Landscape of genomic alterations in cervical carcinomas

Nature (Impact Factor: 41.46). 12/2013; 506(7488). DOI: 10.1038/nature12881
Source: PubMed


Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. 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.

Download full-text


Available from: María Lourdes Garza-Rodríguez, Feb 18, 2014
335 Reads
  • Source
    • "Several cellular genes such as TP53 [10,11], PIK3CA [12], c-Myc (Myc) and ErbB2 [13], cIAP1 [14], Ras [15], PTEN [16] and LKB1 [17] have been found mutated or functional inactivated in variable proportions of cervical cancers. Comprehensive analysis of genomic aberrations in cervical tumors allowed to identify, besides the previously characterized mutations in TP53 and PIK3CA genes, unknown mutations in MAPK1, HLA-B, EP300, FBXW7, NFE2L2, and ERBB2 genes in squamous cell carcinoma and somatic mutations of ELF3 (13%) and CBFB (8%) genes in adenocarcinomas [18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Mutations in the tumor suppressor gene TP53 and proto-oncogene PIK3CA and alterations of p53 and PIK3CA AKT mTOR pathways are common events in several human cancers. We focused on the analysis of TP53 and PIK3CA gene variations in adenocarcinoma, squamous cell carcinoma as well as in intraepithelial neoplasia grade 3 of the cervix.MethodsDNA samples from 28 cervical adenocarcinoma, 55 squamous cell carcinoma and 31 intraepithelial neoplasia grade 3 (CIN3), previously characterized in terms of human papillomavirus (HPV) prevalence and genotype distribution, were analyzed for TP53 and PIK3CA mutations in the exons 4¿9 and exon 9, respectively.ResultsSingle nucleotide substitutions in TP53 and PIK3CA genes were detected in 36% and 11% of adenocarcinoma, in 16% and in 5% of squamous cell carcinoma, and in 13% and none of CIN 3, respectively. Nucleotide changes in TP53 were significantly more frequent in adenocarcinoma cases than in squamous cell carcinoma and CIN3 (P¿=¿0.035) and were independent from HPV infection status.Conclusions Mutations in the TP53 gene and to lesser extent in the PIK3CA gene seem more frequent in cervical adenocarcinoma than in squamous cell carcinoma and CIN3. Whether TP53 and PIK3CA gene mutations have an impact on prognosis and response to molecularly targeted therapies as well as in cytotoxic drugs in different cervical cancer histotypes needs to be analyzed in investigative clinical trials.
    Journal of Translational Medicine 09/2014; 12(1):255. DOI:10.1186/s12967-014-0255-5 · 3.93 Impact Factor
  • Source
    • "During productive HPV infections, transcription is tightly controlled by the binding of cellular transcription factors and the viral E2 gene product within the LCR in a differentiation dependent manner [16]. Integration of HPV DNA into the host genome frequently results in loss of E2 expression, relieving repression of the p97 promoter and leading to cellular transformation [14], although greater expression of HPV16 E6 and E7 has not been associated with HPV16 integration in vivo [17], and 28% of cervical cancers do not contain integrated HPV [18]. Some studies have reported E2 binding site (E2BS) methylation in association with cervical neoplasia and cancer , and suggest that methylation of E2BS might prevent E2 binding, resulting in increased expression of the E6 and E7 ORFs [7] [19] [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Methylation of HPV16 DNA is a promising biomarker for triage of HPV positive cervical screening samples but the biological basis for the association between HPV-associated neoplasia and increased methylation is unclear. Objectives To determine whether HPV16 DNA methylation was associated with viral integration, and investigate the relationships between viral DNA methylation, integration and gene expression. Study design : HPV16 DNA methylation, integration and gene expression were assessed using pyrosequencing, ligation-mediated PCR and QPCR, in biopsies from 25 patients attending a specialist vulval neoplasia clinic and in short-term clonal cell lines derived from vulval and vaginal neoplasia. Results Increased methylation of the HPV16 L1/L2 and E2 regions was associated with integration of viral DNA into the host genome. This relationship was observed both in vivo and in vitro. Increased methylation of E2 binding sites did not appear to be associated with greater expression of viral early genes. Expression of HPV E6 and E7 did not correlate with either integration state or increased L1/L2 methylation. Conclusions The data suggest that increased HPV DNA methylation may be partly attributable to viral integration, and provide a biological rationale for quantification of L1/L2 methylation in triage of HPV positive cervical screening samples.
    Journal of Clinical Virology 08/2014; 61(3). DOI:10.1016/j.jcv.2014.08.006 · 3.02 Impact Factor
  • Source
    • "Cervical cancers (CC) are one of the leading causes of cancer-related death among women in developing countries [1,2], which are classified into squamous cell carcinomas and adenocarcinomas according to their cellular origins [3]. Surgery is still the first choice of CC treatments, but frequent relapse and metastasis lead to poor prognosis of CC patients, especially those at advanced stage [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cervical cancers/CCs are one of the commonest malignancies and the second leading cause of cancer-related death in women. Resveratrol inhibits CC cell growth but its molecular target(s) remains unclear. Since the signaling pathways mediated by STAT3, Notch1 and Wnt2 play beneficial roles in CC formation and progression, the effects of resveratrol on them in cervical adenocarcinoma (HeLa) and squamous cell carcinoma (SiHa) cells were analyzed. The biological significances of the above signaling for HeLa and SiHa cells were evaluated by treating the cells with STAT3, Wnt or Notch selective inhibitors. The frequencies of STAT3, Notch and Wnt activations in 68 cases of CC specimens and 38 non-cancerous cervical epithelia were examined by tissue microarray-based immunohistochemical staining. The results revealed that HeLa and SiHa cells treated by 100μM resveratrol showed extensive apoptosis, accompanied with suppression of STAT3, Notch and Wnt activations. Growth inhibition and apoptosis were found in HeLa and SiHa populations treated by AG490, a STAT3/JAK3 inhibitor but not the ones treated by Notch inhibitor L-685,458 or by Wnt inhibitor XAV-939. Immunohistochemical staining performed on the tissue microarrays showed that the frequencies of Notch1, Notch2, Hes1, Wnt2, Wnt5a and p-STAT3 detection as well as β-catenin nuclear translocation in CC samples were significantly higher than that of noncancerous group (p<0.01), while the expression rate of PIAS3 was remarkably low in cancer samples (p<0.01). Our results thus demonstrate that STAT3, Wnt and Notch signaling are frequently co-activated in human CC cells and specimens and resveratrol can concurrently inhibit those signaling activations and meanwhile lead cervical squamous cell carcinoma and adenocarcinoma cells to growth arrest and apoptosis. STAT3 signaling is more critical for CC cells and is the major target of resveratrol because selective inhibition of STAT3 rather than Wnt or Notch activation commits SiHa and HeLa cells to apoptosis.
    Genes & cancer 05/2014; 5(5-6):154-64.
Show more