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SET domain-containing protein 2 (SETD2) is commonly mutated in renal cell carcinoma. SETD2 methylates histone H3 as well as a growing list of non-histone proteins. To explore SETD2-dependent regulation of the kidney cancer proteome, we performed a systems-wide analysis of protein lysine-methylation and expression in wild type (WT) and SETD2-knock out (KO) kidney cells. We observed decreased lysine methylation of the translation elongation factor eEF1A1. EEF1AKMT2 and EEF1AKMT3 are known to methylate eEF1A1, and we show here that their expression is dependent on SET-domain function of SETD2. Globally, we observe differential expression of hundreds of proteins in WT versus SETD2-KO cells, including increased expression of many involved in protein translation. Finally, we observe decreased progression free survival and loss of EEF1AKMT2 gene expression in SETD2-mutated tumors. Overall, these data suggest that SETD2-mutated ccRCC, via loss of enzymetic function of the SET domain, displays dysregulation of protein translation as a potentially important component of the transformed phenotype.

BACKGROUND: SET domain-containing protein 2 (SETD2) is commonly mutated in renal cell carcinoma. SETD2 methylates histone H3 as well as a growing list of non-histone proteins. OBJECTIVE: Initially, we sought to explore SETD2-dependent changes in lysine methylation of proteins in proximal renal tubule cells. Subsequently, we focused on changes in lysine methylation of the translation elongation factor eEF1A1. METHODS: To accomplish these objectives, we initially performed a systems-wide analysis of protein lysine-methylation and expression in wild type (WT) and SETD2-knock out (KO) kidney cells and later focused our studies on eEF1A1 as well as the expression of lysine methyltransferases that regulate its lysine methylation. RESULTS: We observed decreased lysine methylation of the translation elongation factor eEF1A1. EEF1AKMT2 and EEF1AKMT3 are known to methylate eEF1A1, and we show here that their expression is dependent on SET-domain function of SETD2. Globally, we observe differential expression of hundreds of proteins in WT versus SETD2-KO cells, including increased expression of many involved in protein translation. Finally, we observe decreased progression free survival and loss of EEF1AKMT2 gene expression in SETD2-mutated tumors predicted to have loss of function of the SET domain. CONCLUSION: Overall, these data suggest that SETD2-mutated ccRCC, via loss of enzymatic function of the SET domain, displays dysregulation of protein translation as a potentially important component of the transformed phenotype.

564 Background: Breast cancer (BC) is the leading cause of cancer-related deaths in Black women, who are 41% more likely to die than White women. We’ve recently reported that Black women have a significantly greater proportion of hormone receptor-positive (HR+) tumors further classified as Basal-Type with BluePrint genomic subtyping, which may contribute to their worse outcomes. Here, we evaluated whether there were differences in tumor genomics among patients with clinically assessed HER2+ (cHER2) tumors between Black and White women. Methods: This study includes 204 women with stage I-III cHER2 BC who received BluePrint testing and are participants of the BEST study (5R01CA204819) at Vanderbilt University Medical Center or FLEX study (NCT03053193). Patients were treated per NCCN guidelines based on immunohistochemistry (IHC)/FISH classification. cHER2 tumors were further classified by BluePrint, an 80-gene molecular subtyping test, as Luminal-Type (gLuminal), HER2-Type (gHER2), or Basal-Type (gBasal). White women within FLEX were matched by age, tumor and node status and included as a reference group. A two-tailed proportional z-test was used to assess BluePrint subtype differences. Limma R package was used for differential gene expression analysis (DGEA) of whole transcriptome data. Significant differentially expressed genes had an adjusted p-value < 0.05 and absolute log2 fold change > 1. Results: Of 102 Black women with cHER2 tumors, 59 had gHER2, 34 had gLuminal and 9 had gBasal tumors, and of 102 White women, 63 had gHER2, 28 had gLuminal and 11 had gBasal tumors. There were no significant differences in the frequency of BluePrint subtypes or in gene expression by race among cHER2 tumors. All gHER2 tumors had upregulated HER2 signaling compared to upregulated estrogen signaling genes in gLuminal tumors, and upregulated genes characteristic of metastasis and triple negative tumors in gBasal tumors. Among patients with available neoadjuvant treatment response data, 57.1% (16/28) gHER2, 33.3% (2/6) gLuminal and 50.0% (3/6) gBasal achieved a pathologic complete response (pCR). Conclusions: Unlike HR+HER2- tumors, these data suggest that race may not influence the biology underlying cHER2 tumors. However, there was genomic heterogeneity among cHER2 tumors identified by BluePrint, independent of race. Overall, the rate of BluePrint classification among cHER2 tumors was comparable to NBRST and APHINITY, which demonstrated distinct treatment response and outcome based on BluePrint genomic subtype. In this study, DGEA suggests gHER2 tumors exhibit extensive HER2 signaling and may benefit most from HER2-targeted therapy. Although limited by sample size, rates of pCR to neoadjuvant therapy appear greater in gHER2 than non-HER2 tumors (gLuminal, gBasal). gBasal tumors may harbor more aggressive tumor characteristics, which has important clinical implications for optimizing treatment and improving outcomes in these patients.

Background: There have been renewed calls for greater inclusivity of populations most prominently affected by cancer health inequities across the cancer research enterprise, particularly Black and African American populations. In cancer health services research there are myriad methodologies and data sources to study cancer treatment outcomes including medical records, cancer registries, and primary data collection. These different methodologies have varying levels of resource intensity that may affect the recruitment of marginalized populations. Little is known about how much concordance between data sources may exist among marginalized populations with cancer, which has substantial implications for cancer inequities research. Objective: To evaluate the data concordance between medical records, cancer registries, and self-reported survey data among an underrepresented population in cancer population sciences research. Methods: This investigation used a population-based sample of self-identified Black women recruited through the Tennessee and Florida Cancer registries who were diagnosed with invasive breast cancer at or below the age of 50. Participants completed medical records release forms and questionnaires about their cancer treatment trajectories. Comparing data contained in the cancer registries, medical records, and self-reported data, we quantitatively assessed the concordance between data sources for receipt of surgery, chemotherapy, and radiation, using medical records as the gold standard. Results: In total, 558 Black women at or below 50 with invasive breast cancer had available registry data and also completed a medical records release. In terms of missing data for receipt of surgery, chemotherapy, and radiation, self-report was the most complete, followed by the registry and then the medical records. Among those with complete data, comparing the medical records to the cancer registry, accuracy was high for surgery (94.6% ; 95% CI 92.2, 96.4) and chemotherapy (89.7%; 95% CI: 85.7, 92.8) , but low for radiation (55.4%, 95% CI: 48.5, 62.2) with the cancer registry missing the receipt of radiation that was noted in the medical records. Comparing medical records to self-report data, accuracy was &gt;90% for surgery, chemotherapy, and radiation. Comparing the cancer registry to self-report, accuracy was high for surgery (94.5%; 95% CI: 92.0, 96.4), moderate for chemotherapy (88.2; 95% CI: 85.1,90.9), and low for radiation (67.2%; 95% CI 62.9, 71.3). Conclusion: For receipt of surgery and chemotherapy, there was high concordance between medical records, cancer registries, and self-reported data. The receipt of radiation was inconsistently reported in the cancer registry and medical records. When considering inclusivity in the study of cancer services delivery among marginalized populations, tradeoffs of data validity and resource intensity must be weighed. Citation Format: Mya L. Roberson, Lindsay Venton, Anne Weidner, Sonya Reid, Tuya Pal. Evaluating treatment data concordance among young Black women diagnosed with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1939.

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