ABSTRACT
BACKGROUND/AIMS: Uveal melanoma (UM) is a highly aggressive malignancy and presents a clinically significant unmet need in cancer therapeutics. The aim of this study was to identify previously unreported mutations in UM among an Irish cohort of patients which may have potential clinical relevance. METHODS: DNA was extracted from 36 intraocular melanoma patient samples and 4 metastatic melanoma samples among the patient cohort by microdissection from formalin-fixed paraffin embedded tissue blocks and underwent genotyping to test for known single nucleotide polymorphisms in 42 cancer associated genes. These mutations were analysed using a custom-designed sequenom panel. RESULTS: Using high-throughput genotyping, mutually exclusive GNAQ and GNA11 mutations were detected in 31 of 34 UM patients together with a number of non-synonymous changes in established cancer driver genes, PHLPP2, MET, PIK3R1 and IDH-1, variants which have not been previously associated with UM. CONCLUSION: Given the lack of knowledge regarding the clinical relevance of the variants identified in this UM cohort and their likely pathogenic nature in other cancers, further studies of the functional impact of these variant mutations are warranted to establish possible previously, undescribed roles in UM pathogenesis, which may provide additional targets for future therapies.
Subject(s)
Melanoma/genetics , Uveal Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Genotyping Techniques , Humans , In Situ Hybridization, Fluorescence , Male , Mass Spectrometry , Middle Aged , Polymorphism, Single NucleotideABSTRACT
Purpose Patients with metastatic colorectal cancer (mCRC) have limited benefit from the addition of bevacizumab to standard chemotherapy. However, a subset probably benefits substantially, highlighting an unmet clinical need for a biomarker of response to bevacizumab. Previously, we demonstrated that losses of chromosomes 5q34, 17q12, and 18q11.2-q12.1 had a significant correlation with progression-free survival (PFS) in patients with mCRC treated with bevacizumab in the CAIRO2 clinical trial but not in patients who did not receive bevacizumab in the CAIRO trial. This study was designed to validate these findings. Materials and Methods Primary mCRC samples were analyzed from two cohorts of patients who received bevacizumab as first-line treatment; 96 samples from the European multicenter study Angiopredict (APD) and 81 samples from the Italian multicenter study, MOMA. A third cohort of 90 samples from patients with mCRC who did not receive bevacizumab was analyzed. Copy number aberrations of tumor biopsy specimens were measured by shallow whole-genome sequencing and were correlated with PFS, overall survival (OS), and response. Results Loss of chromosome 18q11.2-q12.1 was associated with prolonged PFS most significantly in both the cohorts that received bevacizumab (APD: hazard ratio, 0.54; P = .01; PFS difference, 65 days; MOMA: hazard ratio, 0.55; P = .019; PFS difference, 49 days). A similar association was found for OS and overall response rate in these two cohorts, which became significant when combined with the CAIRO2 cohort. Median PFS in the cohort of patients with mCRC who did not receive bevacizumab and in the CAIRO cohort was similar to that of the APD, MOMA, and CAIRO2 patients without an 18q11.2-q12.1 loss. Conclusion We conclude that the loss of chromosome 18q11.2-q12.1 is consistently predictive for prolonged PFS in patients receiving bevacizumab. The predictive value of this loss is substantiated by a significant gain in OS and overall response rate.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chromosome Deletion , Chromosomes, Human, Pair 18 , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Bevacizumab/administration & dosage , Capecitabine/administration & dosage , Chromosomes, Human, Pair 17 , Chromosomes, Human, Pair 5 , Clinical Trials, Phase III as Topic , Cohort Studies , Colorectal Neoplasms/pathology , Comparative Genomic Hybridization , Female , Genetic Testing , Humans , Irinotecan/administration & dosage , Male , Middle Aged , Neoplasm Metastasis , Oxaliplatin/administration & dosage , Progression-Free Survival , Reproducibility of ResultsABSTRACT
The objective of this study was to investigate potential associations between an individual's psychophysical maximum acceptable force (MAF) during pushing tasks and biomechanical tissue loads within the lumbar spine. Ten subjects (eight males, two females) pushed a cart with an unknown weight at one push every two minute for a distance of 3.9 m. Two independent variables were investigated, cart control and handle orientation while evaluating their association with the MAF. Dependent variables of hand force and tissue loads for each MAF determination and preceding push trial were assessed using a validated, electromyography-assisted biomechanical model that calculated spinal load distribution throughout the lumbar spine. Results showed no association between spinal loads and the MAF. Only hand forces were associated with the MAF. Therefore, MAFs may be dependent upon tactile sensations from the hands, not the loads on the spine and thus may be unrelated to risk of low back injury. Practitioner Summary: Pushing tasks have become common in manual materials handling (MMH) and these tasks impose different tissue loads compared to lifting tasks. Industry has commonly used the psychophysical tables for job assent and decision of MMH tasks. However, due to the biomechanical complexity of pushing tasks, psychophysics may be misinterpreting risk.
