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Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers.

The RAS‐MAPK, PI (3)K signaling pathways form a network that play a central role in tumorigenesis. The BRAF, KRAS and PI3KCA genes code 3 partners of this network and have been found to be activated by mutation in colorectal cancer; these mutations lead to unrestricted cell growth. We evaluated the clinicopathological features and the prognosis of patients with activated‐network colon cancers in a population‐based study. A total of 586 colon adenocarcinomas were evaluated using sequencing for mutations of KRAS and PI3KCA, and allelic discrimination for mutation of BRAF. Clinicopathological characteristics were correlated to the risk of bearing a mutation of the network using logistic regression. Three‐year survival rates were compared with the Log rank test. A multivariate survival analysis using the Cox model was performed. After adjustment for age and microsatellite instability, activation of the network by mutation of at least 1 of the 3 genes was significantly associated with female sex (p = 0.02) and proximal location (p < 0.001). Lower levels of 3‐year survival were associated with activation of the network by mutation of at least 1 of the 3 genes (59.4 and 69.4%, respectively; p = 0.009). These results remained significant in a multivariate analysis adjusted for sex, age, location, stage and microsatellite instability (HR = 1.48; CI CI95% = [1.07–2.04]). Our study is the first report to underline the potential role of RAS‐MAPK, PI (3)K network mutations on survival in colon cancers. Because of the role of this signaling network on anticancer agents, the evaluation of its mutations could have clinical implications.

Hypermethylator Phenotype in Sporadic Colon Cancer: Study on a Population-Based Series of 582 Cases

The CpG island methylator phenotype (CIMP) is a distinct phenotype in colorectal cancer, associated with specific clinical, pathologic, and molecular features. However, most of the studies stratified methylation according to two subgroups (CIMP-High versus No-CIMP/CIMP-Low). In our study, we defined three different subgroups of methylation (No-CIMP, CIMP-Low, and CIMP-High) and evaluated the prognostic significance of methylation status on a population-based series of sporadic colon cancers. A total of 582 colon adenocarcinomas were evaluated using methylation-specific PCR for 5 markers (hMLH1, P16, MINT1, MINT2, and MINT31). No-CIMP status was defined as no methylated locus, CIMP-Low status as one to three methylated loci, and CIMP-High status as four or five methylated loci. Clinicopathologic and molecular characteristics were correlated to the methylation status. Crude and relative survival was compared according to methylation status. In the microsatellite-stable (MSS) group, CIMP-High was significantly associated with proximal location (P = 0.011) and BRAF mutation (P < 0.001). KRAS mutations were more associated with CIMP-High and CIMP-Low status (P = 0.008). A shorter 5-year survival was observed in MSS cancer patients with CIMP-Low or CIMP-High status. These results remained significant in multivariate analysis adjusted for age, stage, and BRAF and KRAS mutational status [CIMP-Low: hazard ratio (HR), 1.85; 95% confidence interval (95% CI), 1.37-2.51; CIMP-High, HR, 2.90; 95% CI, 1.53-5.49 compared with No-CIMP]. Within the high-level microsatellite instability group, no difference in survival was observed between the different CIMP groups. Our results show the interest of defining three subgroups of patients according to their methylation status (No-CIMP/CIMP-Low/CIMP-High). Methylation is an independent prognostic factor in MSS colon cancer.

TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia

Acquired somatic deletions and loss-of-function mutations in one or several codons of the TET2 (Ten-Eleven Translocation-2) gene were recently identified in hematopoietic cells from patients with myeloid neoplasms. This study shows that TET2 mutations are more frequent in chronic myelomonocytic leukemia than in other subgroups of myeloid neoplasms studied so far. Background Acquired somatic deletions and loss-of-function mutations in one or several codons of the TET2 (Ten-Eleven Translocation-2) gene were recently identified in hematopoietic cells from patients with myeloid malignancies, including myeloproliferative disorders and myelodys-plastic syndromes. The present study was designed to determine the prevalence of TET2 gene alterations in chronic myelomonocytic leukemias. Design and Methods Blood and bone marrow cells were collected from 88 patients with chronic phase chronic myelomonocytic leukemia and from 14 with acute transformation of a previously identified disease. Polymerase chain reaction analysis and direct sequencing were used to sequence exons 3 to 11 of the TET2 gene. Annotated single nucleotide polymorphisms were excluded. Survival curves were constructed by the Kaplan-Meier method. Results We detected TET2 mutations in 44 of 88 (50%) patients with chronic myelomonocytic leukemia, which suggests that TET2 gene mutations are especially frequent in this myeloid disease. A TET2 gene alteration was identified in 18 of the 43 patients studied at diagnosis and was associated with a trend to a lower overall survival rate; confining the analysis to the 29 patients with chronic myelomonocytic leukemia-1, according to the WHO classification, the difference in overall survival between patients with or without TET2 gene mutations became statistically significant. Conclusions TET2 gene alterations are more frequent in chronic myelomonocytic leukemia than in other subgroups of hematopoietic diseases studied so far and could negatively affect the patients’ outcome. The striking association between TET2 gene alterations and monocytosis, already observed in patients with systemic mastocytosis, could indicate a negative role of TET2 in the control of monocytic lineage determination.

Hepatitis C virus-associated hypobetalipoproteinemia is correlated with plasma viral load, steatosis, and liver fibrosis

OBJECTIVES:A relationship between chronic hepatitis C virus (HCV) infection and lipid metabolism has recently been suggested. The aim of this study was to determine the correlation between lipid profile and virology, histologic lesions, and response to α interferon therapy in noncirrhotic, nondiabetic patients with hepatitis C.METHODS:A total of 109 consecutive untreated chronic hepatitis C patients were studied to assess the following: 1) the effects of HCV genotype, viral load, steatosis, hepatic fibrosis, and body mass index (BMI) on lipid profile; and 2) whether lipid parameters could predict response to antiviral therapy.RESULTS:The control group showed a significantly higher apolipoprotein B (apoB) concentration compared with patients with chronic hepatitis C. Hypobetalipoproteinemia (apo B <0.7 g/L) was found in 27 (24.7%) chronic HCV patients and in five (5.3%) control subjects (p = 0.0002). Levels of apo B were negatively correlated with steatosis and HCV viral load (r= − 0.22; p = 0.03). This last correlation was strong for non-1 genotype and genotype 3 (r= − 0.48; p = 0.0005, and r= − 0.47; p = 0.007, respectively) but was not found in genotype 1. In multivariate analysis, low apo B concentration was significantly associated with fibrosis grade 2 or 3 versus grade 0 or 1 (p < 0.001), steatosis >5% (p < 0.001), low body mass index (p < 0.001), and high HCV viral load (p < 0.014). No correlation was found in the 76 treated patients between apo B and response to interferon therapy.CONCLUSION:In chronic HCV patients, hypobetalipoproteinemia occurs already in the early stages of HCV infection before the development of liver cirrhosis. The correlation between apo B levels and HCV viral load seems to confirm the interaction between hepatitis C infection and β-lipoprotein metabolism.

Epidemiology, management and prognosis of colorectal cancer with lung metastases: a 30-year population-based study

Objective Epidemiological data on synchronous and metachronous lung metastases from colorectal cancer are scarce. The aim of this study was to determine trends in the incidence, treatment and survival in colorectal cancer with lung metastases in the general population. Design and patients All cases of lung metastases from colorectal cancer registered in the Burgundy digestive cancer registry between 1976 and 2005 were included. Trends in the incidence of synchronous colorectal cancer lung metastases were estimated. A Cox model was used to analyse the risk of developing a metachronous metastasis. Multivariate analyses were performed using a relative survival model with proportional hazard applied to the net survival by interval. Results Overall, 11.0% of patients had synchronous lung metastases. The frequency of synchronous lung metastases significantly increased for both sexes over time, with a nearly threefold increase between the periods 1976–1985 and 1996–2005. The overall 5-year cumulative risk of developing metachronous lung metastases was 5.8%. It did not significantly vary with time. Compared to colon cancer, rectal cancers had a higher risk of developing synchronous (OR: 2.80 (1.65–4.76)) and metachronous (OR: 2.63 (1.69–4.08)) lung metastases. Overall, 4.1% of synchronous lung metastases and 14.3% of metachronous lung metastases were resected for cure. The 3-year relative survival was 11.3% for synchronous lung metastases and 13.8% for metachronous lung metastases. It was, respectively, 53.0% and 59.2% after resection for cure. In multivariate analysis, the relative risk of death for the 1996–2005 period was about one fifth of that for the 1976–1985 period. Conclusions The incidence of synchronous lung metastases increased over time, whereas the incidence of metachronous lung metastases remained stable. Lung metastases were more frequent in rectal cancer than in colon cancer. Unless surgical resection is possible, the prognosis for lung metastases remains very poor.

The HU Regulon Is Composed of Genes Responding to Anaerobiosis, Acid Stress, High Osmolarity and SOS Induction

Background The Escherichia coli heterodimeric HU protein is a small DNA-bending protein associated with the bacterial nucleoid. It can introduce negative supercoils into closed circular DNA in the presence of topoisomerase I. Cells lacking HU grow very poorly and display many phenotypes. Methodology/Principal Findings We analyzed the transcription profile of every Escherichia coli gene in the absence of one or both HU subunits. This genome-wide in silico transcriptomic approach, performed in parallel with in vivo genetic experimentation, defined the HU regulon. This large regulon, which comprises 8% of the genome, is composed of four biologically relevant gene classes whose regulation responds to anaerobiosis, acid stress, high osmolarity, and SOS induction. Conclusions/Significance The regulation a large number of genes encoding enzymes involved in energy metabolism and catabolism pathways by HU explains the highly pleiotropic phenotype of HU-deficient cells. The uniform chromosomal distribution of the many operons regulated by HU strongly suggests that the transcriptional and nucleoid architectural functions of HU constitute two aspects of a unique protein-DNA interaction mechanism.

Comorbidities Alone Do Not Explain the Undertreatment of Colorectal Cancer in Older Adults: A French Population-Based Study

OBJECTIVES: To investigate the influence of comorbidities on treatment modalities of colorectal cancer according to the age of patients and French recommendations.

Adjuvant Treatments do not Alter the Quality of Life in Elderly Patients With Colorectal Cancer A Population-based Study

The current study was performed to longitudinally assess the impact of adjuvant treatments on the quality of life (QoL) of elderly colorectal cancer survivors.

The lifelong risk of metachronous colorectal cancer justifies long-term colonoscopic follow-up.

BACKGROUND The aim of this study was to calculate the risk of metachronous colorectal cancers, to specify their characteristics and potential risk factors in a well-defined French population over a 27-year period. PATIENTS AND METHODS The 10,801 patients who had colorectal cancers totalled 61,879 person-years of follow-up. The actuarial method was used to obtain crude metachronous colorectal cancer rates. Standardised incidence ratios (SIRs) were calculated. RESULTS The cumulative rate of metachronous colorectal cancer was 1.8% at 5 years, 3.4% at 10 years and 7.2% at 20 years. The incidence of metachronous colorectal cancer following a first colorectal cancer was higher than expected (SIR: 1.5 [1.3-1.7] p<0.001). It remained greater throughout the study period, significantly only between the first and the fifth years following diagnosis (SIR: 1.9 [1.6-2.3] p<0.010). As compared to solitary cancers, metachronous cancers were diagnosed at earlier stages (23.5% versus 40.9% were stage I, p<0.001). None of the personal and tumour characteristics were predicting factors for the development of metachronous colorectal cancer. CONCLUSION Patients with colorectal cancer are at greater risk of developing a metachronous colorectal cancer. Among them, no predicting factors for the development of metachronous tumours were found. Thus lifelong colonoscopic surveillance is needed.

Epidemiology and prognosis of synchronous colorectal cancers.

The aim of this population‐based study was to report on the incidence, treatment and prognosis of synchronous colorectal carcinomas.