Journal Article

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

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

2021

Overview

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.

• Publisher: Elsevier Inc,Nature Publishing Group US,Elsevier Limited
• Subject: 45/23 / 631/67/1517 / 631/67/69 / Adenocarcinoma / Adenocarcinoma - genetics / Adenocarcinoma - pathology / Bioinformatics / Cell cycle / Cervical cancer / Cervix / Copy number / ErbB-2 protein / ErbB-3 protein / Female / Genes, cdc - genetics / Genomes / High-Throughput Nucleotide Sequencing / Human papillomavirus / Humans / Laboratory Medicine / Medicine / Medicine & Public Health / Metastases / Morphology / Mucin / Mutation / p53 Protein / Pancreas / Pancreatic cancer / Pathology / Radiation therapy / Sequence analysis / Sequence Analysis, DNA / Uterine Cervical Neoplasms - genetics / Uterine Cervical Neoplasms - pathology