Wei Yani, Ke Xuexuan, Yu Jiaxiu, Jing Qiuyang, Bu Hong, Zeng Xiangfei, Wei Bing
Department of Pathology, West China Hospital, Sichuan University, Sichuan, China.
Institute of Clinical Pathology, West China Hospital, Sichuan University, Sichuan, China.
Mod Pathol. 2022 Apr;35(4):495-505. doi: 10.1038/s41379-021-00965-w. Epub 2021 Nov 2.
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.
乳腺神经内分泌肿瘤（NENs）是一种罕见的组织学亚型，包括神经内分泌肿瘤（NETs）和神经内分泌癌（NECs）。在本研究中，我们旨在深入了解乳腺NENs的临床和分子特征。从17例NENs患者获取了NENs及配对的远处正常新鲜组织和临床病理数据，并从755例非特殊类型浸润性乳腺癌（IBCs-NST）患者收集了临床病理数据。我们比较了NENs和IBCs-NST的临床病理特征，并对NENs及配对的正常组织进行了全外显子测序（WES）。与IBC-NST患者相比，NENs患者的平均年龄更高，临床分期更低，病理淋巴结（pN）分期更低（分别为P < 0.001、P < 0.001和P = 0.017）。NENs中最常发生突变的基因是KMT2C（3/17，17.6%）。NENs存在8q、11q和17q扩增以及17q和11q缺失的拷贝数变异（CNVs），并含有以下与肿瘤发生相关的特定基因：（i）杂合性缺失（LOH）的抑癌基因，如ACE（2/17，11.8%）；（ii）肿瘤驱动基因，如GATA3（2/17，11.8%）；以及（iii）易感基因，如MAP3K4（17/17，100%）和PDE4DIP（17/17，100%）。PI3K通路基因（50.0%，18.2%；P < 0.001）和MAPK信号通路基因（83.3%，18.2%；P = 0.035）中NETs的致癌/可能致癌突变影响的比例高于NECs。总之，本研究提供了一定的临床和分子证据支持NENs作为乳腺癌的一种独特亚型，并提供了一些区分NETs和NECs的潜在分子特征。
