To develop a comprehensive overview of copy number aberrations (CNAs) in stage-II/III colorectal cancer (CRC), we characterized 302 tumors from the PETACC-3 clinical trial. Microsatellite-stable (MSS) samples (n = 269) had 66 minimal common CNA regions, with frequent gains on 20 q (72.5%), 7 (41.8%), 8 q (33.1%) and 13 q (51.0%) and losses on 18 (58.6%), 4 q (26%) and 21 q (21.6%). MSS tumors have significantly more CNAs than microsatellite-instable (MSI) tumors: within the MSI tumors a novel deletion of the tumor suppressor WWOX at 16 q23.1 was identified (p<0.01). Focal aberrations identified by the GISTIC method confirmed amplifications of oncogenes including EGFR, ERBB2, CCND1, MET, and MYC, and deletions of tumor suppressors including TP53, APC, and SMAD4, and gene expression was highly concordant with copy number aberration for these genes. Novel amplicons included putative oncogenes such as WNK1 and HNF4A, which also showed high concordance between copy number and expression. Survival analysis associated a specific patient segment featured by chromosome 20 q gains to an improved overall survival, which might be due to higher expression of genes such as EEF1B2 and PTK6. The CNA clustering also grouped tumors characterized by a poor prognosis BRAF-mutant-like signature derived from mRNA data from this cohort. We further revealed non-random correlation between CNAs among unlinked loci, including positive correlation between 20 q gain and 8 q gain, and 20 q gain and chromosome 18 loss, consistent with co-selection of these CNAs. These results reinforce the non-random nature of somatic CNAs in stage-II/III CRC and highlight loci and genes that may play an important role in driving the development and outcome of this disease.

Developing countries are interested in using human papillomavirus (HPV) testing as a primary screening test for cervical cancer prevention programs. The low specificity of the HPV assay requires triage testing of HPV-positive women. The aim of the study is to compare visual inspection with acetic acid (VIA) and cytology as triage testing methods in HPV-positive women to detect cervical intraepithelial neoplasia or Grade 2 or higher (CIN21). The study was conducted in two Cameroonian towns (Yaounde and Edea) and included 846 eligible women aged 25 to 65 years. All participants performed self-HPV testing. HPVpositive women (n 5 259) were randomly assigned to be tested either by VIA (VIA group) or cytology (cytology group). HPVpositive women had both cervical biopsy and endocervical curettage to detect biopsy-confirmed CIN21. All statistical tests were two-sided. The prevalence of HPV was 38.5%, and the mean age of HPV-positive women was 41.5 6 10.1 years. One hundred ninety-eight women (97 in the VIA group and 99 in the cytology) were randomly assigned to one of the two testing arms. The sensitivity of VIA was 25.0% (95% CI, 7.1-59.1%), and the sensitivity of cytology was 90.0% (59.6-98.2%). The specificity was 74.2% (95% CI, 64.2-82.1%) for VIA and 85.2% (76.3-91.2%) for cytology. ROC area for cytology was 0.910 against the 0.496 area for VIA. In this trial, VIA was inferior to cytology as a triage test among HPV-positive women. Further investigations are needed to determine the optimal triage method for HPV-positive women.Cervical cancer is a major public health problem, with 530,232 new cases diagnosed and 275,008 deaths occurring annually. More than 80% of cervical cancer occurred in low and medium income countries of South and South East Asia, sub-Saharan Africa and South and Central America. 1,2 In most of these countries, cervical cancer is the leading cause of cancer death among women.Early detection of precursor lesions through the use of screening tests has drastically reduced the incidence of cervical cancer. In Western countries, where Pap smear screening has been introduced and reaches almost all eligible women, the incidence rates of cervical cancer have declined dramatically. 3 Unfortunately, in low-resource settings such as Cameroon, cervical cancer incidence and mortality remain high due to many obstacles facing the organisation of systematic screening programs. 4 Currently, visual inspection with acetic acid (VIA) seems to be a reasonable approach for cervical cancer prevention in low-resource countries due to its safety, feasibility acceptability and affordability. The method is easy to perform, does not require laboratory infrastructure and the material used (acetic acid) is widely available. It can be performed by a nurse after a short training period and provides immediate results. 2 Moreover, a single visit "screen-and-treat" approach might be an optimal screening technique for low-resource countries. However, VIA is limited in that its results greatly depend on the examiner's expertise. A r...

The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

Purpose: The diagnosis of leptomeningeal metastases is usually confirmed by the finding of malignant cells by cytologic examination in the cerebrospinal fluid (CSF). More sensitive and specific cancer biomarkers may improve the detection of tumor cells in the CSF. Promoter methylation of the human telomerase reverse transcriptase (hTERT) gene characterizes most cancer cells. The aim of this study was to develop a sensitive method to detect hTERT methylation and to explore its use as a cancer biomarker in CSF.Experimental Design: In 77 CSF specimens from 67 patients, hTERT promoter methylation was evaluated using real-time methylation-sensitive high-resolution melting (MS-HRM) and real-time TaqMan PCR and MS-HRM in a single-tube assay.Results: Real-time MS-HRM assay was able to detect down to 1% hTERT-methylated DNA in a background of unmethylated DNA. PCR products were obtained from 90% (69/77) of CSF samples. No false positive hTERT was detected in the 21 non-neoplastic control cases, given to the method a specificity of 100%. The sensitivity of the real-time MS-HRM compared with the cytologic gold standard analysis was of 92% (11/12). Twenty-six CSFs from 22 patients with an hTERT-methylated primary tumor showed cytologic results suspicious for malignancy; in 17 (65%) of them, a diagnosis of leptomeningeal metastases could be confirmed by the hTERT methylation test.Conclusion: The hTERT real-time MS-HRM approach is fast, specific, sensitive, and could therefore become a valuable tool for diagnosis of leptomeningeal metastases as an adjunct to the traditional examination of CSF.

Human telomerase reverse transcriptase (hTERT) is expressed in most cancer cells. Paradoxically, its promoter is embedded in a hypermethylated CpG island. A short region escapes to this alteration, allowing a basal level of transcription. However, the methylation of adjacent regions may play a role in the maintenance of low hTERT expression. It is now well established that methyl-CpG binding domain proteins mediate the transcriptional silencing of hypermethylated genes. The potential involvement of these proteins in the control of hTERT expression was firstly investigated in HeLa cells. Chromatin immunoprecipitation assays showed that only methyl-CpG-binding domain protein 2 (MBD2) associated the hypermethylated hTERT promoter. In MBD2 knockdown HeLa cells, constitutively depleted in MBD2, neither methyl CpG binding protein 2 (MeCP2) nor MBD1 acted as substitutes for MBD2. MBD2 depletion by transient or constitutive RNA interference led to an upregulation of hTERT transcription that can be downregulated by expressing mouse Mbd2 protein. Our results indicate that MBD2 is specifically and directly involved in the transcriptional repression of hTERT in HeLa cells. This specific transcriptional repression was also observed in breast, liver and neuroblastoma cancer cell lines. Thus, MBD2 seems to be a general repressor of hTERT in hTERT-methylated telomerase-positive cells.