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
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
WHO Classification of Tumours Editorial Board. Female genital tumours. Vol 4. 5th ed. Lyon: IARC Press; 2020.
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.
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.
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.
Kurman RJ, Carcangiu M-L, Herrington CS, Young RH. World Health Organization classification of tumours of female reproductive organs. Lyon: IARC Press; 2014.
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.
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.
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.
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.
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.
Karamurzin Y, Parkash V, Kiyokawa R, Soslow RA, Park KJ. Gastric type endocervical adenocarcinoma – an aggressive histologic subtype. Mod Pathol. 2012;25:1171A.
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.
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.
McCluggage WG. New developments in endocervical glandular lesions. Histopathology. 2013;62:138–60.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Gala K, Chandarlapaty S. Molecular pathways: HER3 targeted therapy. Clin Cancer Res. 2014;20:1410–6.
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.
Ruiz-Saenz A, Moasser MM. Targeting HER2 by combination therapies. J Clin Oncol. 2018;36:808–11.
Oh DY, Bang YJ. HER2-targeted therapies—a role beyond breast cancer. Nat Rev Clin Oncol. 2020;17:33–48.
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.
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.
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.
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.
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.
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.
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.
Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9:563–75.
Momcilovic M, Shackelford DB. Targeting LKB1 in cancer—exposing and exploiting vulnerabilities. Br J Cancer. 2015;113:574–84.
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.
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.
Ribas A, Flaherty KT. BRAF targeted therapy changes the treatment paradigm in melanoma. Nat Rev Clin Oncol. 2011;8:426–33.
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.
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.
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.
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.
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.
Crook T, Fisher C, Masterson PJ, Vousden KH. Modulation of transcriptional regulatory properties of p53 by HPV E6. Oncogene. 1994;9:1225–30.
Lechner MS, Laimins LA. Inhibition of p53 DNA binding by human papillomavirus E6 proteins. J Virol. 1994;68:4262–73.
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.
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.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
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). https://doi.org/10.1038/s41379-020-00726-1