetic modifications and stromal alterations), could contribute to the morphological pattern of IMPC. Though none of the individual abnormalities demonstrated specificity for IMPC, whether their combination in IMPC may have a cumulative effect that drives the abnormal polarity of IMPC needs to be examined further with  in vitro  experiments.

Polarity gene alterations in pure invasive micropapillary carcinomas of the breast