Generalizability of "GWAS Hits" in Clinical Populations: Lessons from Childhood Cancer Survivors.
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ABSTRACT:
SUBMITTER: Im C
PROVIDER: S-EPMC7536574 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Genome-wide association studies (GWAS) in populations of European ancestry have identified several loci that confer an increased risk of colorectal cancer (CRC).We studied the generalizability of the associations with 11 risk variants for CRC on 8q23 (rs16892766), 8q24 (rs6983267), 9p24 (rs719725), 10p14 (rs10795668), 11q23 (rs3802842), 14q22 (rs4444235), 15q13 (rs4779584), 16q22 (rs9929218), 18q21 (rs4939827), 19q13 (rs10411210), and 20p12 (rs961253) in a multiethnic sample of 2,472 CRC cases, 839 adenoma cases and 4,466 controls comprised of European American, African American, Native Hawaiian, Japanese American, and Latino men and women. Because findings for CRC and adenoma were similar, we combined both groups in the analyses.We confirmed the associations with an increased risk of CRC/adenoma for the 8q24, 11q23 and 15q13 loci in European Americans, and observed significant associations between the 8q24 and 20p12 loci with CRC/adenoma risk in African Americans. Moreover, we found statistically significant cumulative effects of risk alleles on CRC/adenoma risk in all populations (odds ratio [OR] per allele = 1.07-1.09, P ? 0.039) except in Japanese Americans (OR = 1.01, P = 0.52). We found heterogeneity in the associations by tumor subsite, age of CRC/adenoma onset, sex, body mass index (BMI), and smoking status for some of the variants.These results provide evidence that the known variants are in aggregate significantly associated with CRC/adenoma risk in multiple populations except Japanese Americans, and the influences may differ across groups defined by clinicopathological characteristics for some variants.These results underline the importance of studying the epidemiologic architecture of these genetic effects in large and diverse populations.
| S-EPMC3081784 | biostudies-literature
Project description:PurposeGenome-wide association studies (GWAS) have identified dozens of single-nucleotide polymorphisms (SNPs) associated with breast cancer. Few studies focused on young-onset breast cancer, which exhibits etiologic and tumor-type differences from older-onset disease. Possible confounding by prenatal effects of the maternal genome has also not been considered.MethodsUsing a family-based design for breast cancer before age 50, we assessed the relationship between breast cancer and 77 GWAS-identified breast cancer risk SNPs. We estimated relative risks (RR) for inherited and maternally mediated genetic effects. We also used published RR estimates to calculate genetic risk scores and model joint effects.ResultsSeventeen of the candidate SNPs were nominally associated with young-onset breast cancer in our 1296 non-Hispanic white affected families (uncorrected p value <0.05). Top-ranked SNPs included rs3803662-A (TOX3, RR = 1.39; p = 7.0 × 10-6), rs12662670-G (ESR1, RR = 1.56; p = 5.7 × 10-4), rs2981579-A (FGFR2, RR = 1.24; p = 0.002), and rs999737-G (RAD51B, RR = 1.37; p = 0.003). No maternally mediated effects were found. A risk score based on all 77 SNPs indicated that their overall relationship to young-onset breast cancer risk was more than additive (additive-fit p = 2.2 × 10-7) and consistent with a multiplicative joint effect (multiplicative-fit p = 0.27). With the multiplicative formulation, the case sister's genetic risk score exceeded that of her unaffected sister in 59% of families.ConclusionsThe results of this family-based study indicate that no effects of previously identified risk SNPs were explained by prenatal effects of maternal variants. Many of the known breast cancer risk variants were associated with young-onset breast cancer, with evidence that TOX3, ESR1, FGFR2, and RAD51B are important for young-onset disease.
| S-EPMC5226879 | biostudies-literature
Project description:It is not known to what extent prevalence estimates of late effects among childhood cancer survivors derived from clinic based samples represent the actual estimates that would be derived if the entire population of childhood cancer survivors was recruited and evaluated for a particular outcome.In a large retrospective cohort study of childhood cancer survivors, the Childhood Cancer Survivor Study (CCSS), the prevalence of chronic health conditions among participants who reported being seen in a cancer center or long-term follow-up clinic was compared to the prevalence of chronic conditions in the entire cohort.When compared to survivors who had no medical care in the previous 2 years, survivors accessing medical follow-up were significantly more likely to have chronic health conditions. Relative risks of reporting a chronic health condition were 1.4 (95% CI: 1.3-1.5) if seen in a cancer center or long-term follow-up clinic and 1.2 (95% CI: 1.1-1.3) if seen in a general medical care setting. Estimates derived from only those childhood cancer survivors who were seen in a cancer center or long-term follow-up clinic overestimate the prevalence of any chronic disease by 9.3% (95% CI: 7.0-11.6).Applying chronic condition prevalence estimates from a clinical population to the general population of childhood cancer survivors must be undertaken with caution. Survivorship research must maintain a high level of scientific rigor to ensure that results reported in the literature are interpreted within the appropriate context.
| S-EPMC2628420 | biostudies-literature
Project description:PurposeAlthough studies regarding dental developmental disturbances after childhood cancer treatment have increased, they have many limitations. Studies analyzing the significance of independent clinical risk factors with regard to the dental health status are also rare. We aimed to investigate the risk factors for dental developmental disturbances, particularly severe disturbances, in childhood cancer survivors (CCS).Materials and methodsOral examinations and retrospective reviews of medical and panoramic radiographs were performed for 196 CCS (mean age, 15.6 years). Cancer type, age at diagnosis, treatment modality, type and accumulated dose of administered drugs, and dose and site of radiation were recorded. Dental developmental disturbances were diagnosed using panoramic radiographs and graded for severity according to the Modified Dental Defect Index (MDDI). Descriptive statistics and multivariate analyseswere performed to determine the association between dental abnormalities and clinical factors.ResultsIn total, 109 CCS (55.6%) exhibited at least one dental anomaly, and the median value of MDDI was 2.5. Microdontia (30.6%) was the most prevalent anomaly, followed by tooth agenesis (20.4%), V-shaped roots (14.8%), and taurodontism (10.2%). Multivariate analysis revealed that a young age at diagnosis (≤ 3 years), a history of hematopoietic stem cell transplantation, the use of multiple classes of chemotherapeutic agents (≥ 4 classes), and the use of heavy metal agents were significant risk factors for severe dental disturbances.ConclusionCCS with any of the above risk factors for severe developmental disturbances should be comprehensively followed up to minimize adverse consequences to their dental development and preserve their future dental health.
| S-EPMC6056986 | biostudies-literature
Project description:PurposeThe COVID pandemic has greatly impacted cancer care, with survivorship care being accorded low priority. We aimed to assess the impact of the COVID pandemic on survivorship services at our centre, as well as on survivors of childhood cancer (CCS).MethodsWe analyzed the trends in survivorship care at our centre from March 2020 to June 2021 compared to previous years. We also conducted an online survey of adolescent and young adult (AYA-CCS) following up at the After Completion of Treatment Clinic, Mumbai, to assess the impact of the COVID pandemic and ensuing restrictions on our cohort of survivors. Sibling responses were used as comparator (CTRI/2020/11/029029).ResultsThere was a decrease in in-person follow-ups and increase in remote follow-ups over the first few months of the pandemic. While in-person visits steadily increased after October 2020 and reached pre-pandemic numbers, distant follow-ups continue to be higher than pre-pandemic. Evaluable responses from the survey of 88 AYA-CCS and 25 siblings revealed new-onset health concerns in 29.5% of AYA-CCS, missed follow-up visit in 52% and varying degrees of mental health issues in 12.5%. While most survivors were able to cope with the stresses of the pandemic, 20% of siblings reported being unable to cope.ConclusionsSurvivorship services continue to be affected well into the pandemic, with increased use of distant follow-ups. While AYA-CCS experienced significant physical, mental health issues and psychosocial concerns as a result of the COVID pandemic, they coped better than siblings during this stressful time, possibly due to multiple, holistic support systems including family, peer support groups and healthcare team.
| S-EPMC8727237 | biostudies-literature
Project description:We conducted a three-armed trial to assess Cascade, a four-module group videoconferencing cognitive behavior therapy (CBT) intervention for parents of childhood cancer survivors currently aged <18 years. We allocated parents to Cascade, an attention control (peer-support group), or a waitlist. The primary outcome was parents' health-related quality of life (PedsQL-Family Impact/EQ-5D-5L) six months post-intervention. Parents also reported their anxiety/depression, parenting self-agency, fear of recurrence, health service and psychotropic medication use, engagement in productive activities, confidence to use, and actual use of, CBT skills, and their child's quality of life. Seventy-six parents opted in; 56 commenced the trial. Cascade achieved good parent engagement and most Cascade parents were satisfied and reported benefits. Some parents expressed concerns about the time burden and the group format. Most outcomes did not differ across trial arms. Cascade parents felt more confident to use more CBT skills than peer-support and waitlisted parents, but this did not lead to more use of CBT. Cascade parents reported lower psychosocial health scores for their child than waitlisted parents. Cascade parents' health service use, psychotropic medication use, and days engaged in productive activities did not improve, despite some improvements in waitlisted parents. Our trial was difficult to implement, but participants were largely satisfied. Cascade did not improve most outcomes, possibly because many parents were functioning well pre-enrolment. We used these findings to improve Cascade and will trial the new version in future.
| S-EPMC8615912 | biostudies-literature
Project description:Leveraging population-distinct linkage equilibrium (LD) patterns, trans-ethnic follow-up of variants discovered from genome-wide association studies (GWAS) has proved to be useful in facilitating the identification of bona fide causal variants. We previously developed the preferential LD approach, a novel method that successfully identified causal variants driving the GWAS signals within European-descent populations even when the causal variants were only weakly linked with the GWAS-discovered variants. To evaluate the performance of our approach in a trans-ethnic setting, we applied it to follow up breast cancer GWAS hits identified mostly from populations of European ancestry in African Americans (AA). We evaluated 74 breast cancer GWAS variants in 8,315 AA women from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. Only 27% of them were associated with breast cancer risk at significance level α=0.05, suggesting race-specificity of the identified breast cancer risk loci. We followed up on those replicated GWAS hits in the AMBER consortium utilizing the preferential LD approach, to search for causal variants or better breast cancer markers from the 1000 Genomes variant catalog. Our approach identified stronger breast cancer markers for 80% of the GWAS hits with at least nominal breast cancer association, and in 81% of these cases, the marker identified was among the top 10 of all 1000 Genomes variants in the corresponding locus. The results support trans-ethnic application of the preferential LD approach in search for candidate causal variants, and may have implications for future genetic research of breast cancer in AA women.
| S-EPMC5341253 | biostudies-literature
Project description:PurposeThis cross-sectional study compared breastfeeding outcomes among childhood cancer survivors to those of women in the general population and evaluated whether breastfeeding is adversely affected by cancer treatment or endocrine-related late effects.MethodsA self-reported survey ascertained breastfeeding practices and incorporated items from the questionnaires used in the Infant Feeding Practices Study II (IFPS II) to allow comparison with the general population. Among 710 eligible survivors, 472 (66%) responded. The participants were predominantly non-Hispanic White (84%), married (73%), and had some college or less (60%). The mean maternal age at the time of birth of the first child after cancer treatment was 24 years (SD 24.3 ± 4.8).ResultsFewer survivors planned to breastfeed than did IFPS II controls (67% vs. 82%, P < .0001), and fewer survivors initiated breastfeeding (66% vs. 85%, P < .0001). The median breastfeeding duration was shorter among survivors, with early undesired weaning occurring sooner in the survivor group (1.4 months, interquartile range (IQR) 0.5-3.5 months) than in the IFPS II group (2.7 months, IQR 0.9-5.4 months). A higher proportion of survivors reported an unfavorable breastfeeding experience (19% vs. 7.5%, P < .0001) and early, undesired weaning (57.5%, 95% CI 51-64) than did IFPS II participants (45.2%, 95% CI 44-47, P = .0164). Among survivors who expressed intention and chose to breastfeed, 46% endorsed disrupted lactation related to physiologic problems with high risk in those overweight/obese.ConclusionsSurvivors are at risk of negative breastfeeding experiences; however, lactation outcomes were not significantly associated with cancer diagnosis, treatments, or endocrine complications.Implications for cancer survivorsPrior research has not examined the association of cancer treatments and clinically validated late effects with lactation outcomes in a clinically diverse childhood cancer survivor cohort. Findings from this study suggest that childhood cancer survivors, especially those who are overweight/obese, are at risk of having negative breastfeeding experiences. Early undesired weaning, physiologic problems related to lactation and misconceptions about breastfeeding, especially fears of passing on cancer through breastmilk, highlight the need for counseling and specialized support to optimize lactation outcomes in this vulnerable population.
| S-EPMC7384306 | biostudies-literature
Project description:ObjectiveTo estimate the rates and predictors of recurrent stroke among survivors of pediatric cancer who have had a first stroke.MethodsThe Childhood Cancer Survivor Study is a retrospective cohort study with longitudinal follow-up that enrolled 14,358 survivors (<21 years old at diagnosis; diagnosed 1970-1986; survived ≥5 years after cancer diagnosis) and followed them prospectively since 1994. We surveyed 443 survivors who reported a first stroke to identify recurrent stroke, and estimated recurrent stroke rates ≥5 years after cancer diagnosis.ResultsAmong 329 respondents (74% response rate), 271 confirmed a first stroke at a median age of 19 years (range 0-53), and 70 reported a second stroke at a median age of 32 years (range 1-56). In a multivariable Cox proportional hazards model, independent predictors of recurrent stroke included cranial radiation therapy (CRT) dose of ≥50 Gy (vs none, hazard ratio [HR] 4.4; 95% confidence interval [CI] 1.4-13.7), hypertension (HR 1.9; 95% CI 1.0-3.5), and older age at first stroke (HR 6.4; 95% CI 1.8-23; for age ≥40 vs age 0-17 years). The 10-year cumulative incidence of late recurrent stroke was 21% (95% CI 16%-27%) overall, and 33% (95% CI 21%-44%) for those treated with ≥50 Gy of CRT.ConclusionSurvivors of childhood cancer, particularly those previously treated with high-dose cranial radiation, have a high risk of recurrent stroke for decades after a first stroke. Although these strokes are mostly occurring in young adulthood, hypertension, an established atherosclerotic risk factor, independently predicts recurrent stroke in this population.
| S-EPMC4603599 | biostudies-literature
Project description:In this study RNA-Seq was performed in anthracycline- exposed childhood cancer survivors who had cardiomyopathy (cases) matched to those without cardiomyopathy (controls) to understand the pathogenesis of anthrcaycline-related cardiomyopathy
2023-01-31 | GSE218276 | GEO