BACKGROUND Cranial radiation therapy (CRT) is associated with ototoxicity, which manifests as hearing loss and tinnitus. The authors sought to identify clinical determinants and genetic risk factors for ototoxicity among adult survivors of pediatric cancer treated with CRT. METHODS Logistic regression evaluated associations of tinnitus (n = 1991) and hearing loss (n = 2198) with nongenetic risk factors and comorbidities among CRT‐treated survivors in the Childhood Cancer Survivor Study. Genome‐wide association studies (GWASs) of CRT‐related tinnitus and hearing loss were also performed. RESULTS Males were more likely to report CRT‐related tinnitus (9.4% vs 5.4%; P = 5.1 × 10−4) and hearing loss (14.0% vs 10.7%; P = .02) than females. Survivors with tinnitus or hearing loss were more likely to experience persistent dizziness or vertigo (tinnitus: P < 2 × 10−16; hearing loss: P = 6.4 × 10−9), take antidepressants (tinnitus: P = .02; hearing loss: P = .01), and report poorer overall health (tinnitus: P = 1.5 × 10−6; hearing loss: P = 1.7 × 10−6) in comparison with controls. GWAS of CRT‐related tinnitus revealed a genome‐wide significant signal in chromosome 1 led by rs203248 (P = 1.5 × 10−9), whereas GWAS of CRT‐related hearing loss identified rs332013 (P = 5.8 × 10−7) in chromosome 8 and rs67522722 (P = 7.8 × 10−7) in chromosome 6 as nearly genome‐wide significant. A replication analysis identified rs67522722, intronic to ATXN1, as being significantly associated with CRT‐related hearing loss (P = .03) and de novo hearing loss (P = 3.6 × 10−4). CONCLUSIONS CRT‐associated ototoxicity was associated with sex, several neuro‐otological symptoms, increased antidepressant use, and poorer self‐reported health. GWAS of CRT‐related hearing loss identified rs67522722, which was supported in an independent cohort of survivors. LAY SUMMARY Hearing loss and subjective tinnitus (the perception of noise or ringing in the ear) are long‐term side effects of cancer treatment and are common in children treated with radiation to the brain. These toxicities can affect childhood development and potentially contribute to serious learning and behavioral difficulties. This study's data indicate that males are at greater risk for hearing loss and tinnitus than females after radiation therapy to the brain. Those who develop these toxicities are more likely to use antidepressants and report poorer overall health. Health care providers can improve the management of survivors by informing patients and/or their parents of these risks.
Numerous common genetic variants have been linked to breast cancer (BCa) risk, but they only partially explain the total BCa heritability. Inference from Nordic population-based twin data indicates rare high-risk loci as the chief determinant of BCa risk. Here, we use haplotypes, rather than single variants, to identify rare high-risk loci for BCa. With computationally-phased genotypes from 181,034 white British women in the UK Biobank, a genome-wide haplotype-BCa association analysis was conducted using sliding windows of 5-500 consecutive array-genotyped variants. In the discovery stage, haplotype-BCa associations were evaluated retrospectively in the pre-study-enrollment data including 5,487 BCa cases. BCa hazard ratios (HRs) for additive haplotypic effects were estimated using Cox regression. The replication analysis included a prospective cohort of women free of BCa at enrollment, of whom 3,524 later developed BCa. This two-stage analysis detected 13 rare loci (frequency <1%), each associated with an appreciable BCa-risk increase (discovery: HRs=2.84-6.10, P-value<5x10-8; replication: HRs=2.08-5.61, P-value<0.01). In contrast, the variants that formed these rare haplotypes individually exhibited much smaller effects. Functional annotation revealed extensive cis-regulatory DNA elements in BCa-related cells underlying the replicated rare haplotypes. Using phased, imputed genotypes from 30,064 cases and 25,282 controls in the DRIVE OncoArray case-control study, six of the 13 rare-loci associations were found generalizable (odds ratio estimates: 1.48-7.67, P-value<0.05). This study demonstrates the complementary advantage of utilizing rare haplotypes to capture novel risk loci and suggests the potential for the discovery of more genetic elements contributing to cancer heritability as large datasets of germline whole-genome sequencing become available.
Exposure to high doses of alkylating agents is associated with increased risk of impaired spermatogenesis among nonirradiated male survivors of childhood cancer, but there is substantial variation in this risk. Here we conducted a genetic study for impaired spermatogenesis utilizing whole-genome sequencing data from 167 nonirradiated male childhood cancer survivors of European ancestry from the St. Jude Lifetime Cohort treated with cyclophosphamide equivalent dose (CED) ≥4,000 mg/m 2 . Sperm concentration from semen analysis was assessed as the primary outcome. Common variants (MAF > 0.05) were adjusted for age at cancer diagnosis, CED, and top principal components. Rare/low-frequency variants (MAF ≤ 0.05) were evaluated jointly by various functional annotations and 4-kb sliding windows. A novel locus at 7q21.3 containing TAC1/ASNS was associated with decreased sperm concentration (rs7784118: P ¼ 3.5 Â 10 À8 ). This association was replicated in two independent samples of SJLIFE survivors of European ancestry, including 34 nonirradiated male survivors treated with 0 < CED < 4,000 mg/m 2 (P ¼ 3.1 Â 10 À4 ) and 24 male survivors treated with CED ≥4,000 mg/m 2 and radiotherapy <40 Gray (P ¼ 0.012). No association was observed among survivors not exposed to alkylating agents included in the CED (P > 0.29). rs7784118 conferred 3.48-and 9.73-fold increases in risk for clinically defined oligospermia and azoospermia and improved prediction of normospermic, oligospermic, and azoospermic states by 13.7%, 5.3%, and 21.7%. rs7784118 was associated with decreased testosterone level, increased levels of follicle stimulating and luteinizing hormones, and 8.52-fold increased risk of Leydig cell failure. Additional research is warranted to determine how this SNP influences spermatogenesis and to assess its clinical utility in characterizing high-risk survivors and guiding intervention strategies. Significance:The identified genetic markers harbor potential clinical utility in characterizing high-risk survivors and guiding intervention strategies including pretreatment patient counseling and use of fertility preservation services.
PURPOSE To characterize germline genetic risk factors of diabetes mellitus among long-term survivors of childhood cancer. METHODS Adult survivors of childhood cancer from the Childhood Cancer Survivor Study (CCSS) Original Cohort (n = 5,083; 383 with diabetes) were used to conduct a discovery genome-wide association study. Replication was performed using the CCSS Expansion (n = 2,588; 40 with diabetes) and the St Jude Lifetime (SJLIFE; n = 3,351; 208 with diabetes) cohorts. Risk prediction models, stratified on exposure to abdominal radiation, were calculated using logistic regression including attained age, sex and body mass index, diagnosis, alkylating chemotherapy, age at cancer diagnosis, and a polygenic risk score (PRS) on the basis of 395 diabetes variants from the general population. Area under the receiver operating characteristic curve (AUC) was calculated for models on the basis of traditional risk factors, clinical risk factors, and PRS. RESULTS There was a genome-wide significant association of rs55849673-A with diabetes among survivors (odds ratio, 2.9; 95% CI, 2.0 to 4.2; P = 3.7 × 10−8), which is related to expression of ERCC6L2 in the Genotype-Tissue Expression project. The association of rs55849673-A was observed largely among survivors not exposed to abdominal radiation (odds ratio = 3.5, P = 1.1 × 10−7) and the frequency of rs55849673-A was consistently higher among diabetic survivors in the CCSS Expansion and SJLIFE cohorts. Risk prediction models including traditional diabetes risk factors, clinical risk factors and PRS had an optimism-corrected AUC of 0.801, with an AUC of 0.751 in survivors treated with abdominal radiation versus 0.813 in survivors who did not receive abdominal radiation. CONCLUSION There is evidence for a novel locus of diabetes among survivors not exposed to abdominal radiation. Further refinement and validation of clinic-based risk prediction models for diabetes among long-term survivors of childhood cancer is warranted.
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