Next-generation Sequencing Reveals Recurrent Somatic Mutations in Small Cell Neuroendocrine Carcinoma of the Uterine Cervix

Abstract

Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare but extremely aggressive tumor. While high-risk human papillomavirus (HPV) is involved at an early stage of oncogenesis in many tumors, additional driving events have been postulated to facilitate the progression of SCNECs. Identification of oncogenic drivers could guide targeted therapy of this neoplasm. Clinicopathologic features of 10 cervical SCNECs are reported. Analyses included immunohistochemical evaluation of p16, p53, synaptophysin, and chromogranin expression; in situ hybridizations and polymerase chain reaction for high-risk HPV and/or HPV 18; and next-generation sequencing based on a 637-gene panel. The patients ranged in age from 28 to 68 years (mean, 45.6 y; median, 40.5 y). All tumors had diffuse p16 and synaptophysin expression. All but 1 tumor was positive for chromogranin (extent of staining ranged from focal to diffuse). HPV 18 was detected in 6 tumors and HPV 35 in 1 tumor. At least 1 driver mutation was detected in 8 tumors. Four cases harbored TP53 somatic mutations, 3 of which correlated with an aberrant p53 staining pattern. Four PIK3CA mutations (p.G106A, p.N345T, p.E545K, and p.E545D) were detected in 3 tumors, 2 of which also harbored TP53 mutations. Oncogenic driver mutations involving KRAS, Erbb2, c-Myc, NOTCH1, BCL6, or NCOA3 were detected in 4 tumors. Mutations in caretaker tumor suppressors PTEN, RB1, BRCA1, BRCA2, and ARID1B were also identified in 4 tumors that commonly coharbored activating oncogenic mutations. Targeted next-generation gene sequencing identified genetic alterations involving the MAPK, PI3K/AKT/mTOR, and TP53/BRCA pathways in SCNECs. The presence of genetic alterations that are amenable to targeted therapy in SCNECs offers the potential for individualized management strategies for treatment of this aggressive tumor.

PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

“…36,37 In one study, mutations in caretaker tumour suppressors and activating oncogenic mutations (including RB1 in one case) were identified in four of 10 SmCC-Cx cases. 29 Rb-1 loss by immunohistochemistry has been documented in 73% (16 of 21) SmCC-Cx, 38 similar to our study where four of nine (44%) cases exhibited Rb-1 loss. In our cohort, Rb-1 loss was seen only in tumours with PD-L1 expression; however, this association was not statistically significant in this small cohort.…”

“…A recent study using targeted next-generation gene sequencing on 10 patients with SmCC-Cx identified recurrent somatic mutations involving the MAPK, PI3K/AKT/mTOR and TP53/BRCA pathways. 29 Similarly, mutations in PIK3CA, one of the most frequently mutated genes in HPV-related cancers, were detected in 18% (eight of 44) of SmCC-Cx in a hotspot-based study. 30 In contrast, a study using whole exome sequencing identified recurrent mutations in five cases of SmCC-Cx, including ATRX, ERBB4 and AKT/mTOR pathway genes NF1, PTEN, RICTOR and TSC1/2, which is akin to neuroendocrine tumours arising in sites unrelated to HPV infection.…”

“…Some genetic alterations, such as RB1 and TP53 , are commonly seen in different anatomical origins of SmCC. A recent study using targeted next‐generation gene sequencing on 10 patients with SmCC‐Cx identified recurrent somatic mutations involving the MAPK , PI3K/AKT/mTOR and TP53/BRCA pathways . Similarly, mutations in PIK3CA , one of the most frequently mutated genes in HPV‐related cancers, were detected in 18% (eight of 44) of SmCC‐Cx in a hot‐spot‐based study .…”

“…Recent evidence indicates that the tumour suppressor RB1 , which is frequently affected in SmCC, is also involved in immune functions with down‐regulation of a multitude of immune genes in tumours with RB1 loss . In one study, mutations in caretaker tumour suppressors and activating oncogenic mutations (including RB1 in one case) were identified in four of 10 SmCC‐Cx cases . Rb‐1 loss by immunohistochemistry has been documented in 73% (16 of 21) SmCC‐Cx, similar to our study where four of nine (44%) cases exhibited Rb‐1 loss.…”

Updates on the Role of Molecular Alterations and NOTCH Signaling in the Development of Neuroendocrine Neoplasms

“…Up-to-date one next generation sequence study was performed on small cell neuroendocrine carcinoma of uterine cervix (SCNEC). Deyin Xing et al found oncogenic driver mutations in KRAS, Erb-B2, c-Myc, BCL6 and NOTCH1 in a cohort of 10 Small cell neuroendocrine carcinomas (SCNEC) of the uterine cervix, a rare but extremely aggressive tumour [92]. In addition, in a cohort of large cells neuroendocrine carcinoma (LCNEC), the most relevant molecular alteration was detected in DLL3, a well-known NOTCH canonical ligand.…”