Patients Of African Ancestry Research Articles

Abstract 766: Genomic and transcriptomic comparison between breast cancers from patients of African and European genetically determined ancestries demonstrates potential for ancestry specific biomarker-informed therapies

Abstract Background: Therapeutic approaches for breast cancer (BC) are informed by tumor subtypes and molecular heterogeneity, both of which may be associated with particular patient ancestries. While patients of African ancestry (AA) exhibit a relatively high mortality rate compared with patients of European ancestry (EA), the biological underpinnings of this disparity are not entirely understood. Here, we present a genomic and transcriptomic comparison between BC tumors from AA and EA patients stratified by clinical features in a real-world cohort. Methods: De-identified records from AA (n=629) and EA (n=2832) patients with BC were selected from the Tempus Oncology Database. All tumors underwent sequencing with the Tempus|xT assay, including targeted-panel DNA and full-transcriptome RNA-seq. Race metadata was obtained from abstracted records. Genetic ancestry was estimated using a set of ancestry-informative markers and a supervised version of the ADMIXTURE algorithm. Mutational prevalence, gene expression, and transcriptional signatures were compared between EA and AA groups, and stratified by stage and subtype. Statistical significance was assessed with Bonferroni correction applied to adjust for multiple testing. Results: Genetic ancestry estimates and race metadata had strong concordance, with 97% and 91% of race data matching genetic ancestry categories in AA and EA, respectively. Compared to EA patients, AA patients were slightly younger (median age 53.8 years vs. 56.1 years) and more likely to have stage IV disease (59.0% vs. 56.5%). The percentage of triple-negative BC (TNBC) patients was much higher among AA (23.5%) compared to EA (14.3%), while the proportion of HR+/HER2− patients was higher in EA (46.4%) compared to AA (36.5%). In HR+/HER2- patients, AA patients had a higher prevalence of KMT2C (24% vs. 14%), GATA3 (21% vs. 14%), and FGFR1 (18% vs. 12%) mutations, and a lower prevalence of PIK3CA (33% vs. 42%) and PTEN (6% vs. 13%) mutations. PRSS23 expression and estrogen response late signaling were significantly downregulated in late-stage HR+/HER2- AA patients, while PTEN signaling was downregulated in stages I-III. Among TNBC, AA patients had a higher prevalence of KMT2C (23% vs. 12%) mutations. LILRA6 and PTEN were significantly downregulated in early-stage TNBC patients of AA. Conclusions: After controlling for stage at diagnosis and subtype, we observed significant differences in BC mutational spectrums, gene expression, and relevant pathway activities between patients with genetically determined AA and EA, particularly within the TNBC and HR+/HER2- subtypes. These findings may guide future development of treatment strategies by providing data for biomarker-informed research and precision cancer care. Citation Format: Minoru Miyashita, Joshua S. Bell, Ezgi Karaesmen, Brooke Rhead, Stephane Wenric, Kristiyana Kaneva, Francisco M. De La Vega, Yonglan Zheng, Toshio Yoshimatsu, Galina Khramtsova, Elisabeth Sveen, Fang Liu, Fangyuan Zhao, Frederick Howard, Nora T. Jaskowiak, Rita Nanda, Dezheng Huo, Olufunmilayo I. Olopade. Genomic and transcriptomic comparison between breast cancers from patients of African and European genetically determined ancestries demonstrates potential for ancestry specific biomarker-informed therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 766.

Abstract 1845: Exploring the mode of action of a highly efficacious ruthenium-based chemotherapeutic agent in triple negative breast cancer

Abstract Purpose: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is defined by the absence of expression of progesterone receptor, estrogen receptor, and human epidermal growth factor receptor 2. TNBC has a higher incidence in younger women and those of African descent. Due to the inability to target a receptor, treatment is mostly limited to anthracycline and taxane-based nonspecific chemotherapy. Within the past two years more therapies have become available for later stage TNBC, such as antibody-drug conjugate sacituzumab govitecan-hziy. A potential water-soluble ruthenium-based chemotherapeutic agent was developed in our lab, showing high cytotoxicity against different cancer types in a National Cancer Institute 60-cell line panel. A preliminary in vivo study of this complex showed a pronounced 56% reduction of tumor growth with a TNBC MDA-MB-231 cell line xenograft mouse model, with little system toxicity and preferential accumulation of the complex in tumor tissue. These studies prompted us to further evaluate it in TNBC cell lines MDA-MB-231 and HCC-1806, derived from Caucasian and African ancestry patients respectively. This investigation revealed significant anti-angiogenic, anti-invasive, and anti-migratory properties for the complex, along with subcellular accumulation in the mitochondria and an apoptotic mechanism of cell death in both cell lines. Preliminary proteomic analysis was completed to understand the molecular pathway involved, which was determined to be P53-independent. Macrophage colony stimulating factor (M-CSF) showed an inhibition of protein expression, implicating the ruthenium complex as a potential inhibitor of phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) pathway which acts downstream of M-CSF, and is involved with enhanced cancerous proliferation. In light of these findings, we report here on in vitro studies focused on further investigating the involvement of the PI3K/Akt molecular pathway and mechanism of action of this ruthenium complex. Experimental Design: Western blot studies directed toward key markers in the PI3K/Akt pathway will be assessed, which include Akt, c-Raf, PI3K, PTEN, and PDK1. Furthermore, mitochondrial involvement was determined through reactive oxygen species (ROS) generation and changes to mitochondrial membrane potential (MMP). Results: A significant increase of ROS generation was seen with exposure to the compound, along with slight MMP depolarization. Western blot analysis may further implicate an inhibition of the PI3K/Akt pathway. Conclusions: Our results show that the mechanistic action of the tested ruthenium complex has mitochondrial involvement, with inhibitory effects in the PI3K/Akt pathway. The very significant anti-cancer properties outlined in the preclinical evaluation of this complex will be further investigated in PDX mice models. Citation Format: Nazia Nayeem, Karen Hubbard, Maria Contel. Exploring the mode of action of a highly efficacious ruthenium-based chemotherapeutic agent in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1845.

The Impact of CYP2C9*11 Allelic Variant on the Pharmacokinetics of Phenytoin and (S)-Warfarin.

Cytochrome P450 2C9 (CYP2C9) is responsible for the oxidative metabolism of about 15% of commonly used drugs, some of which are characterized by a narrow therapeutic window. CYP2C9 is highly polymorphic, and over 60 alleles have been described. CYP2C9*2 and CYP2C9*3 are the most common polymorphisms among White patients and both are associated with decreased activity. The evidence concerning the functional importance of less frequent variant alleles is scarce. The objective of the current study was to characterize the in vivo activity of CYP2C9 among carriers of CYP2C9*11, one of the "African" alleles and the fourth most common CYP2C9 variant allele among White patients by using two prototype substrates, phenytoin and (S)‐warfarin. Single 300‐mg phenytoin and 20‐mg warfarin doses were given to 150 healthy Ethiopian Jewish participants who were nonsmokers, at least one week apart. (S)‐warfarin oral clearance and phenytoin metabolic ratio (PMR) derived from the ratio of 5‐(4‐hydroxyphenyl)‐5‐phenylhydantoin in 24‐hour urine collection to plasma phenytoin 12 hours (PMR 24/12) or 24 hours (PMR 24/24) post dosing, were used as markers of CYP2C9 activity. PMR 24/12 and PMR 24/24 were reduced by 50% and 62.2%, respectively, among carriers of CYP2C9*1/*11 (n = 13) as compared with carriers of CYP2C9*1/*1 (n = 127) (false discovery rate (FDR) q < 0.001). The respective decrease in (S)‐warfarin oral clearance was 52.6% (FDR q < 0.001). In conclusion, the enzyme encoded by CYP2C9*11 is characterized by a more than 50% decrease in the enzymatic activity, resembling the extent of decrease associated with CYP2C9*3 ("no‐function allele"). Among patients of African ancestry, CYP2C9*11 genetic analysis should be considered prior to prescribing of narrow therapeutic window drugs such as phenytoin, warfarin, nonsteroidal anti‐inflammatory drugs, or siponimod.

FC030: Diagnostic Yield of Exome Sequencing in Hypertensive Nephropathy

Abstract BACKGROUND AND AIMS Hypertensive nephrosclerosis ranks as one of the most frequent causes of chronic kidney disease (CKD) worldwide and is deemed to be especially prevalent among patients of African ancestry [1]. The very existence of hypertensive nephropathy has been called into question, especially in young adults. Its diagnostic framework is based on non-specific clinical criteria, and its histopathological features are in fact unspecific. Genetic testing with exome sequencing (ES) has emerged as a comprehensive tool to detect Mendelian diseases in nephrology with a significant number of post-hoc re-established diagnoses [2]. Nevertheless, ES has yet to be incorporated into the diagnostic workup of patients with hypertensive nephropathy consistently. This study aimed to investigate the diagnostic yield of ES in patients with a clinical diagnosis of hypertensive nephropathy. METHOD Since September 2018, ES is readily available as part of the routine diagnostic workup in our institution. The indication of ES includes hypertensive nephropathy of early onset (i.e. &amp;lt;45 years old). We retrospectively collected the ES performed in the context of hypertensive nephropathy [3] in our institution between September 2018 and February 2021. RESULTS A total of 128 patients were sequenced in the context of hypertensive nephropathy with early-onset. Women were 29 (22.7%), the mean age was 43 (35; 51) years and 60% of them were patients of African ancestry. The main indications of ES was an early onset of CKD (47%), a family history of kidney disease (8%) or both (18%). We detected diagnostic variants (ACM class 4/5) in 22 of the 128 patients (17.2%) encompassing a total of 16 different monogenic disorders. Two diseases accounted for more than half of the genetic diagnoses: nephronophthisis (n = 7, 32%) and Alport syndrome (n = 5, 23%). Complement variation did not account for a significant part of the diagnosis. The diagnostic yield of ES was lower in patients of African ancestry (diagnostic yield of 10.4% versus 27.4% in the non-African ancestry patients; P = 0.01). Co-segregation data was lacking in patients of African ancestry, with significantly more ES performed in singleton (96% compared with 76% in non-African ancestry patients; P &amp;lt; 0.001). In addition to disease reclassification, genetic diagnosis enabled guidance for family counseling (n = 11, 50% of positive patients) and thus helped for potential related donor selection for transplantation. In the whole cohort, ES results modified the therapeutic in 6 patients (5%) and ruled out potential recurrence in the graft in 10 patients (8%). CONCLUSION Physicians should be wary of tentative diagnosis of nephrosclerosis, especially in patients of non-African ethnic background. Instead, it should prompt genetic investigations, which overturned the initial diagnosis in 17% of the cases. The lower diagnostic yield of ES in patients of African ancestry in our cohort might partly be due to the lack of available co-segregation data, as well as the underrepresentation of subjects of African ancestry in the reference genome.

MO043: Role of the I416L variant of complement factor I in the occurrence of thrombotic microangiopathy among patients of African ancestry

Abstract BACKGROUND AND AIMS Complement dependent hemolytic and uremic syndrome (c-HUS) predisposes to hypertensive crisis and chronic hypertension. Reciprocally, hypertensive crisis may precipitate thrombotic microangiopathy (TMA) via endothelial shear stress. Patients of African ancestry have long been recognized for their predisposition to both chronic hypertension and chronic kidney disease (CKD). Yet, despite growing evidence meant to bridge the divide between the complement alternative pathway and hypertensive crisis [1] (i) c-HUS is only known to account for a small fraction of the cases of malignant HTA (5%) [2] or TMA (4%) [3] (ii) complement genetic investigations in the population of African ancestry are sparse. Recently, the I416L CFI variant, which is specific to patients of African ancestry, has been classified as likely pathogenic (https://databases.lovd.nl/shared/variants/0000521158#00005040). By running a query through the BIOMNIS genetic databank, we sought to identify and provide a phenotypic description of the patients carrying the I416L CFI variant. METHOD All samples were sequenced at the BIOMNIS center (Lyon, France) using the Illumina platform and subsequently processed via the in-center bioinformatics pipeline. The BIOMNIS genetic databank compiles a total of 2886 whole exome sequencing (WES) nationwide (single unrelated patients) for renal (n = 1200) and non-renal indications (n = 1686). Once patients were recognized to carry the I416 variant, deidentified clinical data was provided by the attending nephrologist. RESULTS Among 1686 WES performed for non-renal indications, three unrelated patients harbored the I416L variant. Out of the 1200 WES performed for renal indications, we identified eight unrelated patients carrying the I416L CFI variant. All patients were of African Ancestry and were heterozygous for the variant, including five males with median age of 38.5 years. They all shared a common history remarkable for hypertension of early onset at median of 33 years [21–38]. None of these patients were acknowledged to have c-HUS prior to WES. In six cases, the kidney disease was undetermined. Four patients experienced TMA: three during bouts of malignant hypertension with concurrent biological TMA. One of them exhibited signs of TMA on biopsy with superimposed signs of malignant nephrosclerosis and another on a kidney transplant. Three patients disclosed genetic risk factor for kidney disease including Apol1 pathogenic variants (G1 and/or G2) (n = 2) and URAT1-related pathogenic variant (n = 1). Five patients had at least one additional risk factor for renal disease. All but one patient progressed to CKD including end-stage CKD on four instances with a median follow-up of 6.5 years. One patient presented with TMA following kidney transplantation. Only one patient whose hypertensive crisis manifested as preeclampsia and HELLP was free of CKD on last follow-up. CONCLUSION C-HUS may go unrecognized or mimic vascular nephropathy. These results make a case for a streamlined genotyping of patients, especially patients of African ancestry with a history of hypertension of early onset. Additional triggers acting as second ‘hits’ such as hypertension, pregnancy or genetic and non-genetic renal risk factors may aggravate the course of kidney disease. Yet, further investigations are warranted to appreciate the true clinical significance of this variant as it entails momentous therapeutic and medico-economic implications, most notably the use of anti-C5 therapy.

Mutational spectrum of breast cancer susceptibility genes among women ascertained in a cancer risk clinic in Northeast Brazil

PurposeThere is a paucity of data on the spectrum and prevalence of pathogenic variants among women of African ancestry in the Northeast region of Brazil.MethodsWe performed BROCA panel sequencing to identify inherited loss-of-function variants in breast cancer susceptibility genes among 292 Brazilian women referred to a single institution cancer risk assessment program.ResultsThe study included a convenient cohort of 173 women with invasive breast cancer (cases) and 119 women who were cancer-free at the time of ascertainment. The majority of the women self-reported as African-descended (67% for cases and 90.8% for unaffected volunteers). Thirty-seven pathogenic variants were found in 36 (20.8%) patients. While the spectrum of pathogenic variants was heterogeneous, the majority (70.3%) of the pathogenic variants were detected in high-risk genes BRCA1, BRCA2, PALB2, and TP53. Pathogenic variants were also found in the ATM, BARD1, BRIP1, FAM175A, FANCM, NBN, and SLX4 genes in 6.4% of the affected women. Four recurrent pathogenic variants were detected in 11 patients of African ancestry. Only one unaffected woman had a pathogenic variant in the RAD51C gene. Different risk assessment models examined performed well in predicting risk of carrying germline loss-of-function variants in BRCA1 and/or BRCA2 in breast cancer cases.ConclusionThe high prevalence and heterogenous spectrum of pathogenic variants identified among self-reported African descendants in Northeast Brazil is consistent with studies in other African ancestry populations with a high burden of aggressive young onset breast cancer. It underscores the need to integrate comprehensive cancer risk assessment and genomic testing in the management of newly diagnosed Black women with breast cancer across the African Diaspora, enabling improved cancer control in admixed underserved and understudied populations.

Immune mechanisms behind prostate cancer in men of African ancestry: A review.

Men of African ancestry (AA) with prostate cancer suffer from worse outcomes. However, a recent analysis of patients treated with the dendritic cell vaccine sipuleucel-T for prostate cancer suggested that AA patients could have improved outcomes relative to whites. We conducted a focused literature review of Medline-indexed articles and clinical trials listed on clinicaltrials.gov. We identify several studies pointing to enrichment of inflammatory cellular infiltrates and cytokine signaling among AA patients with prostate cancer. We outline potential genomic and transcriptomic alterations that may contribute to immunogenicity. Last, we investigate differences in host immunity and vaccine responsiveness that may be enhanced in AA patients. AA patients with prostate cancer may be enriched for an immunogenic phenotype. Dedicated studies are needed to better understand the immune mechanisms that contribute to existing cancer disparities and test immune-based therapies in this population.

Effects of Testing and Disclosing Ancestry-Specific Genetic Risk for Kidney Failure on Patients and Health Care Professionals

Risk variants in the apolipoprotein L1 (APOL1 [OMIM 603743]) gene on chromosome 22 are common in individuals of West African ancestry and confer increased risk of kidney failure for people with African ancestry and hypertension. Whether disclosing APOL1 genetic testing results to patients of African ancestry and their clinicians affects blood pressure, kidney disease screening, or patient behaviors is unknown. To determine the effects of testing and disclosing APOL1 genetic results to patients of African ancestry with hypertension and their clinicians. This pragmatic randomized clinical trial randomly assigned 2050 adults of African ancestry with hypertension and without existing chronic kidney disease in 2 US health care systems from November 1, 2014, through November 28, 2016; the final date of follow-up was January 16, 2018. Patients were randomly assigned to undergo immediate (intervention) or delayed (waiting list control group) APOL1 testing in a 7:1 ratio. Statistical analysis was performed from May 1, 2018, to July 31, 2020. Patients randomly assigned to the intervention group received APOL1 genetic testing results from trained staff; their clinicians received results through clinical decision support in electronic health records. Waiting list control patients received the results after their 12-month follow-up visit. Coprimary outcomes were the change in 3-month systolic blood pressure and 12-month urine kidney disease screening comparing intervention patients with high-risk APOL1 genotypes and those with low-risk APOL1 genotypes. Secondary outcomes compared these outcomes between intervention group patients with high-risk APOL1 genotypes and controls. Exploratory analyses included psychobehavioral factors. Among 2050 randomly assigned patients (1360 women [66%]; mean [SD] age, 53 [10] years), the baseline mean (SD) systolic blood pressure was significantly higher in patients with high-risk APOL1 genotypes vs those with low-risk APOL1 genotypes and controls (137 [21] vs 134 [19] vs 133 [19] mm Hg; P = .003 for high-risk vs low-risk APOL1 genotypes; P = .001 for high-risk APOL1 genotypes vs controls). At 3 months, the mean (SD) change in systolic blood pressure was significantly greater in patients with high-risk APOL1 genotypes vs those with low-risk APOL1 genotypes (6 [18] vs 3 [18] mm Hg; P = .004) and controls (6 [18] vs 3 [19] mm Hg; P = .01). At 12 months, there was a 12% increase in urine kidney disease testing among patients with high-risk APOL1 genotypes (from 39 of 234 [17%] to 68 of 234 [29%]) vs a 6% increase among those with low-risk APOL1 genotypes (from 278 of 1561 [18%] to 377 of 1561 [24%]; P = .10) and a 7% increase among controls (from 33 of 255 [13%] to 50 of 255 [20%]; P = .01). In response to testing, patients with high-risk APOL1 genotypes reported more changes in lifestyle (a subjective measure that included better dietary and exercise habits; 129 of 218 [59%] vs 547 of 1468 [37%]; P < .001) and increased blood pressure medication use (21 of 218 [10%] vs 68 of 1468 [5%]; P = .005) vs those with low-risk APOL1 genotypes; 1631 of 1686 (97%) declared they would get tested again. In this randomized clinical trial, disclosing APOL1 genetic testing results to patients of African ancestry with hypertension and their clinicians was associated with a greater reduction in systolic blood pressure, increased kidney disease screening, and positive self-reported behavior changes in those with high-risk genotypes. ClinicalTrials.gov Identifier: NCT02234063.

Abstract P3-19-29: Polygenic risk scores predict toxicities in racially diverse breast cancer patients following radiotherapy

Abstract Purpose: Fatigue, fibrosis, and breast asymmetry are the most common side effects of radiotherapy, experienced in up to 40% of survivors long term. Due to the prevalence of these toxicities, a number of patient, tumor, and treatment-related characteristics have been studied in an attempt to identify at risk individuals. Additionally, several single nucleotide polymorphisms (SNPs) such as those that reside in gene TGFB1 have been associated with long-term breast fibrosis following radiotherapy by genome-wide association studies (GWAS). However, these findings are often not consistently replicated in various cohorts, particularly those with racially diverse patients, indicating that these significant SNPs (with p &amp;lt; 5e-8) or clinical factors alone may not provide enough information to determine individual risk for radiation-related toxicities. We hypothesized that the Polygenic Risk Scores (PRS) derived from the GWAS summary statistics of a larger number of potentially significant SNPs (e.g. with p-values &amp;lt; 0.05) have the potential to improve risk prediction, especially by using GWAS data of a racially diverse cohort. Methods: We conducted three prospective, longitudinal studies of breast cancer patients treated with whole breast radiotherapy with or without regional nodal irradiation. In all studies, fatigue, skin thickening, and breast asymmetry were assessed before and 12-18 months post radiotherapy using the following identical measures: percentage breast retraction assessment (pBRA) calculated from digital photographs, skin thickening objectively measured on ultrasound images (STRA), and fatigue assessed by the Multidimensional Fatigue Symptom Inventory (MFI) 20-item scale. We profiled genome-wide SNP data from peripheral blood samples of enrolled patients (n=176; 44% African Ancestry; 56% European Ancestry) by Affymetrix arrays and then imputed these genotyped SNPs to 1000 Genome Phase III reference panel. Genotyped or imputed SNPs with imputation R2&amp;gt;0.3 with minor allele frequency (MAF) &amp;gt; 5% (~10M) were analyzed in our GWAS with baseline, post radiotherapy, and changes in pBRA, STRA, and MFI. GWAS was first conducted separately in African and European ancestry samples, and then combined by meta-analysis for baseline and post radiotherapy measurements. Joint GWAS was conducted on all samples for the change phenotypes as we observed no heterogeneous phenotype distribution for samples of different ancestries. PRS was derived using the GWAS summary statistics for each phenotype. Results: Twelve independent significant SNPs were identified for baseline and post radiotherapy measurements in pBRA, STRA, and MFI, all of which were identified only in patients of African and not European ancestry due to low MAF &amp;lt; 5%. All post radiotherapy PRS were significantly correlated with the corresponding baseline (r&amp;gt;0.29, p &amp;lt; 0.05) and change PRS (r&amp;gt;0.19, p &amp;lt;0.05). Importantly, PRS accounted for 76%, 73%, and 79% of the variance of changes in pBRA, STRA, and MFI after radiation. When clinical (e.g. breast volume and age) and treatment-related factors (e.g. radiation dose, chemotherapy treatment) were added as additional covariates to the respective PRS, the prediction R2 increased to 92%, 96%, and 96% for changes in pBRA, STRA, and MFI, respectively. Conclusions: Our findings indicate that over 70% of the variation in fatigue, skin thickening and breast asymmetry changes experienced by breast cancer patients after radiotherapy may be explained by PRS, which can be derived from our GWAS summary statistics and SNP data profiled from blood samples prior to radiotherapy. Genome-wide significant risk SNPs of baseline and post radiotherapy measurements of pBRA, STRA, and MFI were found only in samples of patients of African ancestry. Future studies aimed at replicating our findings in larger cohorts are needed. Citation Format: Mylin Ann Torres, Tian Liu, Boran Zhou, Xiaofeng Yang, Gabrielle Brown, India Green, Jolinta Lin, Andrew H Miller, Jingjing Yang. Polygenic risk scores predict toxicities in racially diverse breast cancer patients following radiotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-19-29.

Initial combination therapy for hypertension in patients of African ancestry: a systematic review and meta-analysis.

CRD42021238529.

Anti-RNP antibodies are associated with the interferon gene signature but not decreased complement levels in SLE

ObjectivesThe goals of these studies were to elucidate the inter-relationships of specific anti-nuclear antibody (ANA), complement, and the interferon gene signature (IGS) in the pathogenesis of systemic lupus erythematosus (SLE).MethodsData...

Comparison of Demographic and Clinical Features of Bipolar Disorder in Persons of African and European Ancestry.

This study quantified and compared demographic and clinical features of bipolar disorder (BD) in persons of African ancestry (AA) and European ancestry (EUR). Participants enrolled in the Mayo Clinic Bipolar Biobank from 2009 to 2015. The structured clinical interview for DSM-IV was used to confirm the diagnosis of BD, and a questionnaire was developed to collect data on the clinical course of illness. Descriptive statistics and bivariate analyses were completed to compare AA versus EUR participants. Subsequently, clinical outcomes were compared between AA and EUR participants using linear regression for continuous outcomes or logistic regression for binary outcomes while controlling for differences in age, sex, and recruitment site. Of 1865 participants enrolled in the bipolar biobank, 65 (3.5%) self-identified as AA. The clinical phenotype for AA participants, in comparison to EUR participants, was more likely to include a history of PTSD (39.7% vs. 26.2%), cocaine use disorder (24.2% vs. 11.9%), and tardive dyskinesia (7.1% vs. 3%). The low rate of AA enrollment is consistent with other genetic studies. While clinical features of bipolar disorder are largely similar, this study identified differences in rates of trauma, substance use, and tardive dyskinesia that may represent health disparities in bipolar patients of African ancestry. Future bipolar biomarker studies with larger sample sizes focused on underrepresented populations will provide greater ancestry diversity in genomic medicine with greater applicability to diverse patient populations, serving to inform health care policies to address disparities in bipolar disorder.

Germline sequence variants contributing to cancer susceptibility in South African breast cancer patients of African ancestry

Since the discovery of the breast cancer susceptibility genes, BRCA1 and BRCA2, various other genes conferring an increased risk for breast cancer have been identified. Studies to evaluate sequence variants in cancer predisposition genes among women of African ancestry are limited and mostly focused on BRCA1 and BRCA2. To characterize germline sequence variants in cancer susceptibility genes, we analysed a cohort of 165 South African women of self-identified African ancestry diagnosed with breast cancer, who were unselected for family history of cancer. With the exception of four cases, all others were previously investigated for BRCA1 and BRCA2 deleterious variants, and were negative for pathogenic variants. We utilized the Illumina TruSight cancer panel for targeted sequencing of 94 cancer susceptibility genes. A total of 3.6% of patients carried a pathogenic/likely pathogenic variant in a known breast cancer susceptibility gene: 1.2% in BRCA1, 0.6% in each of BRCA2, ATM, CHEK2 and PALB, none of whom had any family history of breast cancer. The mean age of patients who carried deleterious variant in BRCA1/BRCA2 was 39 years and 8 months compared to 47 years and 3 months among women who carried a deleterious variant in other breast cancer susceptibility genes.

Abstract PO-219: The implications of genetic ancestry and allostatic load on clinical outcomes in the ECOG-ACRIN adjuvant breast cancer trial E5103

Abstract Introduction: Elevated allostatic load (AL) has been associated with poor tumor prognostic features in Black breast cancer patients and worse disease specific and overall survival among cancer patients. To date, there are no studies evaluating the relationship between genetic ancestry, allostatic load and clinical trial endpoints such as completion of chemotherapy per protocol or overall survival. Prior evaluations of the ECOG-ACRIN adjuvant breast cancer trial E5103 suggests African ancestry is associated with a worse invasive disease-free survival and lower odds of chemotherapy completion. The objective of this study is to evaluate the association of genetic ancestry and AL with trial completion per protocol and with overall survival among patients in E5103. Methods: ECOG-ACRIN E5103 was a clinical trial that compared doxorubicin and cyclophosphamide (AC) for four cycles, followed by 12 weeks of weekly paclitaxel with placebo (Arm A) to the same chemotherapy with either concurrent bevacizumab (Arm B) or with concurrent plus sequential bevacizumab (Arm C) among women with node positive or high-risk node negative HER2 negative disease. Genetic ancestry groups of African ancestry (AA), European ancestry (EA) and other ancestry (OA) were determined using genome-wide single nucleotide polymorphisms. AL, at trial entry, was comprised of the biomarkers body mass index, systolic blood pressure, diastolic blood pressure, creatinine, IL6, IL10, and TNF alpha. To calculate AL, patients were awarded a point if their biomarker value was above the 75 percentile of the study sample. Logistic regression and Cox-Proportional Hazard models (odds ratio(OR) and hazard ratio (HR) estimates with corresponding 95% confidence intervals (CI)) were used to assess association with chemotherapy completion and with overall mortality. Estimates for AL were adjusted for genetic ancestry. Results: There were 348 patients in the study. The majority of the sample was of EA (EA 80%, AA 10%, OA 10%). Median (range) of AL was 2(0-6). Patients of AA (2.1(1.3)) and EA (1.88(1.4)) had a higher mean (SD) AL score compared to OA patients (0.91(1.1). On adjusted analysis, a 1 unit increased in AL was associated with a 15% reduction in the odds of completing chemotherapy per protocol (OR 0.85, 95% CI 0.72-0.99). Additionally, a 1 unit increase in AL was associated with a 14% increase in the hazard of death (HR 1.14, 95%CI 1.02-1.29). There was no association between ancestry and chemotherapy completion (AA OR 0.95, 95%CI 0.47-1.93; OA 1.82, 95%CI 0.78-4.23; ref EA) or survival (AA HR 1.40, 95% CI 0.85-2.31), OA 0.89 (0.46-1.73; ref EA). Moreover, there was no interaction between AL and ancestry. Conclusion: Among patients enrolled in E5103, AL appeared to be a better predictor of chemotherapy completion and overall survival than genetic ancestry. These results suggest life course exposure to chronic stress has implication in clinical outcomes even within the context of equivalent access to and quality of care. Citation Format: Samilia Obeng-Gyasi, Anne ONeill, Kathy D. Miller, Bryan P. Schneider, Ann H. Patridge, Lava R. Timsina, George W. Sledge, Lynne Wagner, Ruth C. Carlos. The implications of genetic ancestry and allostatic load on clinical outcomes in the ECOG-ACRIN adjuvant breast cancer trial E5103 [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-219.

Proteome Analysis Distinguishes Gallbladder Cancer from Gallstone Disease in Patients of African Ancestry

Introduction: Gallbladder cancer (GBC) has a poor 5-year survival rate prognosis suggesting the need for more effective treatment strategies. Gallstone disease has been identified as a precursor for GBC. Gallbladder tissue proteome analysis may prove beneficial in identifying key players of GBC progression. This study aimed to identify dysregulated proteins implicated in GBC progression from gallstone disease. Methods: Tissue samples were obtained from 29 GBC and 15 gallstones patients (M190555). Protein extraction was performed on tissues. Thereafter, liquid chromatography-mass spectrometry was performed using a Dionex 3000 RSLC system coupled to an AB Sciex 6600 TripleTOF mass spectrometer. A spectral library was built in Spectronaut v14 (Biognosys Schlieren, Switzerland) using the Pulsar search algorithm. Across the complete study sample set, 50,201 peptides were matched to 5,139 protein groups. Results: We observed 247 dysregulated proteins (131 upregulated and 116 downregulated) in the GBC patient group. A q-value <0.01 and fold change (FC) of >3.2 was applied, as per power analysis (0.9 power value selected) performed using the designSampleSize function within MSstats. The top upregulated proteins included MYG (FC = 7.39), SPB5 (FC = 6.21), and OLFM4 (FC = 5.57). The top downregulated proteins include RNAS2 (FC = -4.72), TRYB2 (FC = -4.38), and CNTN1 (FC = -3.90). Pathway analysis showed that the dysregulated proteins were enriched in pathways involved in metabolism and muscle contraction. Conclusion: This study has identified proteins that could distinguish GBC from gallstone disease. Further studies are ongoing to verify the dysregulation and spatial expression of these proteins.

Abstract PO-151: Prognostic relevance of ZNF668 expression in clear cell renal carcinoma: Implications for patients of African Ancestry

Abstract Although the incidence of clear cell renal carcinoma (ccRCC) is higher in Whites, a recent report suggests Blacks suffer worst outcomes relative to White ccRCC patients. These observations underscore the need to determine the molecular basis for survival disparity among Blacks and Whites in clear cell renal carcinoma patients. Since higher stage/grade ccRCC is uniformly lethal, it is imperative that biomarkers and candidate genes be found that can identify patients at greater risk of progressing to advanced stage/grade, drug-resistant clear cell renal carcinoma, as well as that, can point to the drivers of ccRCC progression in different demographic groups. Using KIRC (clear cell renal carcinoma) TCGA dataset, we have observed that ZNF668, a KRAB zinc-finger transcription factor, is significantly overexpressed in ccRCC (p=1.62E-12). Moreover, ZNF668 transcripts were significantly elevated in higher stages and grades (p&amp;lt;.001). Higher ZNF668 transcripts levels were also correlated with metastasis (p&amp;lt;0.01) and were associated with the more aggressive ccB phenotype (p&amp;lt;0.001). Overexpression was also associated with more unsatisfactory overall patient survival (p&amp;lt;.001; HR = 1.76 (1.3 − 2.37) with a median survival of 66 months for the high expression group compared to 120 months for the low expression. In addition, we observed that Blacks exhibited higher expression of ZNF668 transcripts relative to Whites (p=2.22E-04). Taken collectively, data suggests that higher levels of ZNF668 is associated with cancer progression and more aggressive ccRCC subtypes. Moreover, ZNF668 behaves in a manner that indicates that it is a negative prognostic marker and a possible oncogene in clear cell renal cell carcinoma. Lastly, higher expression in Blacks suggests this population may be particularly at risk for developing more aggressive forms of ccRCC. Citation Format: R. Renee Reams, Simone O. Heyliger, Marilyn Saulsbury. Prognostic relevance of ZNF668 expression in clear cell renal carcinoma: Implications for patients of African Ancestry [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-151.

Metabolites Levels Correlate to Tumour Stage and Survival in Pancreatic Ductal Adenocarcinoma Patients

Introduction: Pancreatic Ductal Adenocarcinoma (PDAC) is a lethal cancer with a characteristic dysregulated metabolism. Tumour cells reprogram their metabolism to maintain cell survival and increase proliferation rate. In this study, we investigated the metabolic profiles of PDAC patients of African ancestry. Methods: Upon ethics approval (Study number- M190681) from the University of Witwatersrand Human Research Ethics Committee (Medical), samples were collected from consenting individuals (34 PDAC, 6 Chronic Pancreatitis, and 6 healthy participants) and processed to serum. Nuclear Magnetic Resonance (NMR) spectroscopy was conducted, and seventy-five signals were quantified from each NMR spectrum. Spearman’s rank correlation and Kaplan Meier tests were conducted for correlation and survival analyses respectively. The Wald test was used to calculate the statistical significance of the differences between Kaplan–Meier survival curves. Results: In our patient cohort, the results demonstrated that lactate (rho=0.50; p-value < 0.001; FDR=0.012) and glycine (rho=0.52; p-value < 0.001, FDR=0.012) concentration strongly correlated directly with the disease stage. Conversely, ascorbate (rho= - 0.47; p-value=0.001, FDR=0.021) present in a decreased concentration with PDAC stages. Raised levels of 3-hydroxybutyrate (p-value= 0.015; FDR=0.370) and ethanol (p-value= 0.002; FDR=0.126) were associated with the survival time in PDAC patients and this was independent of the tumour stage. Conclusion: This pilot study demonstrates the potential utility of metabolic profiling in our patient cohort, in predicting PDAC prognosis and therefore enable the identification of high-risk patients for the late-stage disease and consequent prompt therapeutic intervention.

Disparities in Tumor Mutational Burden, Immunotherapy Use, and Outcomes Based on Genomic Ancestry in Non-Small-Cell Lung Cancer.

PURPOSEIn patients with advanced non–small-cell lung cancer (aNSCLC), tumor mutational burden (TMB) may vary by genomic ancestry; however, its impact on treatment outcomes is unclear. This retrospective, observational study describes treatment patterns of patients with aNSCLC by genomic ancestry and electronic health record (EHR)-reported race and/or ethnicity and evaluates differences in TMB, cancer immunotherapy (CIT) access, and treatment outcomes across racial and ancestral groups.METHODSPatients diagnosed with aNSCLC after January 1, 2011, were selected from a real-world deidentified clinicogenomics database and EHR-derived database; continuously enrolled patients were evaluated. Race and/or ethnicity was recorded using variables from the EHR database; genomic ancestry was classified by single-nucleotide polymorphisms on a next-generation sequencing panel. A threshold of 16 mutations per megabase was used to categorize TMB status.RESULTSOf 59,559 patients in the EHR-derived database and 7,548 patients in the clinicogenomics database, 35,016 (58.8%) and 4,392 (58.2%) were continuously enrolled, respectively. CIT use was similar across EHR-reported race groups, ranging from 34.4% to 37.3% for non-Hispanic Asian and non-Hispanic Black patients, respectively. TMB levels varied significantly across ancestry groups (P < .001); patients of African ancestry had the highest median TMB (8.75 mutations per megabase; interquartile range, 4.35-14.79). In patients who had received CIT, high TMB was associated with improved overall survival compared with low TMB (20.89 v 11.83 months; hazard ratio, 0.60; 95% CI, 0.51 to 0.70) across genomic ancestral groups.CONCLUSIONThese results suggest that equitable access to next-generation sequencing may improve aNSCLC outcome disparities in racially and ancestrally diverse populations.

Hispanic or Latin American Ancestry Is Associated with a Similar Genomic Profile and a Trend Toward Inferior Outcomes in Newly Diagnosed Multiple Myeloma As Compared to Non-Hispanic White Patients in the Multiple Myeloma Research Foundation (MMRF) CoMMpassstudy

IntroductionLarge clinical data sets suggest that the natural history and prognosis of newly diagnosed multiple myeloma (NDMM) differs between patients of European and African ancestry, with the latter group exhibiting an earlier age at onset and poorer overall prognosis in some studies. The use of next generation sequencing (NGS) to characterize the genomic landscape of multiple myeloma (MM) suggests that the observed phenotypic differences between these groups of patients may reflect distinct underlying genomic profiles and mutational processes. Thus far, characterizations of this type have focused principally on patients of African ancestry (AA). Here, we characterize the genomic features and outcomes of a large series of patients of Hispanic or Latin American ancestry (HL) as compared to their Non-Hispanic white (NHW) counterparts.MethodsSubjects were selected from the MMRF CoMMpass SM trial, a study that includes 1,154 patients with updated outcome data as of March, 2020. Within this data set, 760 patients had information on race and ethnicity. Among these, 55 HL patients and 478 NHW patients possessed complete clinical and genomic information.We analyzed baseline whole exome sequencing (WES) and long insert whole genome sequencing (WGS) as previously described (Walker, et al. Blood 2019). Our analysis focused on 63 known driver mutations in multiple myeloma and 39 sites of common copy number variation across the study population. Complex structural variants and tumor telomere length were called using previously described bioinformatic tools (Boyle et al. Leukemia 2021). Survival analysis was undertaken using the Kaplan-Meier method with hazard ratios determined by the Cox proportional hazards model.ResultsIn a comparison of clinical features between the Hispanic and NHW population, we did not identify any differences in age of onset, gender, presenting cytogenetics, International Staging System Score (ISS), and IMWG Risk Category. The proportion of patients undergoing autologous stem cell transplantation was similar between groups. We identified no statistically significant differences in the presence of characteristic translocations involving IgH locus or in hyperdiploidy status. No statistically significant differences in tumor mutational burden or loss-of-heterozygosity percentage emerged between HL and NHW patients.We examined non-synonymous variations (NSV) and copy number variations at the loci of known MM driver genes and encountered no statistically significant differences in NSV, copy number, or biallelic status. We further categorized genes into pathways relevant to the pathogenesis of MM and discovered no difference in the proportions of patients harboring mutations in genes related to the MEK/ERK and NF-κB pathways, cell cycle regulation, and epigenetic modification. We were unable to the distinguish either population based on the presence of chromothripsis or in the overall preponderance of an APOBEC mutational signature. Tumor telomere length was not significantly different between the populations.An analysis of overall and progression free survival (PFS) with a median duration of follow up of 44 months revealed a trend toward poorer outcomes among the HL population that did not reach statistical significance. Median PFS was 24 months in HL patients and 35 months in the NHW population (p = 0.19). Median OS was not reached in either ethnic subgroup. In terms of overall survival, age, ISS score, overall number of driver mutations, and the presence of chromothripsis emerged with a negative impact on outcome (Figures 1a, 1b). These variables with the exception of chromothripsis retained their significant impact on progression free survival (Figure 2a, 2b).ConclusionThe correlation between Hispanic or Latin American ancestry and underlying disease biology in MM has yet to be fully elucidated. In our analysis, which was based on self-declared ancestry as opposed to admixture, no obvious differences in significant measures of genomic variation known to impact prognosis in MM emerged between HL and NHW patients. These results may help to inform the future large-scale studies to ascertain the impact of genomics, disease biology and socioeconomic factors on outcomes in this heterogeneous patient population. [Display omitted] DisclosuresWalker: Bristol Myers Squibb: Research Funding; Sanofi: Speakers Bureau. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees.

Racial Disparities in Access to Alternative Donor Allografts Persist in the Era of “Donors for All”

Racial Disparities in Access to Alternative Donor Allografts Persist in the Era of “Donors for All”