Independent and tissue-specific prognostic impact of miR-126 in nonsmall cell lung cancer: coexpression with vascular endothelial growth factor-A predicts poor survival

BACKGROUND:

Angiogenesis is pivotal in tumor development. Vascular endothelial growth factor‐A (VEGF‐A) is considered one of the most important angiogenic factors, but lately several microRNAs (miRs) have been associated with vascular development. miR‐126 has been related to tumor angiogenesis and in the regulation of VEGF‐A. The authors aimed to investigate the prognostic impact of miR‐126 and its co‐expression with VEGF‐A in nonsmall cell lung cancer (NSCLC) patients.

METHODS:

Tumor tissue samples from 335 resected stage I to IIIA NSCLC patients were obtained and tissue microarrays (TMAs) were constructed with 4 cores from each tumor specimen. VEGF‐A expression was evaluated by immunohistochemistry, and in situ hybridization was used to evaluate the expression of miR‐126.

RESULTS:

In the total material, miR‐126 was a significant negative prognostic factor in both univariate (P = .005) and multivariate analyses (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2‐2.8, P = .01). Stratified by histology, miR‐126 was only significant in squamous cell carcinomas (univariate: P < .001; multivariate: HR 3.1, CI 95% 1.7‐5.6, P<.001). Stratified by lymph node status, miR‐126 was significant only in the lymph node‐positive subgroup (univariate: P<.001; multivariate: HR 4.1, CI 95% 2.0‐8.4, P < .001). High miR‐126 expression correlated significantly with high VEGF‐A expression (P = .037). The co‐expression of miR‐126 and VEGF‐A had a significant prognostic impact (P = .002), with 5‐year survival rates of 68%, 51%, and 42% for low/low (n = 150), mixed combinations (n = 129), and high/high (n = 35) expression, respectively.

CONCLUSIONS:

miR‐126 is a strong and independent negative prognostic factor in NSCLC, and its prognostic impact appears related primarily to histology and nodal status. Cancer 2011. © 2011 American Cancer Society.     

Levels and Trophic Transfer of Selected Pesticides in the Lake Ziway Ecosystem

The levels of 30 selected pesticides and trophic biomagnification of DDT were investigated in biota samples of the Lake Ziway in the Rift valley region, Ethiopia. Carbon source and trophic position were calculated by using ¹³C and ¹⁵N stable isotopes, individually, and trophic magnification factors (TMFs) were inferred. Only DDT and its metabolites were quantified in all samples analyzed. The most prominent metabolite was p,p?-DDE with mean concentration ranging from the 0.82–33.69 ng g^?1 lipid weight. Moreover, the ratio of DDT/DDD?+?DDE in all the biota samples was less than 1 signifying historical DDT application. Regression of log [ΣDDT] vs TL (trophic level) among all biota species showed a significant correlation, indicating that DDTs are biomagnifying along with the food web of Lake Ziway with an estimated TMF of 2.75. The concentrations of DDTs and other organochlorine pesticides found in biota from Lake Ziway were, in general, lower than studies found in previous studies carried out in the same lake.

     

APC mutation spectrum of Norwegian familial adenomatous polyposis families: high ratio of novel mutations

Introduction  Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disease caused by mutations in the adenomatous polyposis coli (APC) gene. Massive formation of colorectal adenomas, of which some will inevitably develop into adenocarcinomas, is the hallmark of the disease. Characterization of causative APC mutations allows presymptomatic diagnosis, close follow-up and prophylactic intervention in families. To date more than 900 different germline mutations have been characterized worldwide demonstrating allelic heterogeneity. Purpose  The germline mutation spectrum of APC identified in 69 apparently unrelated Norwegian FAP families are presented and discussed with reference to clinical phenotype and novel mutation rate. Methods  Different methods have been used over the years. However, all mutations were confirmed detectable by an implemented denaturing high-performance liquid chromatography screening approach. Multiplex ligation-dependent probe amplification analysis was employed for potential gross rearrangements. Results  Fifty-three distinctive mutations were detected, of which 22 have been detected in Norway exclusively. Except for two major deletion mutations encompassing the entire APC, all mutations resulted in premature truncation of translation caused by non-sense (31%) or change in reading frame (69%). Conclusion  A high ratio of novel APC mutations continues to contribute to APC mutation heterogeneity causing FAP. This is the first comprehensive report of APC germline mutation spectrum in Norway. This paper is dedicated to late Professor Tobias Gedde-Dahl (deceased in March 2006). An erratum to this article can be found at     

Genetic derangements in the tumor suppressor gene PTEN in endometrial precancers as prognostic markers for cancer development: a population-based study from northern Norway with long-term follow-up

OBJECTIVES: The purpose of the current study was to characterize the role of PTEN in malignant transformation and to evaluate the significance of mutated PTEN exons as prognostic markers in the carcinogenesis of endometrial hyperplasia. A comparison of PTEN mutations as prognostic markers with former investigated prognosticators was also intended. METHODS: Histological material from 68 patients with endometrial hyperplasia and 10-20 years of follow-up of whom 18 later developed cancer was examined. PCR amplification and DNA sequencing were performed, screening the most frequently mutated exons 5a-8b of the PTEN gene. RESULTS: Mutations were demonstrated in 13.2% of the patients. Of the patients with cancer development, five showed to have PTEN mutations corresponding to 28%. Of the patients remaining without carcinoma, only 8% had PTEN mutations (P = 0.04). In total, there were three missense, three nonsense, and four frameshift mutations, and twice as many mutations leading to a truncated protein (six) than mutations altering one amino acid in the entire protein (three). Mutations were distributed in the following manner: three in exon 5a, two in exon 5b, two in exon 6, two in exon 7, and one in exon 8b. Only mutations in exons 6, 7, and 8a were connected with cancer development or coexisting cancer and six out of seven mutations within these exons were frameshift or nonsense mutations. CONCLUSIONS: Our results showed that mutations in the PTEN gene were statistically more frequent in cases with cancer development or coexisting cancer. Although the specificity was acceptable, the sensitivity of PTEN mutations was too low to make it suitable as a tumor marker (sensitivity of 27% and specificity of 91%) in clinical practice.     

A semiautomated test for microsatellite instability and its significance for the prognosis of sporadic endometrial cancer in northern Norway.

Archival histologic material from 105 women (median age 62 years) treated for endometrial cancer was investigated for the replication error phenotype indicated by the observation of widespread microsatellite instability (MSI). Polymerase chain reaction (PCR) of DNA isolated from paraffin-embedded tissue was analyzed for MSI using six microsatellite loci with a fluorescent-based detection system. Flow cytometry and morphometric investigation were performed in the same material for each of the patients. Twenty percent (21 of 105) of screened endometrial cancers were found to have high MSI at two or more of the loci tested. The mean detection frequency per marker was highest in the dinucleotide repeat sequence, D2S123, and the mononucleotide repeat sequences amplified by Bat 25 and Bat 26. Death from endometrial cancer was not related to the occurrence of MSI (p=0.6). There was no significant association between MSI and FIGO stage (p=0.5), myometrial invasion depth (p=0.8), histological grade (p=0.3), or vessel invasion (p=0.5). There were, however, more MSI cases among the group of diploid cases compared with the aneuploid and tetraploid group. MSI is not a valuable prognosticator for survival of sporadic endometrial cancer, and diploid cases are significantly more often MSI positive than aneuploid and tetraploid cases.