Abstract
Cervical cancer is responsible for 10–15% of cancer-related deaths in women worldwide1,2. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established3. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS4,5,6,7 as well as several copy-number alterations in the pathogenesis of cervical carcinomas8,9. Here we report whole-exome sequencing analysis of 115 cervical carcinoma–normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour–normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.
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Data deposits
Sequence data used for this analysis are available in dbGaP under accession phs000600.
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Acknowledgements
This work was conducted as part of the Slim Initiative for Genomic Medicine in the Americas, a project funded by the Carlos Slim Health Institute in Mexico. This work was also partially supported by the Rebecca Ridley Kry Fellowship of the Damon Runyon Cancer Research Foundation (A.I.O.); MMRF Research Fellow Award (A.I.O.); Helse Vest, Research Council of Norway, Norwegian Cancer Society and Harald Andersens legat (H.B.S.); CONACyT grant SALUD-2008-C01-87625 and UANL PAICyT grant CS1038-1 (H.A.B.-S.); and CONACyT grant 161619 (J.M.-Z.). We also thank B. Edvardsen, K. Dahl-Michelsen, Å. Mokleiv, K. Madisso, T. Njølstad and E. Valen for technical and programmatic assistance; the staff of the Broad Institute Genomics Platform for their assistance in processing samples and generating the sequencing data used in the analyses; the Instituto Mexicano del Seguro Social (IMSS) for their Support; and L. Gaffney of Broad Institute Communications for figure layout and design.
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A.I.O., L.L., S.S.F., C.S.P., H.B.S. and M.M. wrote the manuscript with help from co-authors. A.I.O., L.L., K.C., C.S. and G.G. performed whole exome and genome sequencing data analysis. A.I.O., I.I., V.T., K.V.-S., A.S.G., S.R.-C., C.R.E., S.S.F. and C.S.P. performed RNA sequencing data analysis. A.I.O., S.S.F., C.S.P. and T.J.P. performed HPV integration analyses. A.I.O. and A.D.C. performed copy-number analyses. A.I.O., F.D., B.K., R.W. and H.G. performed functional experiments on MAPK1. B.B., N.B.G., G.S.G.-M. and C.P.C. facilitated and performed pathology review. O.K.V., H.M.W. and T.E.C. performed HPV status determination. L.A., E.N. and M.L.C. facilitated project management. L.L., I.I.-R., V.T., K.V.-S., A.S.G., S.R.-C., I.P.R.-S. and C.R.E. performed sequencing data validation. M.E.-C., M.K.H., E.W., E.A.H., C.K. and M.L.G.-R. performed specimen processing, biobanking and data management. K.W., L.B., L.D.V.-C., G.M., J.V., C.R., A.C. and H.B.S. collected patient materials and clinical information. A.I.O., L.L. and D.S.N. performed biostatistical and epidemiological analyses. A.I.O., L.L., S.S.F., C.S.P., I.I.-R., T.J.P., A.D.C., V.T., A.A.W., M.W.R., F.D., M.S.L., C.S., S.L.C., A.M., H.B.S. and M.M. contributed text, figures (including Supplementary Information) and analytical tools. A.H.-M., C.R.E., L.A.A., S.B.G., H.A.B.-S., J.M.-Z., G.G., H.B.S. and M.M. provided leadership for the project. All authors contributed to the final manuscript. Lead authors A.I.O. and L.L. and senior authors M.M. and H.B.S. contributed equally to this work.
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M.M. holds equity in, and consults for, Foundation Medicine.
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Supplementary Information
This file contains Supplementary Notes 1-15 with additional references (see Contents for more details), Supplementary Figures 1-30 and Supplementary Tables 1-11, 13 and 15-21 (see separate files for tables 12 and 14). (PDF 5727 kb)
Supplementary Table 12
This zipped file contains the correlation between RNASeq-derived gene expression and WES-derived copy number across 16898 genes, as well as the full complement of the raw values for these two parameters for 79 tumors with RNASeq data. (ZIP 30025 kb)
Supplementary Table 14
This file contains details of HPV typing and viral integration analyses. (XLSX 56 kb)
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Ojesina, A., Lichtenstein, L., Freeman, S. et al. Landscape of genomic alterations in cervical carcinomas. Nature 506, 371–375 (2014). https://doi.org/10.1038/nature12881
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DOI: https://doi.org/10.1038/nature12881
