Cervical cancer is responsible for 10–15% of cancer-related deaths in women worldwide1,2. The etiological role of infection with high-risk human papilloma viruses (HPV) in cervical carcinomas is well established3. Previous studies have implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS4–7 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 tumor-normal pairs. Novel 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 observed somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas had higher frequencies of somatic mutations in the Tp*C dinucleotide context than adenocarcinomas. Gene expression levels at HPV integration sites were significantly higher in tumors with HPV integration compared with expression of the same genes in tumors without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest novel strategies to combat this disease.

Background: The main forms of mercury (Hg) exposure in the general population are methylmercury (MeHg) from seafood, inorganic mercury (I-Hg) from food, and mercury vapor (Hg 0 ) from dental amalgam restorations. While the distribution of MeHg in the body is described by a one compartment model, the distribution of I-Hg after exposure to elemental mercury is more complex, and there is no biomarker for I-Hg in the brain. The aim of this study was to elucidate the relationships between on the one hand MeHg and I-Hg in human brain and other tissues, including blood, and on the other Hg exposure via dental amalgam in a fish-eating population. In addition, the use of blood and toenails as biological indicator media for inorganic and organic mercury (MeHg) in the tissues was evaluated.

Uterine cervical carcinogenesis is probably dependent on cellular genetic damage in addition to the integration of high-risk HPV DNA in the epithelial cell genome. Gain of chromosome 3q24-29 is commonly observed in cervical neoplasia. The putative oncogene PIK3CA located in this region encodes a phosphatidylinositol 3-kinase (PI3K). In a process reversed by PTEN, PI3K generates inositol phospholipids that trigger AKT phosphorylation, which in turn effects tumor driving signals. We studied 46 specimens of formalin-fixed, paraffin-embedded cervical neoplastic tissue. The activation state of the PI3K-AKT pathway was assessed immunohistochemically using an antibody with specificity towards serine 473-phosphorylated AKT. AKT phosphorylation was found in 39 out of 46 examined specimens. To examine the possible molecular basis for this activation, we searched for PIK3CA amplification using quantitative real-time polymerase chain reaction. PIK3CA gene copy number was estimated to be 3 or more in 28 out of 40 successfully examined cases. Further, a PTEN mutation analysis of all 9 PTEN exons was carried out, but except for 1 metastasis with an exon 9 V369I heterozygosity, all cases showed normal PTEN sequence. Immunohistochemical staining for PTEN was strong in all lesions. In conclusion, an increased activation state of AKT kinase appears to be present in cervical carcinogenesis, and may be accounted for by PIK3CA amplification, whereas PTEN mutation seems to be of little importance. ' 2005 Wiley-Liss, Inc.Key words: cervical cancer; AKT; PIK3CA; PTEN; quantitative realtime PCR Cervical carcinoma is the second most common cancer in women world-wide. 1 High-risk human papillomavirus (HPV) DNA present in the neoplastic cells plays a causative role. 2 Integration of HPV DNA in the epithelial cell genome is accompanied by expression of the viral gene products E6 and E7 that abrogate the Rb and p53 tumor suppressor pathways, increase telomerase activity, and give rise to mitotic defects and numerical and structural chromosome instability. 3-5 Both E6 and E7 are required for the neoplastic process and they cooperate to immortalize human genital keratinocytes. 6 Even so, only a small proportion of highrisk HPV-positive lesions eventually progress to carcinoma, indicating that accumulation of additional genetic events in the host cell is needed for malignant conversion. 3,4 Cervical carcinomas show a recurrent pattern of cytogenetic instability where a gain of the long arm of chromosome 3 is commonly observed. [7][8][9][10][11] The same aberration has been demonstrated in HPV-transfected keratinocytes, pre-malignant cervical precursor lesions and cervical cancer cell lines. 7 , 8 , 12-14 By comparative genomic hybridization (CGH), the areas of gain have been refined to parts of chromosomal bands 3q24-29. 9-11 , 15 A possible oncogene in this region is PIK3CA at 3q26.3, encoding the p110a catalytic subunit of class IA phosphatidylinositol 3-kinase (PI3K). 16 Upon activation by receptor tyrosine kinases, PI3K generates inosito...