Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types.

BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). METHODS: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type. RESULTS: Shared SNV-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 SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), 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 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). CONCLUSIONS: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

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.

Experiencia en el manejo de metástasis cerebrales tratadas con radiocirugía estereotáctica / Experience with the radiosurgical treatment of brain metastases

Objetivos: Analizar la supervivencia de una cohorte de pacientes con metástasis cerebrales tratados con radiocirugía y determinar qué factores pueden influir en los resultados. Pacientes y método: Estudio retrospectivo descriptivo sobre una cohorte de 126 pacientes diagnosticados de metástasis intracraneal tratados con radiocirugía. Se excluyeron aquellos casos en los que se realizó cirugía (antes o después de la radiocirugía). Se analizó la supervivencia en función de factores clínicos (edad, sexo, tumor primario), radiológicos (número, localización y volumen de las lesiones) y de radioterapia (dosis de tratamiento, radioterapia holocraneal). Se realizó análisis univariante y multivariante de regresión de Cox. Resultados: Entre febrero de 2008 y abril de 2015 se trataron 225 metástasis cerebrales en 126 pacientes con edad media de 59,8 ± 11,6 años. La mediana de supervivencia fue de 8,2 meses. La supervivencia global a los 6, 12 y 24 meses fue del 60,3, del 31,5 y del 12,8%, respectivamente. Los orígenes más frecuentes fueron pulmonar (59,5%) y mama (14,3%), y la localización principal, los hemisferios cerebrales (77%). El volumen medio fue de 10,35cc (0,2-43,5). Se encontraron como factores significativos de supervivencia, entre otros: edad menor de 60años (p = 0,046), sexo femenino (p < 0,001), cáncer de mama (p < 0,001); KPS > 80 (p = 0,001), puntuación en la escala SIR > 6,5 (p = 0,031), escala GPA ≥ 2,5 (p = 0,003). Conclusiones: La radiocirugía es una técnica adecuada para el tratamiento de las metástasis cerebrales, y entre los factores pronósticos encontrados destacan la edad menor de 60 años, el sexo femenino y las mejores puntuaciones en las escalas de Karfnosky, SIR y GPA

Objective: To analyse the survival rate of a cohort of patients with intracranial metastases treated with radiosurgery, and to determine the factors that influence the results. Patients and method: Retrospective analysis performed on a cohort of 126 patients undergoing radiosurgery for brain metastases. Patients treated with surgery before or after radiosurgery were excluded. Survival is analysed based on clinical (age, sex, primary tumour), radiological (number, location and volume of lesions), and radiotherapy factors (treatment dose, holocraneal radiation). Univariate and multivariate analyses were performed to determine significant prognostic factors. Results: A total of 225 brain metastases in 126 patients, with a mean age of 59.8 ± 11.6 years, were treated between February 2008 and April 2015. The mean survival was 8.2 months. The overall survival rates at 6 months, 1 year, and 2 years were 60.3%, 31.5%, and 12.8%, respectively. Lung (59.5%) and breast (14.3) were the most common primary tumours, and the most common site for metastases was the cerebral hemisphere (77%) and the average volume was 10.35 cc (0.2-43.5). Significant survival factors were: age under 60 (P = .046), female (P < .001), breast cancer (P < .001), KPS > 80 (P = .001), SIR6 > 5 (P = .031), and GPA ≥ 2.5 (P = .003). Conclusions: Radiosurgery is an appropriate technique for the treatment of brain metastases, and the main prognostic factors include being age under 65, female, breast cancer, and good scores on Karnofsky, SIR, and GPA scales

[Experience with the radiosurgical treatment of brain metastases]. / Experiencia en el manejo de metástasis cerebrales tratadas con radiocirugía estereotáctica.

OBJECTIVE: To analyse the survival rate of a cohort of patients with intracranial metastases treated with radiosurgery, and to determine the factors that influence the results. PATIENTS AND METHOD: Retrospective analysis performed on a cohort of 126 patients undergoing radiosurgery for brain metastases. Patients treated with surgery before or after radiosurgery were excluded. Survival is analysed based on clinical (age, sex, primary tumour), radiological (number, location and volume of lesions), and radiotherapy factors (treatment dose, holocraneal radiation). Univariate and multivariate analyses were performed to determine significant prognostic factors. RESULTS: A total of 225 brain metastases in 126 patients, with a mean age of 59.8±11.6years, were treated between February 2008 and April 2015. The mean survival was 8.2 months. The overall survival rates at 6months, 1year, and 2years were 60.3%, 31.5%, and 12.8%, respectively. Lung (59.5%) and breast (14.3) were the most common primary tumours, and the most common site for metastases was the cerebral hemisphere (77%) and the average volume was 10.35 cc (0.2-43.5). Significant survival factors were: age under 60 (P=.046), female (P<.001), breast cancer (P<.001), KPS >80 (P=.001), SIR6 >5 (P=.031), and GPA ≥2.5 (P=.003). CONCLUSIONS: Radiosurgery is an appropriate technique for the treatment of brain metastases, and the main prognostic factors include being age under 65, female, breast cancer, and good scores on Karnofsky, SIR, and GPA scales.