Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast

Abstract

Micropapillary carcinoma (MPC) is a rare histological special type of breast cancer, characterized by an aggressive clinical behaviour and a pattern of copy number aberrations (CNAs) distinct from that of grade- and oestrogen receptor (ER)-matched invasive carcinomas of no special type (IC-NSTs). The aims of this study were to determine whether MPCs are underpinned by a recurrent fusion gene(s) or mutations in 273 genes recurrently mutated in breast cancer. Sixteen MPCs were subjected to microarray-based comparative genomic hybridization (aCGH) analysis and Sequenom OncoCarta mutation analysis. Eight and five MPCs were subjected to targeted capture and RNA sequencing, respectively. aCGH analysis confirmed our previous observations about the repertoire of CNAs of MPCs. Sequencing analysis revealed a spectrum of mutations similar to those of luminal B IC-NSTs, and recurrent mutations affecting mitogen-activated protein kinase family genes and NBPF10. RNA-sequencing analysis identified 17 high-confidence fusion genes, eight of which were validated and two of which were in-frame. No recurrent fusions were identified in an independent series of MPCs and IC-NSTs. Forced expression of in-frame fusion genes (SLC2A1–FAF1 and BCAS4–AURKA) resulted in increased viability of breast cancer cells. In addition, genomic disruption of CDK12 caused by out-of-frame rearrangements was found in one MPC and in 13% of HER2-positive breast cancers, identified through a re-analysis of publicly available massively parallel sequencing data. In vitro analyses revealed that CDK12 gene disruption results in sensitivity to PARP inhibition, and forced expression of wild-type CDK12 in a CDK12-null cell line model resulted in relative resistance to PARP inhibition. Our findings demonstrate that MPCs are neither defined by highly recurrent mutations in the 273 genes tested, nor underpinned by a recurrent fusion gene. Although seemingly private genetic events, some of the fusion transcripts found in MPCs may play a role in maintenance of a malignant phenotype and potentially offer therapeutic opportunities.

Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer

“…In contrast, extracranial MRD was predicted by ctDNA mutation tracking in all patients who relapsed (n = 12) (P = 0.0022, c 2 test with Yates' correction). Once mutation tracking had confirmed the presence of MRD, we sequenced DNA from the primary cancer, from the residual primary tumor resected after chemotherapy, from the plasma DNA taken before relapse, and from the subsequent metastasis when biopsied, in five patients with a panel targeting all exons of 273 genes recurrently mutated in breast cancer (17). The sequencing strategy was optimized for low DNA inputs using hybrid capture with a custom NimbleGen SeqCap EZ Choice library followed by sequencing on a HiSeq2000 to a mean target depth after duplicate removal of 460× (range, 104× to 1015×).…”

Relationship between morphological and cytogenetic heterogeneity in invasive micropapillary carcinoma of the breast: a report of one case

“…IMPC more often harboured gains of chromosomes 1q, 8q, 17q and 20q, and losses of 1p, 8p, 13q, 16q and 22q,13 14 which were emphasised by Marchio and coauthors13 as previously associated with breast tumours of high histological grade. In contrast, concurrent gain of 1q and 16p and deletion of 16q, related to low tumour grade according to the literature data, were less found in IMPC 13.…”

Invasive Micropapillary Carcinoma of the Breast: An Update

“…33,58 Many genes related to maintaining polarity, cilia formation, and cell morphology are located in these regions. Hao et al 59 compared the expression of prostate stem cell antigen (PSCA) gene located at 8q24 in 66 cases of IMPCs and 67 cases of ICD-NOSs and found that its expression was significantly greater at both the protein and messenger RNA levels in IMPC than it was in IDC-NOS.…”