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 that of 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 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.

Keywords: HPV; mutational signatures; neuroendocrine; small cell carcinoma; uterine cervix; whole-exome sequencing.

Fig. 1

Histologic and immunohistochemical features of small cell carcinomas of the uterine cervix. Representative micrographs of a UCSCCs (case SCC6T). (A) Low‐power magnification of a H&E‐stained section showing the overall growth pattern of small cell carcinomas as dense tumor masses. (B) Higher‐power magnification of an H&E‐stained section highlighting the morphology of small cells, showing scant cytoplasm and small nuclei with finely granulated chromatin. Small cell carcinomas of the uterine cervix generally express (C) cytokeratin, (D) Ki67 and (E) chromogranin A. Scale bars (A, B) 500 µm and (C‐E) 100 µm.

Fig. 2

Somatic mutations identified and cancer cell fractions in small cell carcinomas of the uterine cervix using whole‐exome or targeted MSK‐IMPACT sequencing. Nonsynonymous somatic mutations (left) and cancer cell fractions of somatic mutations identified in the eight small cell carcinomas of the uterine cervix subjected to WES or MSK‐IMPACT sequencing targeting 505 cancer‐related genes. No nonsynonymous somatic mutations were identified in SCC8. Mutation type and cancer cell fractions (CCFs) are color‐coded according to the legend, with clonal mutations highlighted by an orange box. Loss of heterozygosity is depicted by a diagonal bar.

Fig. 3

Copy number alterations in small cell carcinomas of the uterine cervix. Chromosome plots of the nine small cell carcinomas of the uterine cervix subjected to WES or MSK‐IMPACT sequencing targeting 505 cancer‐related genes. copy number log₂ ratios are depicted on the y‐axis with the chromosome location on the x‐axis. Black arrows, amplification and homozygous deletion identified.

Fig. 4

Comparison of the mutational profiles and mutational signatures of small cell carcinomas of the uterine cervix with SCLCs, HPV‐positive head and neck carcinomas, and HPV‐positive cervical carcinomas. (A) Comparison of somatic nonsynonymous mutations in small cell carcinomas of the uterine cervix (this study) with those of SCLCs and HPV‐driven head and neck and HPV‐driven cervical cancers (adenocarcinoma/ squamous cell carcinomas), showing the top 15 recurrently mutated genes across all studies. (B) Mutational signatures in small cell carcinomas of the uterine cervix subjected to WES (n = 6; this study), SCLCs, and HPV‐driven head and neck and HPV‐driven cervical cancers (adenocarcinoma/ squamous cell carcinomas). HNSC, head and neck squamous cell cancer; CESC, cervical adenocarcinoma/ squamous cell carcinomas.