Means, Sydney

Introduction: Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is characterized by chronic kidney disease (CKD) with an average age of end-stage renal disease (ESRD) of approximately 45 years, bland urinary sediment, the absence of proteinuria and autosomal dominant inheritance. While several causative genes have been found, there remain families in whom no molecular diagnosis has been identified (ADTKD-NMD). Methods: We identified BICC1 truncating variants in several families with ADTKD-NMD in the Wake Forest Rare Inherited Kidney Disease Registry and then screened families in our database and other referred families for BICC1 truncating variants. We performed segregation analysis and characterized affected individuals for clinical and histopathologic phenotypes. We analyzed oligomer formation of BICC1 mutants with wild-type BICC1-, ANKS3- and ANKS6 proteins through co-immunoprecipitation and Western blotting, and we tested for posttranscriptional regulation of the BICC1 target mRNA, Dand5, in a Luciferase reporter assay. Results: We found 6 heterozygous truncating mutations in BICC1 segregating with the ADTKD phenotype in 8 independent pedigrees worldwide. Affected individuals developed kidney failure in the 6th to 7th decade of life that was characterized pathologically by tubular atrophy and interstitial fibrosis. The truncated gene products localized to cytoplasmic bodies and demonstrated various degrees of self-association or binding to the known interaction partners, ANKS3 and ANKS6. While the wild-type BICC1 gene product acts as a posttranscriptional repressor of target mRNAs, all truncation variants exhibited increased expression of substrate mRNA. Conclusions: Truncating variants in BICC1 are a novel cause of ADTKD, segregating with the disease phenotype and upregulating BICC1 target gene expression through a dominant-negative- or a gain-of-function mode of action.

Abstract Introduction: Pain is one of the complications of cancer or cancer treatment and affects the quality of life of cancer patients. Unfortunately, factors that alleviate cancer pain have been understudied despite pain being one of the most common symptoms of cancer. The purpose of this secondary comparative analysis study was to identify factors that alleviate cancer pain and their relationship to specific cancer types. Methods: The study comprised 579 participants from inpatient and outpatient cancer care centers in Seattle, WA. The participants used paper or a tablet computer to complete the McGill Pain Questionnaire, which included an open-ended question: “What kinds of things relieve your pain?” Text responses were coded into six outcome categories: 1) Activity level, 2) Cognitive, 3) Environmental, 4) Medical, 5) Physical, and 6) Sedentary behavior. Race and ethnicity categories were collapsed into Black/Other and White based on frequency distribution. We conducted a multivariable regression analysis adjusting for sociodemographic characteristics using the number of activities/factors in each of the six outcome categories. Results: Patients were mostly White (86%), female (27%) and aged 58.7± 12.3 years on average. Nearly 13% of the sample were Black/Other patients. The current pain intensity was more intense for Black/Other patients than White patients (p <0.001). Activity (ρ=0.02), cognition (ρ<0.001), and medication (ρ<0.001) were more frequently used as pain-alleviating factors among lung cancer patients compared to head and neck cancer patients. Males (ρ=0.02) and lung cancer patients (ρ=0.02) engaged in significantly less physical activity alleviating factors than females and head and neck cancer patients. Differences between the race groups were not statistically significant for mean alleviating factors. Conclusion: Although pain intensity is more intense for minority patients than their White counterparts, their behaviors to alleviate their pain do not differ in this sample. Differences in pain alleviating factors by gender and type of cancer warrant additional research to understand the complexity of patients’ self-care behaviors with consideration of demographic and cancer variables as well as analgesics. Citation Format: Dottington Fullwood, Sydney Means, Diana J. Wilkie, Folakemi T. Odedina. Pain alleviating factors reported by cancer patients [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B009.