A genetic model for colorectal tumorigenesis

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.

https://eprints.gla.ac.uk/121/1/Davis%2CH_2002_pdf.pdf

Mutations of the BRAF gene in human cancer

Lessons from Hereditary Colorectal Cancer

Purpose Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. Patients and Methods KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. Results KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. Conclusion Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.

/pdf/wild-type-kras-is-required-for-panitumumab-efficacy-in-44cqqe1bte.pdf

Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer

Background Colon cancers with high-frequency microsatellite instability have clinical and pathological features that distinguish them from microsatellite-stable tumors. We investigated the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II and stage III colon cancer. Methods Tumor specimens were collected from patients with colon cancer who were enrolled in randomized trials of fluorouracil-based adjuvant chemotherapy. Microsatellite instability was assessed with the use of mononucleotide and dinucleotide markers. Results Of 570 tissue specimens, 95 (16.7 percent) exhibited high-frequency microsatellite instability. Among 287 patients who did not receive adjuvant therapy, those with tumors displaying high-frequency microsatellite instability had a better five-year rate of overall survival than patients with tumors exhibiting microsatellite stability or low-frequency instability (hazard ratio for death, 0.31 [95 percent confi...

/pdf/tumor-microsatellite-instability-status-as-a-predictor-of-3w3xrgat2i.pdf

Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer

Genetic Alterations During Colorectal-Tumor Development

Common Inheritance of Susceptibility to Co-Ionic Adenomatous Polyps and Associated Colorectal Cancers

Ethical dilemmas involving confidentiality issues are frequently encountered in occupational medicine. The occupational physician faces a unique challenge because in many circumstances, a physicianpatient relationship, in the ordinary or legal sense, may not exist. The occupational physician ofien faces a conflicting interest between the employee's desire for privacy and the employer's legitimate need to know. The occupational physician must carefully balance these interests for the benefit of society and the parties involved. Occupational physicians also work in a wide variety of practice situations, and the ethical and legal duty of confidentiality may vary substantially with these roles. This article provides an overview of the ethical and legal requirements of confidentiality in the workplace. The constitutional, statutory, and common law framework governing the treatment of employee medical information, as well as defenses to liability, are discussed. Recent legislative changes such as the Americans with Disabilities Act, and new challenges such as the proper handling of HIV information, present unique confidentiality problems.

ACOEM position on the confidentiality of medical information in the workplace

Cocaine-Induced Coronary-Artery Vasoconstriction

There is some controversy regarding the relationship between development of median nerve dysfunction and employment activities. We performed nerve conduction studies of median nerve function on individuals before and after starting employment in the pork processing industry. After working an average of 64 days, employees (n = 45) showed significant prolongation of median motor and sensory nerve latency when comparing initial and final testing results in both dominant and non-dominant hands (P = < 0.01 to 0.03). A similar trend was found when testing a smaller group of employees (n = 17) who were already working (mean of 3 days), though this did not generally reach statistical significance. This study supports the conclusion that prolongation of median motor and sensory nerve latency can occur within as little as 2 months after beginning employment in the pork processing industry.

Elizabeth E. Gresch

Papers

Genetic Alterations During Colorectal-Tumor Development

Common Inheritance of Susceptibility to Co-Ionic Adenomatous Polyps and Associated Colorectal Cancers

ACOEM position on the confidentiality of medical information in the workplace

Cocaine-Induced Coronary-Artery Vasoconstriction

Pre- and post-employment median nerve latency in pork processing employees.