12 research outputs found
All about KRAS for clinical oncology practice: Gene profile, clinical implications and laboratory recommendations for somatic mutational testing in colorectal cancer
The KRAS oncogene has been extensively studied for more than three
decades, however, it is only recently that it attained a central role in
the clinical decision-making process for the practicing oncologist.
Recently, based on retrospective analyses of large randomized clinical
trials, the use of anti-epidermal growth factor (EGFR) monoclonal
antibodies, cetuximab and panitumumab, was restricted to patients with
metastatic colorectal cancer that carry the “wild-type” KRAS
genotype. Challenges remain in the laboratory implementation of KRAS
mutational testing and the clinical application of the test for
treatment planning. This review attempts to offer a global view of KRAS
biology, its functional role in cell signaling, mechanisms of resistance
to anti-EGFR agents and its predictive potential in metastatic
colorectal cancer. We also survey the growing list of candidate
biomarkers that may shortly supplement KRAS in routine clinical patient
stratification. Finally, we discuss practical aspects of KRAS testing
that may be useful for those involved in mutational screening in their
centers. This general overview of KRAS for clinical oncology practice
aims to assist in data interpretation and offer insight into potential
pitfalls of mutational testing. KRAS is a prime example of how
translational research can fulfill the promises of personalized medicine
for tailoring treatment to match the underlying tumor biology. (C) 2010
Elsevier Ltd. All rights reserved
Inherited variation in the PARP1 gene and survival from melanoma
We report the association of an inherited variant located upstream of
the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene
(rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene
encodes a protein involved in a number of cellular processes including
single-strand DNA repair. Survival analysis was conducted for each
cohort using proportional hazards regression adjusting for factors known
to be associated with survival. Survival was measured as overall
survival (OS) and, where available, melanoma-specific survival (MSS).
Results were combined using random effects meta-analysis. Evidence for a
role of the PARP1 protein in melanoma ulceration and survival was
investigated by testing gene expression levels taken from formalin-fixed
paraffin-embedded tumors. A significant association was seen for
inheritance of the rarer variant of PARP1, rs2249844 with OS (hazard
ratio (HR) = 1.16 per allele, 95% confidence interval (CI) 1.04-1.28,
p=0.005, eleven cohorts) and MSS (HR=1.20 per allele, 95% CI 1.01-1.39,
p=0.03, eight cohorts). We report bioinformatic data supportive of a
functional effect for rs2249844. Higher levels of PARP1 gene expression
in tumors were shown to be associated with tumor ulceration and poorer
OS.
What’s new?
Although staging systems predict outcome fairly well for melanoma,
survival still varies among individual patients. In this meta-analysis,
the authors found that inheritance of a rare genetic variant of PARP1
was associated with improved survival of melanoma patients. Increased
expression of PARP1 has been associated with poorer outcome, and
depletion of PARP1 may reduce both melanoma growth and angiogenesis. The
identification of this and other germline variants that affect survival
may help to identify key biological pathways active in host/tumor
interactions, which may lead to the discovery of new therapeutic targets
for treating advanced melanoma. Epidemiolog
Inherited variation in the PARP1 gene and survival from melanoma
We report the association of an inherited variant located upstream of the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single-strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role of the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from formalin-fixed paraffin-embedded tumors. A significant association was seen for inheritance of the rarer variant of PARP1, rs2249844 with OS (hazard ratio (HR) = 1.16 per allele, 95% confidence interval (CI) 1.04-1.28, p=0.005, eleven cohorts) and MSS (HR=1.20 per allele, 95% CI 1.01-1.39, p=0.03, eight cohorts). We report bioinformatic data supportive of a functional effect for rs2249844. Higher levels of PARP1 gene expression in tumors were shown to be associated with tumor ulceration and poorer OS. What's new? Although staging systems predict outcome fairly well for melanoma, survival still varies among individual patients. In this meta-analysis, the authors found that inheritance of a rare genetic variant of PARP1 was associated with improved survival of melanoma patients. Increased expression of PARP1 has been associated with poorer outcome, and depletion of PARP1 may reduce both melanoma growth and angiogenesis. The identification of this and other germline variants that affect survival may help to identify key biological pathways active in host/tumor interactions, which may lead to the discovery of new therapeutic targets for treating advanced melanoma. Epidemiolog