Browsing by Subject "late effects"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Genetic risk factors of pediatric germ cell tumors and the late effects of their treatment
    (2021-09) Hubbard, Aubrey
    Pediatric germ cell tumors (GCTs) are a heterogeneous group of tumors and their etiology is poorly understood. There are distinct differences between GCTs that arise in early childhood and those in adolescents and young adults, but recent studies of GCTs implicate genetics in the etiology of disease across all age groups. In Manuscript 1, we interrogated the genetically regulated expression of genes within the cell cycle control or apoptosis cellular pathways for their role in pediatric GCT risk. Our results suggest a previously identified association with an intronic variant near BAK1, a pro-apoptotic gene, may be acting through the reduced expression of BAK1. Hispanic children have the highest risk of pediatric GCTs overall, although incidence rates by race/ethnicity do vary by tumor location, sex, and age at diagnosis. No risk factors have been identified to date to explain the excess risk in Hispanic children and in countries in Central America. In Manuscript 2, we employed admixture mapping methods to interrogate genomic regions specific to Hispanic admixture to explore genetic loci contributing to the excess risk in GCTs among Hispanic children. We did not find any genetic loci that reached our threshold for statistical significance, but Amerindian ancestry regions on chromosome 7 were overrepresented among our top results and may warrant further exploration in a sample greater powered for subgroup analyses. Pediatric GCT survival has approached 90% due to the success of platinum-based therapies, but there are substantial late effects of treatment. Little is known about the burden of late effects in pediatric GCT survivors, as they were excluded from the Childhood Cancer Survivor Study. However, pediatric GCT survivors comprise the third largest group of pediatric cancer survivors in the United States. Platinum-based chemotherapy is a risk factor for chemotherapy-induced peripheral neuropathy (CIPN), which is a progressive, debilitating condition with significant effects on a survivor’s quality of life. In Manuscript 3, we characterized the prevalence of CIPN in pediatric GCT survivors and explored the genetic susceptibility to CIPN in survivors that received platinum-based chemotherapy. We found that 24% of our pediatric GCT survivors had at least two symptoms of CIPN after an average of 9 years following their diagnosis. Our genetic studies did not identify genetic risk factors although power was limited to detect variants that reached genome-wide significance. Overall, our first project provided information related to the functional significance of a previously identified variant, our second manuscript is the first genetic study in any age group to include cases of non-European ancestry and our final manuscript is the first study of CIPN in the pediatric age group.
  • Thumbnail Image
    Item
    Risk of Subsequent Neoplasms During the Fifth and Sixth Decades of Life in the Childhood Cancer Survivor Study Cohort
    (2015-07) Turcotte, Lucie
    Childhood cancer survivors are at increased risk for subsequent neoplasms (SNs), but the incidence beyond age 40 and associations with therapeutic exposures have not been well- described. Among 14,364 childhood cancer survivors diagnosed between 1970 and 1986, 3,171 had an attained age ≥40 years at the time of last contact. Cumulative incidence of SNs, standardized incidence ratios (SIRs) and excess absolute risk of subsequent malignant neoplasms (SMNs), and relative risks (RR) for SMNs and non-melanoma skin cancers (NMSCs), were calculated. In total, 679 SNs were diagnosed ≥40 years of age, including 196 SMNs, 419 NMSCs, 21 non-malignant meningiomas, and 43 other benign neoplasms. At age 55, the cumulative incidence of new SNs and SMNs occurring beyond age 40 was 34.6% (95% CI 28.7-40.6) and 16.3% (95% CI 11.7-20.9), respectively. Survivors were twice as likely as the general population to be diagnosed with a SMN after age 40 (SIR=2.2, 95% CI 1.9-2.5). Among SMNs, risk was increased for breast cancer (SIR=5.5, 95% CI 4.5-6.7), renal cancer (SIR=3.9, 95% CI 2.0-7.5), soft tissue sarcoma (SIR=2.6, 95% CI 1.5-4.4), and thyroid cancer (SIR=1.9, 95% CI 1.0-3.5). Female sex (RR=1.9, 95% CI 1.3-2.6, P<0.001) and therapeutic radiation exposure (RR=2.2, 95% CI 1.4-3.3, P<0.001) were associated with higher risk for SMN in multivariable analysis. Even beyond 40 years of age, survivors of childhood cancer remain at increased risk for treatment-related SNs. These data suggest the need for lifelong monitoring and should inform anticipatory guidance provided to childhood cancer survivors.