Abstract P6-07-04: Distinct repertoires of somatic mutations affecting driver genes in mucinous and neuroendocrine carcinomas of the breast
Authors: Piscuoglio S , Ng CKY , Marchio C , Eberle CA , Guerini-Rocco E , Mariani O , Vincent-Salomon A , Reis-Filho JS , Weigelt B 
Published: May 2016

Abstract
Introduction: Mucinous carcinoma of the breast (MCB) is a rare histologic type, which accounts for approximately 2% of all invasive breast cancers (IBCs) and is characterized by clusters of tumor cells floating in large amounts of extracellular mucin. MCB comprises two main subtypes based on architectural and cytologic features: mucinous A (paucicellular) and mucinous B (hypercellular). Although MCBs are low-grade ER-positive/HER2-negative tumors of luminal molecular subtype, these cancers lack concurrent losses of 16q and gains of 1q, the hallmark genetic features of low-grade ER+/HER2- breast cancers, and have low levels of genetic instability. Neuroendocrine carcinoma of the breast (NCB) accounts for 2% - 5% of IBCs and displays morphologic features similar to those of neuroendocrine tumors of other organs. Previous transcriptomic analyses have revealed that NCBs and mucinous B, but not mucinous A, breast cancers display similar gene expression profiles. The aims of this study were to determine whether MCBs and NCBs share a similar repertoire of somatic genetic alterations and if these aberrations are distinct from those reported in common forms of ER+/HER2- IBCs.
Material and methods: DNA extracted from microdissected MCBs (n=7 mucinous A, n=6 mucinous B), NCBs (n=14) and adjacent normal tissues were subjected to massively parallel sequencing targeting all exons of 254 genes most frequently mutated in IBC or related to DNA repair. Somatic point mutations were identified using MuTect and somatic insertions and deletions (indels) were defined using Strelka and Varscan2. We retrieved mutations in the same 254 genes in common forms of ER+/HER2- IBC (n=252) from The Cancer Genome Atlas (TCGA).
Results: The most frequently mutated genes in MCBs were GATA3 (31% of cases, 4/13, all frame-shift indels), followed by KMT2C (MLL3) and MAP3K1 (both 23%). GATA3 and KMT2C (29%) were the most frequently mutated genes in mucinous A cancers, whereas MAP3K1 (33%) was the most frequently mutated gene in mucinous B cancers. ARID1A mutations were found in three of 14 (21%) NCBs, of which 2 were truncating mutations. A comparative analysis of the repertoire of somatic mutations found in mucinous A, mucinous B and NCBs did not reveal any statistically significant differences. As compared to common forms of ER+/HER2- IBCs, MCBs were found to have a significantly lower frequency of PIK3CA (8% vs 42%, p=0.02) mutations, which was particularly evident in mucinous A cancers (0% vs 42%, p=0.04). NCBs displayed significantly higher frequencies of somatic mutations affecting ARID1A (21% vs 2%, respectively, p=0.006), FOXA1 (14% vs 2%, respectively, p&lt;0.05) and a lower frequency of PIK3CA somatic mutations (14% vs 42%, respectively, p&lt;0.05) than common forms of ER+/HER2- IBCs.
Conclusion: The frequency of mutations affecting bona fide breast cancer genes differed among mucinous A, mucinous B and NCBs. The repertoire of somatic mutations found in MCBs and NCBs differed from that of common forms of ER+/HER2- IBCs, in particular by the low frequency of somatic mutations affecting PIK3CA.
Citation Format: Piscuoglio S, Ng CKY, Marchio C, Eberle CA, Guerini-Rocco E, Mariani O, Vincent-Salomon A, Reis-Filho JS, Weigelt B. Distinct repertoires of somatic mutations affecting driver genes in mucinous and neuroendocrine carcinomas of the breast. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-07-04.