Clinical and genomic analyses of neuroendocrine neoplasms of the breast

Breast neuroendocrine neoplasms (NENs) constitute a rare histologic subtype that includes both neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). In this study, we aimed to gain insight into the clinical and molecular characteristics of NENs of the breast. NEN and paired distant normal fresh tissues and clinicopathological data were obtained from 17 patients with NENs, and clinicopathological data were collected from 755 patients with invasive breast carcinomas of no special type (IBCs-NST). We compared the clinicopathological characteristics of NENs and IBCs-NST and performed whole-exome sequencing (WES) of both NEN and paired normal tissues. Compared with the IBC-NST patients, the NEN patients had a higher mean age, lower clinical stage, and lower pathological nodal (pN) stage (P < 0.001, P < 0.001, and P = 0.017, respectively). The most frequently mutated gene in NENs was KMT2C (3/17, 17.6%). NENs had copy number variations (CNVs) of 8q, 11q, and 17q amplification and 17q and 11q deletion and harbored the following specific genes related to tumorigenesis: (i) suppressor genes with loss of heterozygosity (LOH) such as ACE (2/17, 11.8%); (ii) tumor driver genes such as GATA3 (2/17, 11.8%); and (iii) susceptibility genes such as MAP3K4 (17/17, 100%) and PDE4DIP (17/17, 100%). The oncogenic/likely oncogenic mutations of NETs in PI3K pathway genes (50.0%, 18.2%; P < 0.001) and MAPK signaling pathway genes (83.3%, 18.2%; P = 0.035) affected higher proportions than those of NECs. In conclusion, this study provides certain clinical and molecular evidence supporting NENs as a distinct subtype of breast cancer and provides some potential molecular features for distinguishing NETs from NECs.