Genomic characterization of small cell carcinomas of the uterine cervix. Issue 4 (13th May 2021)

• Record Type: Journal Article
• Authors: Schultheis, Anne M.; de Bruijn, Ino; Selenica, Pier; Macedo, Gabriel S.; da Silva, Edaise M.; Piscuoglio, Salvatore; Jungbluth, Achim A.; Park, Kay J.; Klimstra, David S.; Wardelmann, Eva; Hartmann, Wolfgang; Gerharz, Claus Dieter; von Petersdorff, Mareike; Buettner, Reinhard; Reis‐Filho, Jorge S.; Weigelt, Britta
• Is Part Of: Molecular oncology. Volume 16:Issue 4(2022)
• Page Start: 833
• Page End: 845
• Publication Date: 2021-05-13
• Subjects: HPV -- mutational signatures -- neuroendocrine -- small cell carcinoma -- uterine cervix -- whole‐exome sequencing; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12962
• Languages: English
• ISSNs: 1574-7891

Abstract

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. Abstract : Small cell carcinoma (SCC) of the uterine cervix is a rare and aggressive neuroendocrine carcinoma. Here, we show that uterine cervix SCCs are primarily HPV18‐positive. Using whole‐exome and/or targeted massively parallel sequencing, we found that uterine cervix SCCs have a low mutation burden, rarely harbor TP53 and lack RB1 mutations, display primarily dominant aging mutational signatures, and lack recurrent amplifications/homozygous deletions.