Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1.

    WHO Classification of Tumours Editorial Board. Female genital tumours. Vol 4. 5th ed. Lyon: IARC Press; 2020.

  2. 2.

    Ishii K, Hosaka N, Toki T, Momose M, Hidaka E, Tsuchiya S, et al. A new view of the so-called adenoma malignum of the uterine cervix. Virchows Arch. 1998;432:315–22.

    CAS  PubMed  Google Scholar 

  3. 3.

    Mikami Y, Kiyokawa T, Hata S, Fujiwara K, Moriya T, Sasano H, et al. Gastrointestinal immunophenotype in adenocarcinomas of the uterine cervix and related glandular lesions: a possible link between lobular endocervical glandular hyperplasia/pyloric gland metaplasia and ‘adenoma malignum’. Mod Pathol. 2004;17:962–72.

    PubMed  Google Scholar 

  4. 4.

    Kojima A, Mikami Y, Sudo T, Yamaguchi S, Kusanagi Y, Ito M, et al. Gastric morphology and immunophenotype predict poor outcome in mucinous adenocarcinoma of the uterine cervix. Am J Surg Pathol. 2007;31:664–72.

    PubMed  Google Scholar 

  5. 5.

    Kurman RJ, Carcangiu M-L, Herrington CS, Young RH. World Health Organization classification of tumours of female reproductive organs. Lyon: IARC Press; 2014.

    Google Scholar 

  6. 6.

    Carleton C, Hoang L, Sah S, Kiyokawa T, Karamurzin YS, Talia KL, et al. A detailed immunohistochemical analysis of a large series of cervical and vaginal gastric-type adenocarcinomas. Am J Surg Pathol. 2016;40:636–44.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Kusanagi Y, Kojima A, Mikami Y, Kiyokawa T, Sudo T, Yamaguchi S, et al. Absence of high-risk human papillomavirus (HPV) detection in endocervical adenocarcinoma with gastric morphology and phenotype. Am J Pathol. 2010;177:2169–75.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Holl K, Nowakowski AM, Powell N, McCluggage WG, Pirog EC, Collas De Souza S, et al. Human papillomavirus prevalence and type-distribution in cervical glandular neoplasias: results from a European multinational epidemiological study. Int J Cancer. 2015;137:2858–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    An HJ, Kim KR, Kim IS, Kim DW, Park MH, Park IA, et al. Prevalence of human papillomavirus DNA in various histological subtypes of cervical adenocarcinoma: a population-based study. Mod Pathol. 2005;18:528–34.

    CAS  PubMed  Google Scholar 

  10. 10.

    Kido A, Mikami Y, Koyama T, Kataoka M, Shitano F, Konishi I, et al. Magnetic resonance appearance of gastric-type adenocarcinoma of the uterine cervix in comparison with that of usual-type endocervical adenocarcinoma: a pitfall of newly described unusual subtype of endocervical adenocarcinoma. Int J Gynecol Cancer. 2014;24:1474–9.

    PubMed  Google Scholar 

  11. 11.

    Karamurzin Y, Parkash V, Kiyokawa R, Soslow RA, Park KJ. Gastric type endocervical adenocarcinoma – an aggressive histologic subtype. Mod Pathol. 2012;25:1171A.

    Google Scholar 

  12. 12.

    Karamurzin YS, Kiyokawa T, Parkash V, Jotwani AR, Patel P, Pike MC, et al. Gastric-type endocervical adenocarcinoma: an aggressive tumor with unusual metastatic patterns and poor prognosis. Am J Surg Pathol. 2015;39:1449–57.

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Nishio S, Mikami Y, Tokunaga H, Yaegashi N, Satoh T, Saito M, et al. Analysis of gastric-type mucinous carcinoma of the uterine cervix—an aggressive tumor with a poor prognosis: a multi-institutional study. Gynecol Oncol. 2019;153:13–9.

    PubMed  Google Scholar 

  14. 14.

    McCluggage WG. New developments in endocervical glandular lesions. Histopathology. 2013;62:138–60.

    PubMed  Google Scholar 

  15. 15.

    Mikami Y, McCluggage WG. Endocervical glandular lesions exhibiting gastric differentiation: an emerging spectrum of benign, premalignant, and malignant lesions. Adv Anat Pathol. 2013;20:227–37.

    CAS  PubMed  Google Scholar 

  16. 16.

    Turashvili G, Morency EG, Kracun M, DeLair DF, Chiang S, Soslow RA, et al. Morphologic features of gastric-type cervical adenocarcinoma in small surgical and cytology specimens. Int J Gynecol Pathol. 2019;38:263–75.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Takako K, Hoang L, Terinte C, Pesci A, Aviel-Ronen S, Alvarado-Cabrero I, et al. Trefoil factor 2 (TFF2) as a surrogate marker for endocervical gastric-type carcinoma. Int J Gynecol Pathol. 2020;40:65–72.

    Google Scholar 

  18. 18.

    Pirog EC, Park KJ, Kiyokawa T, Zhang X, Chen W, Jenkins D, et al. Gastric-type adenocarcinoma of the cervix: tumor with wide range of histologic appearances. Adv Anat Pathol. 2019;26:1–12.

    PubMed  Google Scholar 

  19. 19.

    Garg S, Nagaria TS, Clarke B, Freedman O, Khan Z, Schwock J, et al. Molecular characterization of gastric-type endocervical adenocarcinoma using next-generation sequencing. Mod Pathol. 2019;32:1823–33.

    CAS  PubMed  Google Scholar 

  20. 20.

    Hodgson A, Howitt BE, Park KJ, Lindeman N, Nucci MR, Parra-Herran C. Genomic characterization of HPV-related and gastric-type endocervical adenocarcinoma: correlation with subtype and clinical behavior. Int J Gynecol Pathol. 2020;39:578–86.

    CAS  PubMed  Google Scholar 

  21. 21.

    Mikami Y, Hata S, Melamed J, Fujiwara K, Manabe T. Lobular endocervical glandular hyperplasia is a metaplastic process with a pyloric gland phenotype. Histopathology. 2001;39:364–72.

    CAS  PubMed  Google Scholar 

  22. 22.

    Nucci MR, Clement PB, Young RH. Lobular endocervical glandular hyperplasia, not otherwise specified: a clinicopathologic analysis of thirteen cases of a distinctive pseudoneoplastic lesion and comparison with fourteen cases of adenoma malignum. Am J Surg Pathol. 1999;23:886–91.

    CAS  PubMed  Google Scholar 

  23. 23.

    Nishio S, Tsuda H, Fujiyoshi N, Ota S, Ushijima K, Sasajima Y, et al. Clinicopathological significance of cervical adenocarcinoma associated with lobular endocervical glandular hyperplasia. Pathol Res Pract. 2009;205:331–7.

    PubMed  Google Scholar 

  24. 24.

    Matsubara A, Sekine S, Ogawa R, Yoshida M, Kasamatsu T, Tsuda H, et al. Lobular endocervical glandular hyperplasia is a neoplastic entity with frequent activating GNAS mutations. Am J Surg Pathol. 2014;38:370–6.

    PubMed  Google Scholar 

  25. 25.

    Talia KL, Stewart CJR, Howitt BE, Nucci MR, McCluggage WG. HPV-negative gastric type adenocarcinoma in situ of the cervix: a spectrum of rare lesions exhibiting gastric and intestinal differentiation. Am J Surg Pathol. 2017;41:1023–33.

    PubMed  Google Scholar 

  26. 26.

    Kawauchi S, Kusuda T, Liu XP, Suehiro Y, Kaku T, Mikami Y, et al. Is lobular endocervical glandular hyperplasia a cancerous precursor of minimal deviation adenocarcinoma?: a comparative molecular-genetic and immunohistochemical study. Am J Surg Pathol. 2008;32:1807–15.

    PubMed  Google Scholar 

  27. 27.

    Cheng DT, Mitchell TN, Zehir A, Shah RH, Benayed R, Syed A, et al. Memorial sloan kettering-integrated mutation profiling of actionable cancer targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. 2015;17:251–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Da Cruz Paula A, da Silva EM, Segura SE, Pareja F, Bi R, Selenica P, et al. Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary. Mod Pathol. 2020;33:1606–17.

  29. 29.

    Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31:213–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Saunders CT, Wong WS, Swamy S, Becq J, Murray LJ, Cheetham RK. Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics. 2012;28:1811–7.

    CAS  PubMed  Google Scholar 

  31. 31.

    Koboldt DC, Zhang Q, Larson DE, Shen D, McLellan MD, Lin L, et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 2012;22:568–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Narzisi G, Corvelo A, Arora K, Bergmann EA, Shah M, Musunuri R, et al. Genome-wide somatic variant calling using localized colored de Bruijn graphs. Commun Biol. 2018;1:20.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Narzisi G, O’Rawe JA, Iossifov I, Fang H, Lee YH, Wang ZH, et al. Accurate de novo and transmitted indel detection in exome-capture data using microassembly. Nat Methods. 2014;11:1033–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Shen R, Seshan VE. FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res. 2016;44:e131.

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Martelotto LG, Baslan T, Kendall J, Geyer FC, Burke KA, Spraggon L, et al. Whole-genome single-cell copy number profiling from formalin-fixed paraffin-embedded samples. Nat Med. 2017;23:376–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Chang MT, Bhattarai TS, Schram AM, Bielski CM, Donoghue MTA, Jonsson P, et al. Accelerating discovery of functional mutant alleles in cancer. Cancer Discov. 2018;8:174–83.

    CAS  PubMed  Google Scholar 

  37. 37.

    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, Weerasinghe A, et al. Comprehensive characterization of cancer driver genes and mutations. Cell. 2018;174:1034–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Gulhan DC, Lee JJ, Melloni GEM, Cortes-Ciriano I, Park PJ. Detecting the mutational signature of homologous recombination deficiency in clinical samples. Nat Genet. 2019;51:912–9.

    CAS  PubMed  Google Scholar 

  40. 40.

    Smith ES, Da Cruz Paula A, Cadoo KA, Abu-Rustum NR, Pei X, Brown DN, et al. Endometrial cancers in BRCA1 or BRCA2 germline mutation carriers: assessment of homologous recombination DNA repair defects. JCO Precis Oncol. 2019;3:PO.19.00103.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I. Controlling the false discovery rate in behavior genetics research. Behav Brain Res. 2001;125:279–84.

    CAS  PubMed  Google Scholar 

  42. 42.

    Gala K, Chandarlapaty S. Molecular pathways: HER3 targeted therapy. Clin Cancer Res. 2014;20:1410–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018;554:189–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Ruiz-Saenz A, Moasser MM. Targeting HER2 by combination therapies. J Clin Oncol. 2018;36:808–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Oh DY, Bang YJ. HER2-targeted therapies—a role beyond breast cancer. Nat Rev Clin Oncol. 2020;17:33–48.

    CAS  PubMed  Google Scholar 

  46. 46.

    Patnaik A, Appleman LJ, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, et al. First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Ann Oncol. 2016;27:1928–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, Driscoll KE, Estrem ST, et al. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des Devel Ther. 2015;9:4479–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Cunanan KM, Gonen M, Shen R, Hyman DM, Riely GJ, Begg CB, et al. Basket trials in oncology: a trade-off between complexity and efficiency. J Clin Oncol. 2017;35:271–3.

    PubMed  Google Scholar 

  49. 49.

    Tao JJ, Schram AM, Hyman DM. Basket studies: redefining clinical trials in the era of genome-driven oncology. Annu Rev Med. 2018;69:319–31.

    CAS  PubMed  Google Scholar 

  50. 50.

    Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575:217–23.

    CAS  PubMed  Google Scholar 

  51. 51.

    Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, et al. The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10:54–71.

    CAS  PubMed  Google Scholar 

  52. 52.

    Beggs AD, Latchford AR, Vasen HF, Moslein G, Alonso A, Aretz S, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. 2010;59:975–86.

    CAS  PubMed  Google Scholar 

  53. 53.

    Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9:563–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Momcilovic M, Shackelford DB. Targeting LKB1 in cancer—exposing and exploiting vulnerabilities. Br J Cancer. 2015;113:574–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Koyama S, Akbay EA, Li YY, Aref AR, Skoulidis F, Herter-Sprie GS, et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress t-cell activity in the lung tumor microenvironment. Cancer Res. 2016;76:999–1008.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 2018;8:822–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Ribas A, Flaherty KT. BRAF targeted therapy changes the treatment paradigm in melanoma. Nat Rev Clin Oncol. 2011;8:426–33.

    CAS  PubMed  Google Scholar 

  58. 58.

    Holderfield M, Deuker MM, McCormick F, McMahon M. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer. 2014;14:455–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Proietti I, Skroza N, Michelini S, Mambrin A, Balduzzi V, Bernardini N, et al. BRAF inhibitors: molecular targeting and immunomodulatory actions. Cancers. 2020;12:1823.

    CAS  PubMed Central  Google Scholar 

  60. 60.

    Ojesina AI, Lichtenstein L, Freeman SS, Pedamallu CS, Imaz-Rosshandler I, Pugh TJ, et al. Landscape of genomic alterations in cervical carcinomas. Nature. 2014;506:371–5.

    CAS  PubMed  Google Scholar 

  61. 61.

    Li X, Coffino P. High-risk human papillomavirus E6 protein has two distinct binding sites within p53, of which only one determines degradation. J Virol. 1996;70:4509–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Zimmermann H, Degenkolbe R, Bernard HU, O’Connor MJ. The human papillomavirus type 16 E6 oncoprotein can down-regulate p53 activity by targeting the transcriptional coactivator CBP/p300. J Virol. 1999;73:6209–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Crook T, Fisher C, Masterson PJ, Vousden KH. Modulation of transcriptional regulatory properties of p53 by HPV E6. Oncogene. 1994;9:1225–30.

    CAS  PubMed  Google Scholar 

  64. 64.

    Lechner MS, Laimins LA. Inhibition of p53 DNA binding by human papillomavirus E6 proteins. J Virol. 1994;68:4262–73.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


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.

Author information



Corresponding author

Correspondence to Rajmohan Murali.

Ethics declarations

Conflict of interest

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation


Quick links