Massively parallel sequencing analysis of 68 gastric-type cervical adenocarcinomas reveals mutations in cell cycle-related genes and potentially targetable mutations

Pier Selenica, Barbara Alemar, Cathleen Matrai, Karen L. Talia, Emanuela Veras, Yaser Hussein, Esther Oliva, Regina G. H. Beets-Tan, Yoshiki Mikami, W. Glenn McCluggage, Takako Kiyokawa, Britta Weigelt, Kay J. Park, Rajmohan Murali*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Web of Science)

Abstract

Gastric-type cervical adenocarcinoma (GCA) is an aggressive type of endocervical adenocarcinoma characterized by mucinous morphology, gastric-type mucin, lack of association with human papillomavirus (HPV) and resistance to chemo/radiotherapy. We characterized the landscape of genetic alterations in a large cohort of GCAs, and compared it with that of usual-type HPV-associated endocervical adenocarcinomas (UEAs), pancreatic adenocarcinomas (PAs) and intestinal-type gastric adenocarcinomas (IGAs). GCAs (n = 68) were subjected to massively parallel sequencing targeting 410-468 cancer-related genes. Somatic mutations and copy number alterations (CNAs) were determined using validated bioinformatics methods. Mutational data for UEAs (n = 21), PAs (n = 178), and IGAs (n = 148) from The Cancer Genome Atlas (TCGA) were obtained from cBioPortal. GCAs most frequently harbored somatic mutations in TP53 (41%), CDKN2A (18%), KRAS (18%), and STK11 (10%). Potentially targetable mutations were identified in ERBB3 (10%), ERBB2 (8%), and BRAF (4%). GCAs displayed low levels of CNAs with no recurrent amplifications or homozygous deletions. In contrast to UEAs, GCAs harbored more frequent mutations affecting cell cycle-related genes including TP53 (41% vs 5%, p <0.01) and CDKN2A (18% vs 0%, p = 0.01), and fewer PIK3CA mutations (7% vs 33%, p = 0.01). TP53 mutations were less prevalent in GCAs compared to PAs (41% vs 56%, p <0.05) and IGAs (41% vs 57%, p <0.05). GCAs showed a higher frequency of STK11 mutations than PAs (10% vs 2%, p <0.05) and IGAs (10% vs 1%, p <0.05). GCAs harbored more frequent mutations in ERBB2 and ERBB3 (9% vs 1%, and 10% vs 0.5%, both p <0.01) compared to PAs, and in CDKN2A (18% vs 1%, p <0.05) and KRAS (18% vs 6%, p <0.05) compared to IGAs. GCAs harbor recurrent somatic mutations in cell cycle-related genes and in potentially targetable genes, including ERBB2/3. Mutations in genes such as STK11 may be used as supportive evidence to help distinguish GCAs from other adenocarcinomas with similar morphology in metastatic sites.

Original languageEnglish
Pages (from-to)1213-1225
Number of pages13
JournalModern Pathology
Volume34
Issue number6
Early online date14 Dec 2020
DOIs
Publication statusPublished - Jun 2021

Keywords

  • ENDOCERVICAL GLANDULAR HYPERPLASIA
  • COPY NUMBER
  • UTERINE CERVIX
  • CANCER
  • P53
  • INHIBITOR
  • DISCOVERY
  • DNA
  • IMMUNOPHENOTYPE
  • PREVALENCE

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