Genomic characterization of small cell carcinomas of the uterine cervix

Abstract

Small cell carcinoma (SCC) of the uterine cervix is a rare and aggressive form of neuroendocrine carcinoma, which resembles small cell lung cancer (SCLC) in its histology and poor survival rate.Here we sought to define the genetic underpinning of SCCs of the uterine cervix and compare their mutational profiles with those of human papillomavirus (HPV)-positive head and neck squamous cell carcinomas, HPV-positive cervical carcinomas and SCLCs using publicly available data. Using a combination of whole-exome and targeted massively parallel sequencing, we found that the nine uterine cervix SCCs, which were HPV18-positive (n=8) or HPV16-positive (n=1), harbored a low mutation burden, few copy number alterations and other than TP53 in two cases no recurrently mutated genes. The majority of mutations were likely passenger missense mutations, and only few affected previously described cancer-related genes. Using RNA-Sequencing, we identified putative viral integration sites on 18q12.3 and on 8p22 in two SCCs of the uterine cervix. The overall nonsilent mutation rate of uterine cervix SCCs was significantly lower than those described for SCLCs, HPV-driven cervical adeno-and squamous cell carcinomas or HPV-positive head and neck squamous cell carcinomas. Unlike SCLCs, which are reported to harbor almost universal inactivating TP53 and RB1 mutations and a dominant tobacco smoke-related signature 4, uterine cervix SCCs rarely harbored mutations affecting these genes (2/9, 22% TP53; 0% RB1) and displayed a dominant aging (67%) or APOBEC mutational signature (17%), akin to HPV-driven cancers, including cervical adeno-and squamous cell carcinomas and head and neck squamous cell carcinomas. Taken together, in contrast to SCLCs, which are characterized by highly recurrent TP53 and RB1 alterations, uterine cervix SCCs were positive for HPV leading to inactivation of the suppressors p53 and RB, suggesting that these SCCs are convergent phenotypes.

Neuroendocrine Neoplasms of the Gynecologic Tract

“…Similarly, a study by Cho et al described recurring mutations in ATRX, EBRR4, and AKT/mTOR pathway genes in the pathogenesis of small-cell cervical NEC [ 44 ]. Schultheis et al characterized genomes and discovered highly recurring Tp53 and Rb1 alterations in lung NEC and p53 and RB tumor suppressor protein inactivation in cervical NEC, indicating small-cell NECs are convergent phenotypes [ 45 ].…”

Small cell neuroendocrine carcinoma of the cervix: Analysis of prognostic factors and patterns of metastasis

“…In addition to changes in staging and treatment of cervical cancers over time, SCNCC is now recognized as an HPV-driven cancer ( Schultheis et al, 2022 ). With our historical cohort, we did not have adequate data to determine associations with HPV status and outcomes.…”

Diagnosis and management of an endometrial cancer patient with Cowden syndrome

“…To compare whether the profile of somatic mutations affecting cancer-related genes in this CS-related EC harboring a germline PTEN mutation would be distinct from that of sporadic ECs with somatic PTEN mutations, we performed hierarchical cluster analysis, which groups tumors based on their similarity in mutation profiles. Using the CS-related EC described here and 77 sporadic PTEN-mutant ECs of CN-L molecular subtype from TCGA [23] and a curated set of 505 cancerrelated genes [27], we found that the CS-related EC intermingled with the sporadic PTEN-mutant ECs rather than forming a separate branch/ cluster (Fig. 3D).…”

“…Both the EC and OC occurring in this CS patient share the same copy number gains and losses, including a 1q gain. D, Hierarchical cluster analysis of somatic mutations identified in 505 cancer-related genes [27] using complete linkage and Euclidian distance metric, including the CS patient's EC from this study (Cowden_EC), which harbors a PTEN germline mutation and is of CN-L molecular subtype, and 77 sporadic PTEN-mutant ECs of CN-L molecular subtype from The Cancer Genome Atlas [23]. This CS-related EC intermingles with the sporadic PTEN-mutant ECs, rather than forming a distinct cluster, suggesting that their somatic mutational profiles are similar.…”