A genome-wide association study of radiotherapy induced toxicity in head and neck cancer patients identifies a susceptibility locus associated with mucositis

PURPOSE: A two-stage genome-wide association study was carried out in head and neck cancer (HNC) patients aiming to identify genetic variants associated with either specific radiotherapy-induced (RT) toxicity endpoints or a general proneness to develop toxicity after RT.MATERIALS AND METHODS: The analysis included 1780 HNC patients treated with primary RT for laryngeal or oro/hypopharyngeal cancers. In a non-hypothesis-driven explorative discovery study, associations were tested in 1183 patients treated within The Danish Head and Neck Cancer Group. Significant associations were later tested in an independent Dutch cohort of 597 HNC patients and if replicated, summary data obtained from discovery and replication studies were meta-analysed. Further validation of significantly replicated findings was pursued in an Asian cohort of 235 HNC patients with nasopharynx as the primary tumour site.RESULTS: We found and replicated a significant association between a locus on chromosome 5 and mucositis with a pooled OR for rs1131769*C in meta-analysis = 1.95 (95% CI 1.48-2.41; ppooled = 4.34 × 10-16).CONCLUSION: This first exploratory GWAS in European cohorts of HNC patients identified and replicated a risk locus for mucositis. A larger Meta-GWAS to identify further risk variants for RT-induced toxicity in HNC patients is warranted.</p

Correlation between DNA damage responses of skin to a test dose of radiation and late adverse effects of earlier breast radiotherapy

Aim: To correlate residual double strand breaks (DSB) 24 h after 4 Gy test doses to skin in vivo and to lymphocytes in vitro with adverse effects of earlier breast radiotherapy (RT). Patients and methods: Patients given whole breast RT P5 years earlier were identified on the basis of moderate/marked or minimal/no adverse effects despite the absence (‘RT-Sensitive’, RT-S) or presence (‘RT-Resistant’, RT-R) of variables predisposing to late adverse effects. Residual DSB were quantified in skin 24 h after a 4 Gy test dose in 20 RT-S and 15 RT-R patients. Residual DSB were quantified in lymphocytes irradiated with 4 Gy in vitro in 30/35 patients. Results: Mean foci per dermal fibroblast were 3.29 (RT-S) vs 2.80 (RT-R) (p = 0.137); 3.28 (RT-S) vs 2.60 (RT-R) in endothelium (p = 0.158); 2.50 (RT-S) vs 2.41 (RT-R) in suprabasal keratinocytes (p = 0.633); 2.70 (RT-S) vs 2.35 (RT-R) in basal epidermis (p = 0.419); 12.1 (RT-S) vs 10.3 (RT-R) in lymphocytes (p = 0.0052). Conclusions: Residual DSB in skin following a 4 Gy dose were not significantly associated with risk of late adverse effects of breast radiotherapy, although exploratory analyses suggested an association in severely affected individuals. By contrast, a significant association was detected based on the in vitro response of lymphocytes

SSTR2 in Nasopharyngeal Carcinoma:Relationship with Latent EBV Infection and Potential as a Therapeutic Target

SIMPLE SUMMARY: Nasopharyngeal cancer (NPC) is a malignant epithelial tumor endemic to parts of Asia and associated with infection by the Epstein–Barr virus (EBV) in these regions. The cancer is often detected at a late stage which is associated with poor outcomes (63% 5-year survival). Advances for the management of this disease have remained largely stagnant and treatment relies primarily on radiotherapy and chemotherapy, as well as surgery when indicated. Nevertheless, our understanding of its underlying biology has grown rapidly in the past two decades, laying the foundation for the development of improved therapeutics which have the potential to improve outcomes. This review offers a comprehensive, up-to-date summary of this disease, with a focus on the role of somatostatin receptor 2 (SSTR2) in NPC and how this increased knowledge may lead to improved diagnosis and management of this disease. ABSTRACT: Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor, most commonly located in the pharyngeal recess and endemic to parts of Asia. It is often detected at a late stage which is associated with poor prognosis (5-year survival rate of 63%). Treatment for this malignancy relies predominantly on radiotherapy and/or systemic chemotherapy, which can be associated with significant morbidity and impaired quality of life. In endemic regions NPC is associated with infection by Epstein–Barr virus (EBV) which was shown to upregulate the somatostatin receptor 2 (SSTR2) cell surface receptor. With recent advances in molecular techniques allowing for an improved understanding of the molecular aetiology of this disease and its relation to SSTR2 expression, we provide a comprehensive and up-to-date overview of this disease and highlight the emergence of SSTR2 as a key tumor biomarker and promising target for imaging and therapy

Meta-GWAS identifies the heritability of acute radiation-induced toxicities in head and neck cancer

Background and purpose: We aimed to the genetic components and susceptibility variants associated with acute radiation-induced toxicities (RITs) in patients with head and neck cancer (HNC). Materials and methods: We performed the largest meta-GWAS of seven European cohorts (n = 4,042). Patients were scored weekly during radiotherapy for acute RITs including dysphagia, mucositis, and xerostomia. We analyzed the effect of variants on the average burden (measured as area under curve, AUC) per each RIT, and standardized total average acute toxicity (STATacute) score using a multivariate linear regression. We tested suggestive variants (p < 1.0x10-5) in discovery set (three cohorts; n = 2,640) in a replication set (four cohorts; n = 1,402). We meta-analysed all cohorts to calculate RITs specific SNP-based heritability, and effect of polygenic risk scores (PRSs), and genetic correlations among RITS. Results: From 393 suggestive SNPs identified in discovery set; 37 were nominally significant (preplication < 0.05) in replication set, but none reached genome-wide significance (pcombined < 5 × 10-8). In-silico functional analyses identified “3′-5'-exoribonuclease activity” (FDR = 1.6e-10) for dysphagia, “inositol phosphate-mediated signalling” for mucositis (FDR = 2.20e-09), and “drug catabolic process” for STATacute (FDR = 3.57e-12) as the most enriched pathways by the RIT specific suggestive genes. The SNP-based heritability (±standard error) was 29 ± 0.08 % for dysphagia, 9 ± 0.12 % (mucositis) and 27 ± 0.09 % (STATacute). Positive genetic correlation was rg = 0.65 (p = 0.048) between dysphagia and STATacute. PRSs explained limited variation of dysphagia (3 %), mucositis (2.5 %), and STATacute (0.4 %). Conclusion: In HNC patients, acute RITs are modestly heritable, sharing 10 % genetic susceptibility, when PRS explains < 3 % of their variance. We identified numerus suggestive SNPs, which remain to be replicated in larger studies

ASCO's Leadership Development Program: Focusing on the Next Generation of Leaders in Asia Pacific

PURPOSEThe demand for high-quality and more comprehensive oncology care will continue to rise globally. Effective leadership is particularly important.METHODSThe evolving endeavor of ASCO to reach out globally has covered the development of the next-generation leaders from Asia Pacific. Through the Leadership Development Program, the untapped talent of the region and the future leaders in oncology will gain the knowledge and skill sets, which prepares them to navigate the complex dynamics of oncology health care.RESULTSThe region is the largest and the most populous with more than 60% of the world's population. It has 50% of cancer cases and is estimated to account for 58% of cancer deaths worldwide. The demand for high-quality and more comprehensive oncology care will continue to rise in the years to come. This growth will intensify the need for capable leaders. Leadership styles and behaviors are different. These are shaped within the context of cultural and philosophical views and beliefs. The pan-Asian interdisciplinary group of young leaders are expected to gain knowledge and skillsets through the Leadership Development Program. They will learn to work on strategic projects within a team and gain knowledge about advocacy. Communication and presentation skills and conflict management are also important components of the program. Through learning culturally relevant skills, participants can effectively collaborate with others, build relationships, and lead within their own institutions and societies and within ASCO.CONCLUSIONInstitutions and organizations need to have a deeper and more sustained focus on leadership development. Successfully addressing the challenges on leadership development in Asia Pacific is important