Identification of Fusion Genes in Papillary Carcinomas of the Breast
Jorge S Reis-Filho, Alan Mackay, Paul M Wilkerson, Maryou B Lambros, Arnaud Gauthier, Odette Mariani, Raphaelle Duprez, Daniel Nava Rodrigues, Marthe Mandour, Christopher Maher, Britta Weigelt, Rachael Natrajan, Anne Vincent-Salomon. The Institute of Cancer Research, London, United Kingdom; Institut Curie, Paris, France; Washington University in St Louis, St Louis; Cancer Research UK London Research Institute, London, United Kingdom
Background: Papillary carcinoma is a histological special type of breast cancer accounting for approximately 1% of all invasive breast cancers. Papillary carcinomas constitute a group of tumours that are part of the spectrum of oestrogen receptor (ER)-positive 'luminal' breast cancers. Three variants of papillary carcinomas are currently recognised: encapsulated (EPC), solid (SPC) and invasive (IPC) papillary carcinomas. The aim of this study was to investigate whether papillary carcinomas of the breast are underpinned by novel expressed fusion genes/ chimaeric transcripts.
Design: Eight frozen papillary carcinomas (three EPCs, three IPCs, and two SPCs) were subjected to paired-end massively parallel RNA sequencing. cDNA libraries were prepared according to a modified Illumina mRNA protocol and run on the Genome Analyzer II sequencers (read length of each mate pair = 72bp; two lanes per sample). Data were aligned to the genome and transcriptome using Bowtie and mate-pairs supporting novel chimaeric transcripts identified using Chimerascan version 4.0. High confidence nominated fusion genes were validated using reverse transcription (RT)-PCR.
Results: Analysis of papillary carcinomas led to the identification of high confidence chimaeric transcripts in seven samples. One EPC did not harbour any high confidence chimaeric transcripts. Using validated approaches, 22 high confidence novel expressed chimaeric transcripts were found, of which 17 were intra-chromosomal and five were inter-chromosomal chimaeric transcripts. Seven of these chimaeric transcripts were predicted to produce in-frame fusion proteins, and these included a reciprocal inter-chromosomal translocation t(1;12)(q23.3;q23.1) fusing exon 7 of USF1 to exon 14 of CCDC38. We also observed an out-of frame chimaeric transcript involving ZNF57 and TMPRSS9 that was recurrent in two of the samples analysed (one EPC and one IPC). This out-of-frame chimaeric transcript may lead to loss of function of both genes. Out of the in-frame chimaeric transcripts identified, one of the 5' gene partners contained an oestrogen-responsive element.
Conclusions: Unlike other special histological types of breast cancer, which are underpinned by specific recurrent fusion genes (e.g. secretory and adenoid cystic carcinomas), papillary carcinomas are unlikely to be characterised by the presence of a highly recurrent fusion gene.
Monday, March 19, 2012 1:00 PM
Poster Session II # 75, Monday Afternoon