Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers

BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity (RIT) across four cancer types (prostate, head and neck, breast, and lung).METHODS: A GWAS meta-analysis was performed using 19 cohorts including 12,042 patients. Acute standardized total average toxicity (rSTATacute) was modelled using a generalized linear regression model for additive effect of genetic variants adjusted for demographic and clinical covariates. LD score regression estimated shared SNP-based heritability of rSTATacute in all patients and for each cancer type.RESULTS: Shared SNP-based heritability of STATacute among all cancer types was estimated at 10% (se = 0.02), and was higher for prostate (17%, se = 0.07), head and neck (27%, se = 0.09), and breast (16%, se = 0.09) cancers. We identified 130 suggestive associated SNPs with rSTATacute (5.0x10-8&lt;P-value&lt;1.0x10-5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size -0.17; P-value=1.7x10-7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 x10-6, Pcorrected =0.079) as the top gene set associated with rSTATacute among all patients. In-silico gene expression analysis showed the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed Pcorrected=0.004; sun exposed Pcorrected=0.026).CONCLUSIONS: There is shared SNP-based heritability for acute RIT across and within individual cancer sites. Future meta-GWAS among large radiotherapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.</p

Leaders, leadership and future primary care clinical research

Background: A strong and self confident primary care workforce can deliver the highest quality care and outcomes equitably and cost effectively. To meet the increasing demands being made of it, primary care needs its own thriving research culture and knowledge base. Methods: Review of recent developments supporting primary care clinical research. Results: Primary care research has benefited from a small group of passionate leaders and significant investment in recent decades in some countries. Emerging from this has been innovation in research design and focus, although less is known of the effect on research output. Conclusion: Primary care research is now well placed to lead a broad re-vitalisation of academic medicine, answering questions of relevance to practitioners, patients, communities and Government. Key areas for future primary care research leaders to focus on include exposing undergraduates early to primary care research, integrating this early exposure with doctoral and postdoctoral research career support, further expanding cross disciplinary approaches, and developing useful measures of output for future primary care research investment

Quality of life and outcomes research in head and neck cancer: A review of the state of the discipline and likely future directions

Quality of life (QOL) is by definition a multi-dimensional global construct that has become an increasingly important outcome measure in cancer treatment. The impact of a head and neck cancer (HNC) diagnosis on the person and the consequences of its treatment cross multiple functional domains that have a clear and direct influence on one’s post-treatment well-being and associated QOL. The evaluation of QOL and performance outcome in cancer is critical to optimal patient care, comprehensive evaluation of treatment alternatives, and the development of informed rehabilitation and patient education services. Despite the difficulties of going from concept to quantification of patient perceptions, the number of instruments available to measure QOL psychometrically has increased rapidly. Assessments can now be made in a variety of distinctive ways using both specific and generic measures. There is no gold-standard questionnaire and the choice is based on psychometric properties, research objectives and study design. QOL assessment has evolved over the years into an organised scientific discipline, such that useful insights can be obtained by a review of the current literature. However, more work needs to be done to improve the applicability and clinical utility of QOL assessment. Most importantly. QOL studies should be reported in such a way as to provide clinically meaningful data to physicians and surgeons, in order to link research to clinical practice. Further attention should be paid to the development of newer theoretical models, minimalist approaches, development of more sensitive and specific instruments and the effective use of modern technology to achieve this objective. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved

Challenges for the future modifications of the TNM staging system for head and neck cancer: Case for a new computational model?

The TNM system of staging cancers is a simple and effective method to map the extent of tumours. It had traditionally strived to maintain a balance between being simple and user-friendly on one hand and comprehensive on the other. A number of revisions have taken place over the years with the goal of improving utility. However, numerous controversies surround the TNM system. There is a school of thought that contends that patient co-morbidity and specific tumour-related factors should be incorporated to add further prognostic capabilities in the TNM system, but this raises concerns that such an approach may unnecessarily complicate the system. This review highlights some controversies that surround the TNM system and suggests prognostic indicators that may be added to make it more useful in guiding treatment decisions and predicting outcomes. (C) 2009 Elsevier Ltd. All rights reserve

CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines

Purpose: The objective of this project was to define consensus guidelines for delineating organs at risk (OARS) for head and neck radiotherapy for routine daily, practice and for research purposes