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Comprehensive genomic profiling and prognostic analysis of cervical gastric-type mucinous adenocarcinoma

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Abstract

Gastric-type mucinous adenocarcinoma (GAS) is an uncommon cervical adenocarcinoma, which is not associated with human papillomavirus (HPV) infection. Compared with HPV-associated cervical adenocarcinoma, GAS has characteristics of larger volume, deep invasion, and easy to metastasize to distant sites. Also, GAS is typically resistant to chemo/radiotherapy. Few studies have reported the molecular genetic characteristics of GAS. In order to investigate the molecular genetic characteristics of GAS and reveal its possible pathogenesis, 15 GAS patients were enrolled from Peking University People’s Hospital (2009–2019) and examined with next-generation sequencing (NGS). Based on the clinicopathologic feature analysis, we found that the presence of lymph node metastasis and extensive lymphovascular invasion were associated with poor survival outcomes of GAS (p = 0.0042 and p = 0.005, respectively). Based on the NGS testing, our results showed that the most frequently mutated gene was TP53 (8/15, 53.3%), followed by STK11, CDKN2A, and ARID1A. STK11 mutations were more frequent in well-differentiated GAS (33.3% vs. 0.0%, p = 0.026) and patients with extensive lymphovascular invasion (33.3% vs. 0.0%, p = 0.044). Survival analysis revealed that STK11 mutations were significantly associated with the poor prognosis of GAS (p = 0.01). Our results also showed that mutations in the target drug were detected in 53.3% of GAS patients. Patients with ERBB2 amplification (13.3%) presented the highest level of evidence according to OncoKB recommendations. These results indicate that the genomic alterations of GAS mainly involved the cell cycle and PI3K/AKT signaling pathways, and some therapeutic candidates were identified in GAS patients.

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Acknowledgments

The authors would like to thank the Department of Pathology, Peking University People’s Hospital, for providing access to archival materials and a great study team. The authors also wish to thank OrigiMed for the NGS service.

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Authors and Affiliations

  1. Department of Pathology, Peking University People’s Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China

    Shanshan Lu, Xiaobo Zhang, Fangzhou Kong, Lili Liu & Danhua Shen

  2. OrigiMed, No. 115 Xinjunhuan Road, 5th Floor, Building 3, Shanghai, 201114, China

    Junping Shi, Xiaowei Dong & Kai Wang

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  1. Shanshan Lu
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Contributions

Study conception and design: D.S. and S.L. Case selection and review: S.L. and X.Z. Data analysis and interpretation: S.L. and J.S. Administrative, technical, or material support: F.K., L.L., X.D., and K.W. Manuscript preparation: all authors.

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Correspondence to Danhua Shen.

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Fig. S1

Histopathologic appearances of GAS. A Well-differentiated GAS with clear and vacuolated cytoplasm and limited desmoplasia; STK11 truncation SNV (HE, ×100). B Moderately to poorly differentiated GAS, which glands are lined by cells with variable nuclear changes, including large vesicular nuclei with visible nucleoli; TP53 hotspot mutation with loss of heterozygosity (HE, ×100). C Well-differentiated GAS with lymph node metastases; STK11 substitution/indel SNV (HE, ×100). D Well-differentiated GAS with fallopian tube involvement; STK11 substitution/indel SNV (HE, ×100). E GAS with diffuse positivity of MUC6 (IHC, ×100). F GAS displays negative immunoreactivity of p16 (IHC, ×100). G GAS shows diffuse p53 overexpression (mutation type-diffuse, MTD) (IHC, ×100). H GAS exhibits a complete absence of p53 IHC (mutation type-null, MTN) (IHC, ×100) (JPG 693 kb)

Fig. S2

The prognosis difference between the well-differentiated and the moderately/poorly differentiated GAS patients (PDF 46 kb)

Fig. S3

The Integrative Genomics Viewer (IGV) results of STK11 mutations (PDF 242 kb)

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Lu, S., Shi, J., Zhang, X. et al. Comprehensive genomic profiling and prognostic analysis of cervical gastric-type mucinous adenocarcinoma. Virchows Arch 479, 893–903 (2021). https://doi.org/10.1007/s00428-021-03080-y

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