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

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.

New Pathological and Clinical Insights in Endometrial Cancer in View of the Updated ESGO/ESTRO/ESP Guidelines

“…To date, there are still no data regarding the TCGA groups in endometrial GTEC. In endocervical GTEC, genomic profiling showed frequent (about 40%) TP53 mutation, although with low level of somatic copy number alterations and occasional microsatellite instability in the absence of high mutational burden [ 77 ]. If endometrial GTEC is similar to its endocervical counterpart, it is possible that it does not fit to the TCGA group of endometrial carcinoma.…”

Molecular Pathology of Human Papilloma Virus-Negative Cervical Cancers

“…Recent evidence has revealed the molecular profile of GAS ( Table 5 ) [ 74 , 75 , 76 , 78 ]. For instance, Garg et al described genetic changes in 161 cancer driver genes in 14 GAS cases using next-generation sequencing, identifying gene alterations in TP53 (50%), MSH6 (43%), CDKN2A/B (36%), POLE (36%), SLX4 (36%), ARID1A (29%), STK11 (29%), BRCA2 (21%), and MSH2 (21%) [ 77 ].…”

“…Park et al discovered altered TP53 (52.4%), STK11 , HLA-B , PTPRS (19%), and FGFR4 (14.3%) expression in 21 cases of GAS [ 75 ] with genes involved in signal transduction, DNA damage repair, and epithelial-mesenchymal transition. Recently, Selenica et al examined 68 cases of GAS and discovered that most somatic mutations occurred in TP53 (41%), CDKN2A (18%), KRAS (18%), and STK11 (10%), with potentially targetable mutations identified in ERBB3 (10%), ERBB2 (8%), and BRAF (4%) [ 74 ]. In addition, these studies revealed that GAS has more TP53, STK11, CDKN2A, ATM , and NTRK3 [ 78 ] mutations and fewer PIK3CA mutations [ 74 ] than typical type endocervical adenocarcinoma.…”

“…Recently, Selenica et al examined 68 cases of GAS and discovered that most somatic mutations occurred in TP53 (41%), CDKN2A (18%), KRAS (18%), and STK11 (10%), with potentially targetable mutations identified in ERBB3 (10%), ERBB2 (8%), and BRAF (4%) [ 74 ]. In addition, these studies revealed that GAS has more TP53, STK11, CDKN2A, ATM , and NTRK3 [ 78 ] mutations and fewer PIK3CA mutations [ 74 ] than typical type endocervical adenocarcinoma. MDA, a very well-differentiated form of GAS, is part of the tumor spectrum and is known to be associated with Peutz-Jeghers syndrome characterized by germline mutations in STK11 [ 95 ].…”

Pain experience and mood disorders during the lockdown of the COVID-19 pandemic in the United States: an opportunistic study

“…The pandemic of coronavirus disease 2019 (COVID-19) 24 , 42 is one of the most serious outbreaks over the past century. It has induced significant distress and anxiety for patients 55 and providers. 7 , 62 Stress is the acute response to something fearful, unpredictable, and uncontrollable; it can also potentiate anxiety, an adaptive response that promotes harm avoidance.…”