Characterization and prognostic value of mutations in exons 5 and 6 of the p53 gene in patients with colorectal cancers in central Iran

Background/Aims: We aimed to investigate the relation-ships among various mutations of the p53 gene and their protein products, histological characteristics, and disease prognosis of primary colorectal cancer in Isfahan, central Iran. Methods: Sixty-one patients with colorectal adenocarcinoma were enrolled in the study. Mutations of the p53 gene were detected by single-stranded conformation polymorphism and DNA sequencing. The protein stability was evaluated by immunohistochemistry. Patients were followed up to 48 months. Results: Twenty-one point mutations in exons 5 and 6 were detected in the tumor specimens of 14 patients (23%). Of those, 81% and 9.5% were missense and nonsense mutations, respectively. There were also two novel mutations in the intronic region between exons 5 and 6. In 11 mutated specimens, protein stability and protein accumulation were identified. There was a relationship between the type of mutation and protein accumulation in exons 5 and 6 of the p53 gene. The presence of the mutation was associated with an advanced stage of cancer (trend, p<0.009). Patients with mutated p53 genes had significantly lower survival rates than those with wild type p53 genes (p<0.01). Conclusions: Mutations in exons 5 and 6 of the p53 gene are common genetic alterations in colorectal adenocarcinoma in central Iran and are associated with a poor prognosis of the disease

Identification of genes expressed by immune cells of the colon that are regulated by colorectal cancer-associated variants.

A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry. Two previously uncharacterized genes, COLCA1 and COLCA2, were found to be co-regulated genes that are transcribed from opposite strands. Expression levels of COLCA1 and COLCA2 transcripts correlate with rs3802842 genotypes. In colon tissues, COLCA1 co-localizes with crystalloid granules of eosinophils and granular organelles of mast cells, neutrophils, macrophages, dendritic cells and differentiated myeloid-derived cell lines. COLCA2 is present in the cytoplasm of normal epithelial, immune and other cell lineages, as well as tumor cells. Tissue microarray analysis demonstrates the association of rs3802842 with lymphocyte density in the lamina propria (p = 0.014) and levels of COLCA1 in the lamina propria (p = 0.00016) and COLCA2 (tumor cells, p = 0.0041 and lamina propria, p = 6 × 10(-5)). In conclusion, genetic, expression and immunohistochemical data implicate COLCA1 and COLCA2 in the pathogenesis of colon cancer. Histologic analyses indicate the involvement of immune pathways

The Relationship between Electromyographically Documented Peripheral Neuropatny and Falls

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111114/1/j.1532-5415.1992.tb04477.x.pd

Absence of microsatellite instability and BRAF (V600E) mutation in testicular germ cell tumors

Testicular germ cell tumors (TGCT) are the most common malignant neoplasm in young men. DNA mismatch repair deficiency can lead to microsatellite instability (MSI), an important mechanism of genetic instability. A mutation of the BRAF gene has been implicated in the pathogenesis of several solid tumors and has recently become an important therapeutic target. The role of MSI and BRAF gene mutation in TGCT, particularly in refractory disease, is poorly understood and reported findings are controversial. In this study, we aimed to determine the frequency and clinical impact of MSI status and BRAF mutations in TGCT. DNA was isolated from formalin-fixed paraffin embedded (FFPE) tissue from 150 TGCT cases. The MSI phenotype was evaluated using multiplex PCR for five quasimonomorphic mononucleotide repeat markers. Exon 15 of the BRAF oncogene (V600E) was analyzed by PCR, followed by direct sequencing. Sixteen percent of cases were considered to have refractory disease. In a small subset of cases (17 for MSI and 18 for BRAF), the quantity and quality of DNA recovery were poor and therefore, were unable to be analyzed. The remaining 133 TGCT cases showed a complete absence of MSI. Of the 132 cases successfully evaluated for BRAF mutations, all were V600E wild-type. In conclusion, despite a distinct response of testicular germ cell tumors to therapy, microsatellite instability, and the BRAF V600E mutation were absent in all testicular germ cell tumors tested in this study.This project was financially supported by Barretos Cancer Hospital internal research funds (PAIP). The authors acknowledge Dr. Laura Musselwhite for her critical review of the manuscript

Predictors for falls and fractures in the longitudinal aging study Amsterdam

The objective of this study was to identify easily measurable predictors for falls, recurrent falls, and fractures using a population-based prospective cohort study of 1469 elderly, born before 1931, in three regions of the Netherlands. The baseline at-home interview was in 1992. In 1995, falls experienced in the preceding year and fractures over the preceding 38- month period were registered. In a period of 1 year, 32% of the participants fell at least once, and 15% fell two or more times. The rate of recurrent falls was similar in men and women up until the age of 75 years. The total number of fractures was 85, including 23 wrist fractures, 12 hip fractures, and 9 humerus fractures. The incidence density per 1000 person-years for any fracture was 25.1 (95% confidence interval [CI], 18.9-31.4) for women and 8.2 (95% CI, 4.5-12.0) for men, respectively. Multiple logistic regression identified urinary incontinence, impaired mobility, use of analgetics, and use of antiepileptic drugs as the predictors most strongly associated with recurrent falls. Female gender, living alone, past fractures, inactivity, body height, and use of analgetics proved to be the predictors most strongly associated with fractures. The probabilities of recurrent falls were 4.7% (95% CI, 2.9-7.5%) to 59.2% (95% CI, 24.1-86.9%) with zero to four predictors, respectively. The probability of fractures ranged from 0.0% (95% CI, 0.0-0.4%) without any of the identified predictors to 12.9% (95% CI, 4.4- 32.2%) with all six predictors present. Our study shows that the risk of recurrent falls and of fractures can be predicted using up to, respectively, four and six easily measurable predictors. This study emphasizes the importance of impaired mobility and inactivity as predictors for falls and fractures

Exome-wide somatic mutation characterization of small bowel adenocarcinoma

Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (Al) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.Peer reviewe

A Patient-Based Needs Assessment for Living Well with Parkinson Disease: Implementation via Nominal Group Technique

Background. Parkinson’s disease (PD) is a neurodegenerative condition with complex subtleties, making it challenging for physicians to fully inform their patients. Given that approximately 50% of Americans access the Internet for health information, the development of a multimedia, web-based application emphasizing targeted needs of people with Parkinson’s disease (PwP) has the potential to change patient’s lives.Objectives. To determine what information PwP perceive could enhance their quality of life.Methods. Group sessions utilizing nominal group technique (NGT) were conducted. Participants were asked “what information do you want to know about that would help you live well with PD?” Silent generation of ideas preceded discussion followed by anonymous ranking of items. A “summary score” (sum of rank × frequency) was calculated.Results. 36 individual items were collapsed into 9 categories. Coping with emotions, changing relationships, and social implications of PD were ranked as most important. Financial supports and skills for self-advocacy were also highly ranked.Conclusions. Qualitative research methodology was utilized to determine the unmet needs of PwP. Results of this survey will inform the development of a patient-oriented, online resource, the goal will be to provide information and strategies to improve symptom management, reduce disability and address all relevant concerns important to those affected by PD.</jats:p

A review on the molecular diagnostics of Lynch syndrome: A central role for the pathology laboratory

Lynch syndrome (LS) is caused by mutations in mismatch repair genes and is characterized by a high cumulative risk for the development of mainly colorectal carcinoma and endometrial carcinoma. Early detection of LS is important since surveillance can reduce morbidity and mortality. However, the diagnosis of LS is complicated by the absence of a pre-morbid phenotype and germline mutation analysis is expensive and time consuming. Therefore it is standard practice to precede germline mutation analysis by a molecular diagnostic work-up of tumours, guided by clinical and pathological criteria, to select patients for germline mutation analysis. In this review we address these molecular analyses, the central role for the pathologist in the selection of patients for germline diagnostics of LS, as well as the molecular basis of LS