Role of Cisplatin Dose Intensity and TPMT Variation in the Development of Hearing Loss in Children.

BACKGROUND: Cisplatin, widely used in the treatment of solid tumors, causes permanent hearing loss in more than 60% of treated children. Previous studies have implicated several clinical factors in the development of ototoxicity, including cumulative cisplatin dose. However, the role of cisplatin dose intensity in the development of hearing loss in children remains unclear. Pharmacogenetic studies have also identified genetic variants in TPMT that increase the risk of cisplatin-induced hearing loss. This study aims to determine whether cisplatin dose intensity contributes to the risk of hearing loss in children and whether genetic variations in TPMT further modifies the risk of cisplatin-induced hearing loss. METHODS: The authors genotyped 371 cisplatin-treated children for the presence of any 3 TPMT -risk variants. Patients were categorized into high-, moderate-, and low-intensity cisplatin dosing groups according to the cisplatin dose administered per unit time. Kaplan-Meier curves were plotted to compare the cumulative incidence of hearing loss between the genotype and dose intensity groups. RESULTS: Patients receiving cisplatin at high dose intensity experienced significantly higher incidences of ototoxicity than those receiving cisplatin at low dose intensity ( P = 9 × 10 -7 ). Further stratification by TPMT genotype revealed that carriers of ≥1 TPMT variants receiving high-intensity cisplatin developed ototoxicity sooner and more often than their wild-type counterparts (93.8% vs. 56.6% at 12 months; P = 5 × 10 -5 ) and noncarriers receiving low-intensity cisplatin (21.2% at 12 months). CONCLUSIONS: Cisplatin dose intensity is strongly associated with ototoxicity development in children, and this risk is further increased by the presence of TPMT -risk alleles.

Development of a Dose-Adjusted Polygenic Risk Model for Anthracycline-Induced Cardiotoxicity.

BACKGROUND: Anthracyclines, which are effective chemotherapeutic agents, cause cardiac dysfunction in up to 57% of patients. The cumulative anthracycline dose is a crucial predictor of cardiotoxicity; however, the cumulative dose alone cannot explain all cardiotoxic events. Strongly associated genetic variants in SLC28A3 , UGT1A6 , and RARG contribute to anthracycline-induced cardiotoxicity in pediatric patients and may help identify those most susceptible. This study aimed to examine how these pharmacogenetic effects are modulated by cumulative anthracycline doses in the development of cardiotoxicity. METHODS: A total of 595 anthracycline-treated children were genotyped and cardiotoxicity cases were identified. A dose-stratified analysis was performed to compare the contributions of SLC28A3 rs7853758, UGT1A6 rs17863783, and RARG rs2229774 variants to the development of cardiotoxicity in low-dose (<150 mg/m 2 cumulative dose) and high-dose (>250 mg/m 2 cumulative dose) patient groups. Logistic regression was used to model the relationships between the cumulative anthracycline dose, genetic variants, and cardiotoxicity in the full cohort. RESULTS: At < 150 mg/m 2 cumulative anthracycline dose, the SLC28A3 protective variant did not reach statistical significance [odds ratio (OR) 0.46 (95% confidence interval (CI) 0.10-1.45), P = 0.23], but it was statistically significant at doses >250 mg/m 2 [OR 0.43 (95% CI 0.22-0.78), P = 0.0093]. Conversely, the UGT1A6 and RARG risk variants were either statistically significant or approaching significance at doses <150 mg/m 2 [OR 7.18 (95% CI 1.78-28.4), P = 0.0045 for UGT1A6 and OR 2.76 (95% CI 0.89-7.63), P = 0.057 for RARG ], but not at doses >250 mg/m 2 [OR 2.91 (95% CI 0.80-11.0), P = 0.10; OR 1.56 (95% CI 0.89-2.75), P = 0.12]. CONCLUSIONS: These findings suggest that the SLC28A3 variant imparts more significant protection for patients receiving higher anthracycline doses, whereas the UGT1A6 and RARG risk variants significantly increased the risk of cardiotoxicity at low anthracycline doses.

A Systematic Review of Polygenic Models for Predicting Drug Outcomes.

Polygenic models have emerged as promising prediction tools for the prediction of complex traits. Currently, the majority of polygenic models are developed in the context of predicting disease risk, but polygenic models may also prove useful in predicting drug outcomes. This study sought to understand how polygenic models incorporating pharmacogenetic variants are being used in the prediction of drug outcomes. A systematic review was conducted with the aim of gaining insights into the methods used to construct polygenic models, as well as their performance in drug outcome prediction. The search uncovered 89 papers that incorporated pharmacogenetic variants in the development of polygenic models. It was found that the most common polygenic models were constructed for drug dosing predictions in anticoagulant therapies (n = 27). While nearly all studies found a significant association with their polygenic model and the investigated drug outcome (93.3%), less than half (47.2%) compared the performance of the polygenic model against clinical predictors, and even fewer (40.4%) sought to validate model predictions in an independent cohort. Additionally, the heterogeneity of reported performance measures makes the comparison of models across studies challenging. These findings highlight key considerations for future work in developing polygenic models in pharmacogenomic research.

Pan-cancer pervasive upregulation of 3' UTR splicing drives tumourigenesis.

Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3' UTR ends via alternative polyadenylation can activate oncogenes. However, internal 3' UTR splicing remains poorly understood as splicing studies have traditionally focused on protein-coding alterations. Here we systematically map the pan-cancer landscape of 3' UTR splicing and present this in SpUR ( http://www.cbrc.kaust.edu.sa/spur/home/ ). 3' UTR splicing is widespread, upregulated in cancers, correlated with poor prognosis and more prevalent in oncogenes. We show that antisense oligonucleotide-mediated inhibition of 3' UTR splicing efficiently reduces oncogene expression and impedes tumour progression. Notably, CTNNB1 3' UTR splicing is the most consistently dysregulated event across cancers. We validate its upregulation in hepatocellular carcinoma and colon adenocarcinoma, and show that the spliced 3' UTR variant is the predominant contributor to its oncogenic functions. Overall, our study highlights the importance of 3' UTR splicing in cancer and may launch new avenues for RNA-based anti-cancer therapeutics.

After genomic testing results: Parents' long-term views.

Many parents are motivated to pursue genome-wide (exome or genome) sequencing to find a diagnosis for their child with a suspected but undiagnosed genetic condition. However, the impact of the genomic test extends beyond the provision of results and the so-called 'diagnostic odyssey'. Our goal was to quantify post-test decisional regret and characterize long-term, post-test experiences and unmet needs of the parents of children with suspected genetic diseases after they had received the results of genome-wide sequencing. Study participants were parents of children who underwent trio genome-wide sequencing as part of the CAUSES research study at Children's & Women's Health Centre of British Columbia. About half of the participants received a definite or likely genetic diagnosis after clinical interpretation of the genome-wide sequencing results. Parents who participated in the current study (n = 121) completed the Decisional Regret Scale four weeks after receiving results. A subset of these parents (n = 32) had semi-structured interviews a median of 7 months (range 3-20 months) after results disclosure and post-test genetic counseling. Most parents expressed either no regret or mild regret about having undergone genome-wide sequencing on both the Decisional Regret Scale and in the interviews. Parents whose children did not receive a genetic diagnosis were slightly more likely to have decisional regret on this quantitative scale. Analysis of transcribed interviews revealed the following major themes: (a) a lack of decisional conflict around having the testing; (b) a lack of decisional regret post-testing; (c) expressions of both relief and continued uncertainty around the meaning of a genetic diagnosis; (d) expression of initial disappointment and evolving interpretation surrounding a result yielding no genetic diagnosis; and (e) needing time to absorb the test results. Our results suggest that parents need time to absorb the testing results and that long-term post-test counseling, including acknowledging feelings of relief, loss, and disappointment, may help parents adapt to the genomic test results and assist families to anticipate and plan for the next steps in their child's medical trajectory, whether or not a diagnosis is found.

Integration of genetic counsellors in genomic testing triage: Outcomes of a genomic consultation service in British Columbia, Canada.

PURPOSE: Clinical diagnostic genome-wide (exome or genome) sequencing (GWS) in British Columbia requires funding approval by a provincial agency on a case-by-case basis. The CAUSES Clinic was a pediatric translational trio-based GWS study at BC Children's and Women's Hospitals. Referrals to the CAUSES Clinic were made through a Genomic Consultation Service (GCS), a multidisciplinary team led by genetic counsellors that provided advice regarding genomic testing for physicians considering GWS for their patients. Here we review the outcomes of the GCS, focusing on patients not recommended for the CAUSES Study. METHODS: Demographic, clinical, and testing data were abstracted from patient charts. Logistic regression analysis was used to explore associations between demographic and clinical variables and two outcomes: the type of recommendation and referring physicians' decisions to follow the recommendation. RESULTS: Of 972 GCS referrals, 248 patients were not referred to the CAUSES Study. GWS (vs. a targeted test; e.g. multi-gene panel) was more likely to be recommended to physicians of patients with ID than physicians of patients without ID (OR = 2.98; 95% CI = 1.46 to 6.27; n = 149). In total, 40% of physicians who were recommended to pursue clinical genomic testing submitted an application for funding approval; 71% of applications were approved for funding. Among approved tests, 50% resulted in a diagnosis, including 33% of targeted tests and 82% of GWS tests (χ2 (1) = 5.0, p = 0.026). CONCLUSION: The GCS provided an effective model in which physicians can interface with genetic specialists, including genetic counsellors, to facilitate appropriate genomic test selection.

A novel SOCS5/miR-18/miR-25 axis promotes tumorigenesis in liver cancer.

The role of miRNAs with tumor suppressive activity in liver cancer has been well studied. However, little is known about potential oncomiRs in HCC. In our study, we conducted a systematic evaluation of candidate oncomiRs and found that upregulation of miR-18a and miR-25 in HCC was associated with poor patient survival and promoted proliferation in HCC cell lines. These two miRNAs belong to the polycistronic paralogous miR-17-92 and miR-25-106b clusters respectively. Although the members of both clusters are often upregulated in HCC, the contribution of individual miRNAs in these clusters to HCC tumorigenesis is not fully understood. We validated SOCS5 as a bona fide target of both miRNAs, and established, for the first time, the tumor suppressive role of SOCS5 in liver cancer. We further investigated the mechanism by which SOCS5 contributes to tumorigenesis, demonstrated that this SOCS5/miR-18a/miR-25 axis regulates the tumor suppressor TSC1 and downstream mTOR signaling, and highlighted the potential therapeutic use of miR-18a and miR-25 inhibition in restoring SOCS5 levels in HCC.