Abstract 91: The mutational landscape of mucinous carcinomas of the breast
Authors: Piscuoglio Salvatore , Ng Charlotte KY , Geyer Felipe C. , Eberle Carey A. , Guerini-Rocco Elena , Marchio Caterina , Vincent-Salomon Anne , Reis-Filho Jorge S. , Weigelt Britta 
Published: July 2016

Background: Mucinous breast carcinoma (MBC) is a special histologic type of breast cancer, comprising approximately 2% of all invasive breast carcinomas. Morphologically, MBCs are characterized by clusters of tumor cells floating in large amounts of extracellular mucin. MBCs are preferentially of low histologic grade and estrogen receptor (ER)-positive and HER2-negative. MBCs have been shown to lack the hallmark 1q gains and 16q losses found in low-grade ER-positive invasive ductal carcinomas of no special type (IDC-NSTs). Here we sought to characterize the mutational landscape and copy number alterations (CNA) of MBCs by whole exome sequencing analysis.

Material and Methods: Frozen sections from 25 pure MBCs (n = 13 mucinous A (paucicellular), n = 12 mucinous B (hypercellular)) were subjected to microdissection to ensure a tumor cell content &gt;85%. In addition, five cases of mixed mucinous carcinomas composed of mucinous and IDC-NST components were included in this study. In these cases, the MBC and IDC-NST components were microdissected separately. DNA samples extracted from microdissected tumors and matched normal counterparts were subjected to whole exome sequencing on an Illumina HiSeq2000. Somatic single nucleotide variants (SNVs) were identified using MuTect and somatic insertions and deletions (indels) were identified using Strelka and Varscan2. Somatic CNAs were defined using FACETS. Mutational frequencies in MBCs were compared to those of luminal IDC-NSTs from The Cancer Genome Atlas.

Results: A median of 26 (range 5-71) non-synonymous SNVs and indels were identified per MBC. GATA3, mutated in 28% of cases, was the only significantly mutated gene as defined by MutSigCV (q&lt;0.1). Compared to IDC-NSTs of luminal molecular subtype, MBCs were found to harbor significantly fewer mutations in TP53 (3% vs 19%, p&lt;0.001) and PIK3CA (6% vs 41%, p&lt;0.001). Mucinous subtypes A and B did not differ in terms of mutations and/ or CNAs, whereas MBCs of mixed phenotype harbored a greater extent of genomic instability. While MBC and IDC-NST components of mixed MBCs shared the majority of the somatic genetic alterations, indicating their clonal relatedness, mutations and CNAs restricted to either the MBC or the IDC-NST components were also identified. Furthermore, CNA analysis confirmed our previous observations that MBCs, contrary to low-grade ER-positive IDC-NSTs, lack concurrent copy number gains of 1q and 16p and losses of 16q.

Conclusions: Our data suggest that the repertoires of somatic mutations and gene CNAs of MBCs are distinct from those of luminal IDC-NSTs, and that MBCs are an entity distinct from low-grade ER-positive IDC-NSTs not only at the morphologic but also at the genetic level.

Citation Format: Salvatore Piscuoglio, Charlotte KY Ng, Felipe C. Geyer, Carey A. Eberle, Elena Guerini-Rocco, Caterina Marchio, Anne Vincent-Salomon, Jorge S. Reis-Filho, Britta Weigelt. The mutational landscape of mucinous carcinomas of the breast. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 91.