Genome Analysis of Latin American Cervical Cancer: Frequent Activation of the PIK3CA Pathway
Open accessPublished version of a preprint
Abstract
Purpose: Cervical cancer is one of the most common causes of cancer mortality for women living in poverty, causing more than 28,000 deaths annually in Latin America and 266,000 worldwide. To better understand the molecular basis of the disease, we ascertained blood and tumor samples from Guatemala and Venezuela and performed genomic characterization. Experimental Design: We performed human papillomavirus (HPV) typing and identified somatically mutated genes using exome and ultra-deep targeted sequencing with confirmation in samples from Mexico. Copy number changes were also assessed in the exome sequence. Results: Cervical cancer cases in Guatemala and Venezuela have an average age of diagnosis of 50 years and 5.6 children. Analysis of 675 tumors revealed activation of PIK3CA and other PI3K/AKT pathway genes in 31% of squamous carcinomas and 24% of adeno- and adenosquamous tumors, predominantly at two sites (E542K, E545K) in the helical domain of the PIK3CA gene. This distribution of PIK3CA mutations is distinct from most other cancer types and does not result in the in vitro phosphorylation of AKT. Somatic mutations were more frequent in squamous carcinomas diagnosed after the age of 50 years. Frequent gain of chromosome 3q was found, and low PIK3CA mutation fractions in many tumors suggest that PI3K mutation can be a late event in tumor progression. Conclusions: PI3K pathway mutation is important to cervical carcinogenesis in Latin America. Therapeutic agents that directly target PI3K could play a role in the therapy of this common malignancy. Clin Cancer Res; 21(23); 5360–70. ©2015 AACR.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PIK3CA K111E mutation activated p-AKT more significantly than PIK3CA WT in USO2 osteosarcoma cell models.
“previous studies indicated that PIK3CAK111E mutation activated p-AKT more significantly than PIK3CAWT in USO2 osteosarcoma cell models22”
From Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization (2025) · cites this paper as [22]
The Materials and Methods section (page unavailable) describes comparing mutant and wild-type PIK3CA in U2OS cells. The Results section (page unavailable) reports increased p-AKT at Thr308 for H1047R, but does not report testing K111E or finding that K111E increased p-AKT relative to wild type. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Jemal, A., Bray, F., Ferlay, J., Ward, E., & Forman, D. (2011) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.20107 · Cited by 54,708 · see citing works
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., et al. (2010) · Genome Research · doi:10.1101/gr.107524.110 · Cited by 27,895 · see citing works
Global cancer statistics, 2012
Torre, L. A., Bray, F., Siegel, R. L., Ferlay, J., Lortet‐Tieulent, J., & Jemal, A. (2015) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21262 · Cited by 26,858 · see citing works
Global Cancer Statistics, 2002
Parkin, D. M., Bray, F., Ferlay, J., & Pisani, P. (2005) · CA A Cancer Journal for Clinicians · doi:10.3322/canjclin.55.2.74 · Cited by 18,573 · see citing works
Robinson, J. T., Thorvaldsdóttir, H., Winckler, W., Guttman, M., Lander, E. S., Getz, G., & Mesirov, J. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1754 · Cited by 15,390 · see citing works
A framework for variation discovery and genotyping using next-generation DNA sequencing data
DePristo, M. A., Banks, E., Poplin, R. E., Garimella, K. V., Maguire, J., Hartl, C., Philippakis, A., del Angel, G., Rivas, M. A., Hanna, M., et al. (2011) · Nature Genetics · doi:10.1038/ng.806 · Cited by 11,216 · see citing works
Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., & Kinzler, K. W. (2013) · Science · doi:10.1126/science.1235122 · Cited by 7,863 · see citing works
Mutational landscape and significance across 12 major cancer types
Kandoth, C., McLellan, M. D., Vandin, F., Ye, K., Niu, B., Lu, C., Xie, M., Zhang, Q., McMichael, J. F., Wyczalkowski, M. A., et al. (2013) · Nature · doi:10.1038/nature12634 · Cited by 4,419 · see citing works
High Frequency of Mutations of the PIK3CA Gene in Human Cancers
Samuels, Y., Wang, Z., Bardelli, A., Silliman, N., Ptak, J., Szabo, S., Yan, H., Gazdar, A. F., Powell, S. M., Riggins, G. J., et al. (2004) · Science · doi:10.1126/science.1096502 · Cited by 3,448 · see citing works
Discovery and saturation analysis of cancer genes across 21 tumour types
Lawrence, M. S., Stojanov, P., Mermel, C. H., Robinson, J. T., Garraway, L. A., Golub, T. R., Meyerson, M., Gabriel, S. B., Lander, E. S., & Getz, G. (2014) · Nature · doi:10.1038/nature12912 · Cited by 3,096 · see citing works
Comprehensive molecular characterization of urothelial bladder carcinoma
Perou, C. M. (2019) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/za09-dk57 · Cited by 2,964 · see citing works
de Sanjose, S., Quint, W. G., Alemany, L., Geraets, D. T., Klaustermeier, J. E., Lloveras, B., Tous, S., Felix, A., Bravo, L. E., Shin, H.-R., et al. (2010) · The Lancet Oncology · doi:10.1016/s1470-2045(10)70230-8 · Cited by 2,728 · see citing works
Husman, A. D. R., Walboomers, J. M. M., van den Brule, A. J. C., Meijer, C. J. L. M., & Snijders, P. J. F. (1995) · Journal of General Virology · doi:10.1099/0022-1317-76-4-1057 · Cited by 1,283 · see citing works
An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers
Roberts, S. A., Lawrence, M. S., Klimczak, L. J., Grimm, S. A., Fargo, D. C., Stojanov, P., Kieżun, A., Kryukov, G. V., Carter, S. L., Saksena, G., et al. (2013) · Nature Genetics · doi:10.1038/ng.2702 · Cited by 1,145 · see citing works
Khan, M. J., Castle, P. E., Lorincz, A. T., Wacholder, S., Sherman, M. E., Scott, D. R., Rush, B. B., Glass, A. G., & SCHIFFMAN, M. H. (2005) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dji187 · Cited by 1,057 · see citing works
Guan, P., Howell‐Jones, R., Li, N., Bruni, L., de Sanjosé, S., Franceschi, S., & Clifford, G. M. (2012) · International Journal of Cancer · doi:10.1002/ijc.27485 · Cited by 927 · see citing works
Landscape of genomic alterations in cervical carcinomas
Ojesina, A. I., Lichtenstein, L., Freeman, S. S., Pedamallu, C. S., Imaz-Rosshandler, I., Pugh, T. J., Cherniack, A. D., Ambrogio, L., Cibulskis, K., Bertelsen, B. I., et al. (2013) · Nature · doi:10.1038/nature12881 · Cited by 861 · see citing works
Hu, Z., Zhu, D., Wang, W., Li, W., Jia, W., Zeng, X., Ding, W., Yu, L., Wang, X., Wang, L., et al. (2015) · Nature Genetics · doi:10.1038/ng.3178 · Cited by 568 · see citing works
The Structure of a Human p110α/p85α Complex Elucidates the Effects of Oncogenic PI3Kα Mutations
Huang, C., Mandelker, D. L., Schmidt‐Kittler, O., Samuels, Y., Velculescu, V. E., Kinzler, K. W., Vogelstein, B., Gabelli, S. B., & Amzel, L. M. (2007) · Science · doi:10.1126/science.1150799 · Cited by 564 · see citing works
AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer
Vasudevan, K. M., Barbie, D. A., Davies, M. A., Rabinovsky, R., McNear, C. J., Kim, J. J., Hennessy, B. T., Tseng, H., Pochanard, P., Kim, S. Y., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.04.012 · Cited by 524 · see citing works
Human papillomavirus genome variants
Burk, R. D., Harari, A., & Chen, Z. (2013) · Virology · doi:10.1016/j.virol.2013.07.018 · Cited by 487 · see citing works
Guo, G., Sun, X., Chen, C., Wu, S., Huang, P., Li, Z., Dean, M. C., Huang, Y. F., Jia, W., Zhou, Q., et al. (2013) · Nature Genetics · doi:10.1038/ng.2798 · Cited by 479 · see citing works
Self-citationAkagi, K., Li, J., Broutian, T. R., Padilla‐Nash, H. M., Xiao, W., Jiang, B., Rocco, J. W., Teknos, T. N., Kumar, B., Wangsa, D., et al. (2013) · Genome Research · doi:10.1101/gr.164806.113 · Cited by 476 · see citing works
Hausen, H. Z., & de Villiers, E. M. (1994) · Annual Review of Microbiology · doi:10.1146/annurev.mi.48.100194.002235 · Cited by 475 · see citing works
Heselmeyer, K. M., Schröck, E., du Manoir, S., Blegen, H., Shah, K. V., Steinbeck, R. G., Auer, G., & Ried, T. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.1.479 · Cited by 468 · see citing works
Wentzensen, N., Vinokurova, S., & Doeberitz, M. V. K. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0009 · Cited by 467 · see citing works
Zhao, L., & Vogt, P. K. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712169105 · Cited by 438 · see citing works
Mechanism of Two Classes of Cancer Mutations in the Phosphoinositide 3-Kinase Catalytic Subunit
Miled, N., Yan, Y., Hon, W., Perišić, O., Zvelebil, M., Inbar, Y., Schneidman‐Duhovny, D., Wolfson, H. J., Backer, J., & Williams, R. L. (2007) · Science · doi:10.1126/science.1135394 · Cited by 410 · see citing works
Rare cancer-specific mutations in PIK3CA show gain of function
Gymnopoulos, M., Elsliger, M., & Vogt, P. K. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701005104 · Cited by 378 · see citing works
The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line
Adey, A., Burton, J. N., Kitzman, J. O., Hiatt, J. B., Lewis, A. P., Martin, B., Qiu, R., Lee, C., & Shendure, J. (2013) · Nature · doi:10.1038/nature12064 · Cited by 345 · see citing works
Henderson, S. R., Chakravarthy, A., Su, X., Boshoff, C., & Fenton, T. R. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.05.012 · Cited by 340 · see citing works
Jankú, F., Wheler, J. J., Naing, A., Falchook, G. S., Hong, D. S., Stepanek, V. M. T., Fu, S., Piha-Paul, S. A., Lee, J. J., Luthra, R., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1726 · Cited by 300 · see citing works
Burke, J. E., Perisic, O., Masson, G. R., Vadas, O., & Williams, R. L. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1205508109 · Cited by 300 · see citing works
A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane
Mandelker, D. L., Gabelli, S. B., Schmidt‐Kittler, O., Zhu, J., Cheong, I., Huang, C., Kinzler, K. W., Vogelstein, B., & Amzel, L. M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908444106 · Cited by 298 · see citing works
The Promise of Global Cervical-Cancer Prevention
Schiffman, M., & Castle, P. E. (2005) · New England Journal of Medicine · doi:10.1056/nejmp058171 · Cited by 286 · see citing works
Smoking as a major risk factor for cervical cancer and pre-cancer: Results from the EPIC cohort
Roura, E., Castellsagué, X., Pawlita, M., et al. (2013) · International Journal of Cancer · doi:10.1002/ijc.28666 · Cited by 284 · see citing works
Oncogenic mutations in cervical cancer
Wright, A. A., Howitt, B. E., Myers, A. P., Dahlberg, S. E., Palescandolo, E., Hummelen, P. V., MacConaill, L. E., Shoni, M., Wagle, N., Jones, R. T., et al. (2013) · Cancer · doi:10.1002/cncr.28288 · Cited by 275 · see citing works
A Unique Spectrum of Somatic PIK3CA (p110α) Mutations Within Primary Endometrial Carcinomas
Rudd, M. L., Price, J. C., Fogoros, S. K., Godwin, A. K., Sgroi, D. C., Merino, M. J., & Bell, D. W. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-0540 · Cited by 222 · see citing works
The role of TP53 in Cervical carcinogenesis
Tommasino, M., Accardi, R., Caldeira, S., Dong, W., Malanchi, I., Smet, A., & Zehbe, I. (2003) · Human Mutation · doi:10.1002/humu.10178 · Cited by 207 · see citing works
Human Papillomavirus Type 16 E7 Up-regulates AKT Activity through the Retinoblastoma Protein
Menges, C. W., Baglia, L. A., LaPoint, R., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0499 · Cited by 165 · see citing works
Rositch, A. F., Nowak, R. G., & Gravitt, P. E. (2014) · Cancer · doi:10.1002/cncr.28548 · Cited by 152 · see citing works
Rosty, C., Sheffer, M., Tsafrir, D., Stransky, N., Tsafrir, I., Peter, M., de Crémoux, P., de la Rochefordière, A., Salmon, R. J., Dorval, T., et al. (2005) · Oncogene · doi:10.1038/sj.onc.1208854 · Cited by 143 · see citing works
Human papillomavirus in a necessary cause of invasive cervical cancer worldwide
(1999) · Pure Amsterdam UMC · doi:10.1002/(sici)1096-9896(199909)189:1 · Cited by 140 · see citing works
Multiplex Identification of Human Papillomavirus 16 DNA Integration Sites in Cervical Carcinomas
Xu, B., Chotewutmontri, S., Wolf, S., Klos, U., Schmitz, M., Dürst, M., & Schwarz, E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0066693 · Cited by 121 · see citing works
Zhao, L., & Vogt, P. K. (2010) · Cell Cycle · doi:10.4161/cc.9.3.10599 · Cited by 107 · see citing works
Schwarz, J. K., Payton, J. E., Rashmi, R., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2485 · Cited by 99 · see citing works
AKT-independent PI3-K signaling in cancer – emerging role for SGK3
Hannan, R. D., Bruhn, Pearson, R., & Sheppard (2013) · Cancer Management and Research · doi:10.2147/cmar.s35178 · Cited by 84 · see citing works
Boland, J., Chung, C. C., Roberson, D., Mitchell, J., Zhang, X.-J., Im, K., He, J., Chanock, S., Yeager, M., & Dean, M. (2013) · Human Genetics · doi:10.1007/s00439-013-1321-4 · Cited by 82 · see citing works
Self-citationPIK3CA-mediated PI3-kinase signalling is essential for HPV-induced transformation in vitro
Henken, F. E., Banerjee, N. S., Snijders, P. J. F., et al. (2011) · Molecular Cancer · doi:10.1186/1476-4598-10-71 · Cited by 61 · see citing works
de la Rochefordière, A., Kamal, M. T., Floquet, A., Thomas, L., Petrow, P. K., Petit, T., Pop, M., Fabbro, M., Kerr, C., Joly, F., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2368 · Cited by 55 · see citing works
Genomic aberrations in cervical adenocarcinomas in Hong Kong Chinese women
Chung, T. K. H., Hummelen, P. V., Chan, P. K. S., Cheung, T. H., Yim, S. F., Yu, M. Y., Ducar, M. D., Thorner, A. R., MacConaill, L. E., Doran, G., et al. (2015) · International Journal of Cancer · doi:10.1002/ijc.29456 · Cited by 48 · see citing works
Mutation of PIK3CA: Possible risk factor for cervical carcinogenesis in older women
Wallin (1992) · International Journal of Oncology · doi:10.3892/ijo_00000164 · Cited by 35 · see citing works
Comprehensive molecular characterization of urothelial bladder carcinoma
Weinstein, J. N., Akbani, R., Broom, B. M., et al. (2014) · Nature · doi:10.1038/nature12965 · Cited by 10 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Maruyama, K., Shimizu, Y., Nomura, Y., Oh-hara, T., Takahashi, Y., Nagayama, S., Fujita, N., & Katayama, R. (2025) · npj Precision Oncology · doi:10.1038/s41698-024-00793-6 · Cited by 16 · see citing works
- Authors
- Lou, H., Villagran, G., Boland, J. F., Im, K. M., Polo, S., Zhou, W., Odey, U., Juárez-Torres, E., Medina-Martínez, I., Roman-Basaure, E., Mitchell, J., Roberson, D., Sawitzke, J., Garland, L., Rodríguez-Herrera, M., Wells, D., Troyer, J., Pinto, F. C., Bass, S., Zhang, X., Castillo, M., Gold, B., Morales, H., Yeager, M., Berumen, J., Alvirez, E., Gharzouzi, E., & Dean, M.
- Affiliations
- Leidos Biomedical Research Inc. (United States) (US)
- 2Instituto de Cancerologia, Guatemala City, Guatemala.
- Frederick National Laboratory for Cancer Research (US)
- 5Hospital Central Universitario “Dr. Antonio M Pineda,” Barquisimeto, Lara State, Venezuela.
- Hospital General de México (MX)
- 6Unidad de Medicina Genómica, Hospital General de México/Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F. México.
- 7Servicio de Oncología, Hospital General de México, México, D.F. México.
- Corresponding author
- Dean, Michael
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2015-11-30
- Volume
- 21
- Issue
- 23
- Pages
- 5360-5370
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4668220
- OpenAlex
- W1542680377
- Semantic Scholar
- 89e5456af2c39db4f2c14ee51e5c32793cae7b44
- Cited by
- 88
- References
- 53
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 8 · 2023: 5 · 2022: 11 · 2021: 10 · 2020: 5 · 2019: 9 · 2018: 7 · 2017: 11 · 2016: 7 · 2015: 2
- FWCI
- 7.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (HHSN261200800001C)
- National Cancer Institute (HHSN261200800001E), Z01BC005652)
- Topics
- Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- cervical cancer, PIK3CA mutation, PI3K/Akt signaling, human papillomavirus, somatic mutations, squamous cell carcinoma, adenosquamous carcinoma, chromosome 3q gain, tumor progression, PI3K inhibitors, Latin America, Guatemala, Venezuela
- MeSH terms
- Adult, Aged, Uterine Cervical Neoplasms, Chromosome Mapping, Female, Guatemala, Humans, Mexico, Middle Aged, Mutation, Phosphorylation, Risk Factors, Biomarkers, Tumor, Venezuela, Signal Transduction, Gene Expression, Genome, Human, Phosphatidylinositol 3-Kinases, Genomics, Papillomavirus Infections, Proto-Oncogene Proteins c-akt, Alphapapillomavirus, DNA Copy Number Variations, Class I Phosphatidylinositol 3-Kinases, High-Throughput Nucleotide Sequencing, Exome, Neoplasm Grading
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
