Browsing by Author "Morton, Lindsay M."

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    Clinical and Genetic Risk Factors for Radiation-Associated Ototoxicity: A Report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort
    (Wiley, 2021) Trendowski, Matthew R.; Baedke, Jessica L.; Sapkota, Yadav; Travis, Lois B.; Zhang, Xindi; El Charif, Omar; Wheeler, Heather E.; Leisenring, Wendy M.; Robison, Leslie L.; Hudson, Melissa M.; Morton, Lindsay M.; Oeffinger, Kevin C.; Howell, Rebecca M.; Armstrong, Gregory T.; Bhatia, Smita; Dolan, M. Eileen; Epidemiology, School of Public Health
    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.
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    Common genetic polymorphisms contribute to the association between chronic lymphocytic leukaemia and non-melanoma skin cancer
    (Oxford University Press, 2021-08-30) Besson, Caroline; Moore, Amy; Wu, Wenting; Vajdic, Claire M.; de Sanjose, Silvia; Camp, Nicola J.; Smedby, Karin E.; Shanafelt, Tait D.; Morton, Lindsay M.; Brewer, Jerry D.; Zablotska, Lydia; Engels, Eric A.; Cerhan, James R.; Slager, Susan L.; Han, Jiali; Berndt, Sonja I.; Medical and Molecular Genetics, School of Medicine
    Background: Epidemiological studies have demonstrated a positive association between chronic lymphocytic leukaemia (CLL) and non-melanoma skin cancer (NMSC). We hypothesized that shared genetic risk factors between CLL and NMSC could contribute to the association observed between these diseases. Methods: We examined the association between (i) established NMSC susceptibility loci and CLL risk in a meta-analysis including 3100 CLL cases and 7667 controls and (ii) established CLL loci and NMSC risk in a study of 4242 basal cell carcinoma (BCC) cases, 825 squamous cell carcinoma (SCC) cases and 12802 controls. Polygenic risk scores (PRS) for CLL, BCC and SCC were constructed using established loci. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Higher CLL-PRS was associated with increased BCC risk (OR4th-quartile-vs-1st-quartile = 1.13, 95% CI: 1.02-1.24, Ptrend = 0.009), even after removing the shared 6p25.3 locus. No association was observed with BCC-PRS and CLL risk (Ptrend = 0.68). These findings support a contributory role for CLL in BCC risk, but not for BCC in CLL risk. Increased CLL risk was observed with higher SCC-PRS (OR4th-quartile-vs-1st-quartile = 1.22, 95% CI: 1.08-1.38, Ptrend = 1.36 × 10-5), which was driven by shared genetic susceptibility at the 6p25.3 locus. Conclusion: These findings highlight the role of pleiotropy regarding the pathogenesis of CLL and NMSC and shows that a single pleiotropic locus, 6p25.3, drives the observed association between genetic susceptibility to SCC and increased CLL risk. The study also provides evidence that genetic susceptibility for CLL increases BCC risk.