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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.

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Fig. 1: Histopathologic appearances of selected cases of GCA with associated genetic alterations.
Fig. 2: Somatic mutations in 68 GCAs.
Fig. 3: DNA copy number alterations in 68 GCAs.
Fig. 4: Signaling pathways affected by somatic mutations in 68 GCAs.
Fig. 5: Comparison of the mutational profiles of 68 GCAs in this study with those reported in usual endocervical adenocarcinomas, pancreatic adenocarcinomas, and intestinal/tubular gastric adenocarcinomas.

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Acknowledgements

We are grateful to the Integrated Genomics Operation at Memorial Sloan Kettering Cancer Center for their assistance with sequencing. This work was funded in part by a Cycle for Survival grant (to RM, KJP and BW), and in part by the NIH/NCI Cancer Center Support Grant P30 CA008748.

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Correspondence to Rajmohan Murali.

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BW is supported in part by Breast Cancer Research Foundation and Stand Up to Cancer grants. The authors have no other relevant disclosures or conflicts of interest.

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Selenica, P., Alemar, B., Matrai, C. et al. Massively parallel sequencing analysis of 68 gastric-type cervical adenocarcinomas reveals mutations in cell cycle-related genes and potentially targetable mutations. Mod Pathol 34, 1213–1225 (2021). https://doi.org/10.1038/s41379-020-00726-1

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