Abstract P2-05-08: Mucinous breast carcinomas: A genomically distinct subtype of estrogen receptor-positive invasive breast cancers
Authors: Pareja F , Geyer FC , Piscuoglio S , Selenica P , Kumar R , Lim RS , Guerini-Rocco E , Marchio C , Mariani O , Ng CKY , Brogi E , Norton L , Vincent-Salomon A , Weigelt B , Reis-Filho JS 
Published: February 2018

Abstract
Introduction: Mucinous carcinoma of the breast (MCB) is a rare histologic form of estrogen receptor (ER)-positive invasive carcinoma, accounting for up to 2% of breast cancers. MCBs are characterized by clusters of tumor cells floating in lakes of extracellular mucin, and are classified into mucinous A (paucicellular) and mucinous B (hypercellular) subtypes. Some MCBs are found admixed with invasive ductal carcinoma components, and then classified as mixed MCBs. The aims of this study were to determine the repertoire of somatic mutations of MCBs and to ascertain whether these genetic alterations are distinct from those identified in common forms of ER+/HER2- invasive breast cancers (IBCs). We also sought to determine whether the mucinous and ductal components of mixed MCBs would be clonally related.
Materials and methods: Thirty MCBs including 25 pure MCBs (n=13 mucinous A, n=12 mucinous B) and five mixed MCBs were microdissected and subjected to whole exome sequencing. Each tumor component of mixed cases was microdissected and analyzed separately. Somatic mutations, copy number alterations and mutational signatures were defined using state-of-the-art bioinformatics methods. The mutational repertoire of MCBs was compared with that of ER+/HER2- IBCs (n = 240) from The Cancer Genome Atlas (TCGA) breast cancer study.
Results: The genes most frequently mutated in MCBs were GATA3 (27%, 8/30, all frameshift mutations), KMT2C (13%, 4/30) and MAP3K1 (10%, 3/30). No significant differences were identified in single gene comparisons between mucinous A and mucinous B MCBs or between pure MCBs and the mucinous component of mixed MCBs (Fisher's exact tests, p&gt;0.05). As compared to common forms of ER+/HER2- IBC, MCBs had a lower frequency of PIK3CA mutations (7% vs 42%, p&lt;0.001) and a higher frequency of GATA3 mutations (27% vs 12%, p=0.04). Mucinous B MCBs had a higher frequency of KMT2C mutations than ER+/HER2- IBCs (25% vs 6%, p=0.04). Most MCBs displayed the mutational signature 1 (aging-related; 20/30, 67%), and no differences in the frequency of specific mutational signatures according to the type of MCBs were observed. Concurrent 1q gains and 16q losses, which are the hallmark genetic alterations of low-grade ER+/HER2- breast cancers, were not observed in pure MCBs, but were found in three of the five mixed MCBs analyzed. The mucinous and ductal components of all five mixed MCBs shared a median of 58% of somatic mutations (range 42%-64%), including clonal GATA3 frameshift mutations in two of them, as well as a similar pattern of copy number alterations, supporting their clonal relatedness. Additional somatic mutations found to be restricted to the ductal or mucinous components of all mixed MCBs analyzed were identified, including clonal missense mutations in PIK3C2B and PIK3R2 in the ductal component of one case, and a PIK3R5 missense mutation in the mucinous component of another case.
Conclusions: The repertoire of somatic mutations in MCBs is distinct from that of common forms of ER+/HER2- IBCs. These differences include the lack of concurrent 1q gains/16q losses, a lower frequency of PIK3CA mutations and a higher frequency of GATA3 mutations in pure MCBs.
Citation Format: Pareja F, Geyer FC, Piscuoglio S, Selenica P, Kumar R, Lim RS, Guerini-Rocco E, Marchio C, Mariani O, Ng CKY, Brogi E, Norton L, Vincent-Salomon A, Weigelt B, Reis-Filho JS. Mucinous breast carcinomas: A genomically distinct subtype of estrogen receptor-positive invasive breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-05-08.