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Ana Vega and colleagues report the results of a three-stage genome-wide association study of radiotherapy toxicity following treatment for prostate cancer. They find that susceptibility to late radiation-induced toxicity is associated with variants in the TANC1 gene at 2q24.1. There is increasing evidence supporting the role of genetic variants in the development of radiation-induced toxicity 1 . However, previous candidate gene association studies failed to elucidate the common genetic variation underlying this phenotype 2 , which could emerge years after the completion of treatment 3 . We performed a genome-wide association study on a Spanish cohort of 741 individuals with prostate cancer treated with external beam radiotherapy (EBRT). The replication cohorts consisted of 633 cases from the UK 4 and 368 cases from North America 5 . One locus comprising TANC1 (lowest unadjusted P value for overall late toxicity = 6.85 × 10 −9 , odds ratio (OR) = 6.61, 95% confidence interval (CI) = 2.23–19.63) was replicated in the second stage (lowest unadjusted P value for overall late toxicity = 2.08 × 10 −4 , OR = 6.17, 95% CI = 2.25–16.95; P combined = 4.16 × 10 −10 ). The inclusion of the third cohort gave unadjusted P combined = 4.64 × 10 −11 . These results, together with the role of TANC1 in regenerating damaged muscle, suggest that the TANC1 locus influences the development of late radiation-induced damage.

PurposeA 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 methodsThe 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.ResultsWe 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).ConclusionThis 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.

'Radiogenomics' is the study of genetic variation associated with response to radiotherapy. Radiogenomics aims to uncover the genes and biologic pathways responsible for radiotherapy toxicity that could be targeted with radioprotective agents and; identify genetic markers that can be used in risk prediction models in the clinic. The long-term goal of the field is to develop single nucleotide polymorphism-based risk models that can be used to stratify patients to more precisely tailored radiotherapy protocols. The field has evolved over the last two decades in parallel with advances in genomics, moving from narrowly focused candidate gene studies to large, collaborative genome-wide association studies. Several confirmed genetic variants have been identified and the field is making progress toward clinical translation.

In many organisms early development is under control of the maternal genome and zygotic gene expression is delayed until the mid-blastula transition (MBT). As zygotic transcription initiates, cell cycle checkpoints become activated and the tempo of cell division slows. The mechanisms that activate zygotic transcription at the MBT are incompletely understood, but they are of interest because they may resemble mechanisms that cause stem cells to stop dividing and terminally differentiate. The unstable regulatory protein Geminin is thought to coordinate cell division with cell differentiation. Geminin is a bi-functional protein. It prevents a second round of DNA replication during S and G2 phase by binding and inhibiting the essential replication factor Cdt1. Geminin also binds and inhibits a number of transcription factors and chromatin remodeling proteins and is thought to keep dividing cells in an undifferentiated state. We previously found that the cells of Geminin-deficient Xenopus embryos arrest in G2 phase just after the MBT then disintegrate at the onset of gastrulation. Here we report that they also fail to express most zygotic genes. The gene expression defect is cell-autonomous and is reproduced by over-expressing Cdt1 or by incubating the embryos in hydroxyurea. Geminin deficient and hydroxyurea-treated blastomeres accumulate DNA damage in the form of double stranded breaks. Bypassing the Chk1 pathway overcomes the cell cycle arrest caused by Geminin depletion but does not restore zygotic gene expression. In fact, bypassing the Chk1 pathway by itself induces double stranded breaks and abolishes zygotic transcription. We did not find evidence that Geminin has a replication-independent effect on transcription. We conclude that Geminin is required to maintain genome integrity during the rapid cleavage divisions, and that DNA damage disrupts zygotic gene transcription at the MBT, probably through activation of DNA damage checkpoint pathways.

We observed a number of patients who developed Lhermitte's sign (LS) following radiation to the head and neck (H/N), since instituting volumetric modulated arc therapy (VMAT). We aimed to investigate the incidence of LS following VMAT-based RT without chemotherapy, and determine the dosimetric parameters that predict its development. We explored whether the role of inhomogeneous dose distribution across the spinal cord, causing a \"bath-and-shower\" effect, explains this finding. From 1/20/2010-12/9/2013, we identified 33 consecutive patients receiving adjuvant RT using VMAT to the H/N without chemotherapy at our institution. Patients' treatment plans were analyzed for dosimetric parameters, including dose gradients along the anterior, posterior, right, and left quadrants at each cervical spine level. Institutional Review Board approval was obtained. 5 out of 33 (15.2%) patients developed LS in our patient group, all of whom had RT to the ipsilateral neck only. LS patients had a steeper dose gradient between left and right quadrants across all cervical spine levels (repeated-measures ANOVA, p = 0.030). Within the unilateral treatment group, LS patients received a higher mean dose across all seven cervical spinal levels (repeated-measures ANOVA, p = 0.046). Dose gradients in the anterior-posterior direction and mean doses to the cord were not significant between LS and non-LS patients. Dose gradients along the axial plane of the spinal cord may contribute to LS development; however, a threshold dose within the high dose region of the cord may still be required. This is the first clinical study to suggest that inhomogeneous dose distributions in the cord may be relevant in humans. Further investigation is warranted to determine treatment-planning parameters associated with development of LS.

Background Little is known about the effects of chemotherapeutic drugs on DNA methylation status of leukocytes, which may be predictive of treatment benefits and toxicities. Based on a prospective national study, we characterize the changes in leukocyte DNA methylome from pre- to post-chemotherapy (approximately 4 months apart) in 93 patients treated for early stage breast cancer and 48 matched non-cancer controls. We further examined significant methylation changes with perceived cognitive impairment, a clinically significant problem related to cancer and chemotherapy. Results Approximately 4.2% of the CpG sites measured using the Illumina 450K methylation array underwent significant changes after chemotherapy ( p  < 1e-7), in comparison to a stable DNA methylome in controls. Post-chemotherapy, the estimated relative proportions of B cells and CD4 + T cells were decreased by a median of 100% and 39%, respectively, whereas the proportion of monocytes was increased by a median of 91%. After controlling for leukocyte composition, 568 CpGs from 460 genes were still significantly altered following chemotherapy. With additional adjustment for chemotherapy regimen, cumulative infusions, growth factors, and steroids, changes in four CpGs remained significant, including cg16936953 in VMP1 / MIR21 , cg01252023 in CORO1B , cg11859398 in SDK1 , and cg19956914 in SUMF2 . The most significant CpG, cg16936953, was also associated with cognitive decline in breast cancer patients. Conclusions Chemotherapy profoundly alters the composition and DNA methylation landscape of leukocytes in breast cancer patients. Our results shed light on the epigenetic response of circulating immune cell populations to cytotoxic chemotherapeutic drugs and provide possible epigenetic links to the degeneration of cognitive function associated with chemotherapy.

Cancer-related fatigue (CRF) is a common side effect of adjuvant therapy and becomes a chronic problem for approximately one-third of survivors. Omega-3 polyunsaturated fatty acids (O3-PUFA) demonstrated preliminary antifatigue effects in previous research, but have not been investigated in fatigued cancer survivors. Breast cancer survivors 4-36 months posttreatment with a CRF score of 4 or more of 10 using the symptom inventory (SI) were randomly assigned to O3-PUFA (fish oil, 6 g/d), omega-6 PUFA (O6-PUFA; soybean oil, 6 g/d), or a low-dose combination of O3-/O6-PUFA (3 g/d O3-PUFA and O6-PUFA) for 6 weeks. CRF was assessed by the SI (screening question), the Brief Fatigue Inventory, and the Multidimensional Fatigue Symptom Index. Protein and mRNA levels of inflammatory and antioxidant biomarkers, along with fatty acid and lipid levels, were assessed at baseline and week 6. Statistical tests were two-sided. A total of 108 breast cancer survivors consented; 97 subjects were randomly assigned and 81 completed the trial. The SI CRF score decreased by 2.51 points at week 6 with O6-PUFA and by 0.93 points with O3-PUFA, with statistically significant between-group difference (effect size = -0.86,  < .01). Similar changes were observed for the Brief Fatigue Inventory and Multidimensional Fatigue Symptom Index but were not statistically significant. Stratified analyses showed the largest benefit was observed in those with severe baseline CRF (≥7). Compared with O3-PUFA, O6-PUFA supplementation statistically significantly decreased proinflammatory markers in the TNF-α signaling pathway. Contrary to our original hypothesis, O6-PUFA statistically significantly reduced CRF compared with O3-PUFA. Further research is needed to confirm these findings and to elucidate mechanisms of action.

Abstract Background Few data exist on the relationship of cisplatin-related adverse health outcomes (AHOs) with disability, unemployment, and self-reported health (SRH) among testicular cancer survivors (TCS). Methods A total of 1815 TCS at least 1 year postchemotherapy underwent clinical examination and completed questionnaires. Treatment data were abstracted from medical records. A cumulative burden of morbidity score (CBMPt) encompassed the number and severity of platinum-related AHOs (peripheral sensory neuropathy [PSN], hearing loss, tinnitus, renal disease). Multivariable regression assessed the association of AHOs and CBMPt with employment status and SRH, adjusting for sociodemographic and clinical characteristics. Unemployment was compared with a male normative population of similar age, race, and ethnicity. Results Almost 1 in 10 TCS was out of work (2.4%, disability leave; 6.8%, unemployed) at a median age of 37 years (median follow-up = 4 years). PSN (odds ratio [OR] = 2.89, 95% confidence interval [CI] = 1.01 to 8.26, grade 3 vs 0, P = .048), renal dysfunction defined by estimated glomerular filtration rate (OR = 12.1, 95% CI = 2.06 to 70.8, grade 2 vs 0, P = .01), pain (OR = 10.6, 95% CI = 4.40 to 25.40, grade 2 or 3 vs 0, P < .001), and CBMPt (OR = 1.46, 95% CI = 1.03 to 2.08, P = .03) were associated with disability leave; pain strongly correlated with PSN (r2 = 0.40, P < .001). Statistically significantly higher percentages of TCS were unemployed vs population norms (age-adjusted OR = 2.67, 95% CI = 2.49 to 3.02, P < .001). PSN (OR = 2.44, 95% CI = 1.28 to 4.62, grade 3 vs 0, P = .006), patient-reported hearing loss (OR = 1.82, 95% CI = 1.04 to 3.17, grade 2 or 3 vs 0, P = .04), and pain (OR = 3.75, 95% CI = 2.06 to 6.81, grade 2 or 3 vs 0, P < .001) were associated with unemployment. Increasing severity of most cisplatin-related AHOs and pain were associated with statistically significantly worse SRH. Conclusions Our findings have important implications regarding treatment-associated productivity losses and socioeconomic costs in this young population. Survivorship care strategies should include inquiries about disability and unemployment status, with efforts made to assist affected TCS in returning to the workforce.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84–5.29) for men of European ancestry to 3.74 (95% CI, 3.36–4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14–2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71–0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry ( P  = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups. A multi-ancestry genome-wide association study of prostate cancer performed in 156,319 cases and 788,443 controls identifies 187 novel risk variants associated with the disease. Genetic risk scores associated with overall risk, and risk of aggressive disease in men of African ancestry.