Patients Of African Ancestry Research Articles

Abstract C022: Clinical, morphological, and immunohistochemical characterization of Nigerian prostatic adenocarcinomas: Current challenges and promising global initiatives

Abstract (A) AN INTRODUCTORY SENTENCE INDICATING THE PURPOSES OF THE STUDY: Prostate cancer, a major leading cancer among men worldwide, still poses a considerable medical and public health challenge in many parts of the world. Despite advances in screening and multimodal management of this disease, overall survival remains poor. The need to identify tumour markers as indicators for prognosis and targets for new therapeutic strategies, still remains a major challenge in prostate carcinoma research. The present study was conducted at a tertiary care teaching hospital at Uyo, South-South Nigeria to assess the expression of Ki-67 and p53 in histologically proven cases of prostatic carcinoma and to evaluate any correlation between the two as well as correlating the expression of both markers with tumour grading and scoring. (B) A BRIEF DESCRIPTION OF PERTINENT EXPERIMENTAL PROCEDURES: The study was conducted on120 histopathologically proven cases of prostate carcinoma received in ourTeaching Hospital, Uyo, South South Nigeria. Formalin fixed, paraffin embedded tissue blocks of prostate adenocarcinoma of those patients with complete clinical details were retrieved, stained and analysed for p53 and Ki67 proteins using immunohistochemistry. The results were analyzed. (C) A SUMMARY OF THE NEW, UNPUBLISHED DATA: The mean age of the prostate cancer patients was 61.7 years + 4.5 (range: 45–96 years). The most common pattern of Gleason grade seen was Group 5 (5+4) constituting 46.0% of the total cases while the Gleason score of 8-9 was the most predominant, constituting 65.0% of the total cases. The p53 positivity was observed in 31.0% of cases with percentage positive cells varying from 3-44% with mild, moderate and strong staining intensity. It was observed that with increase in the grade and score the number of cases showing positivity also increased with statistical significance seen with the same (p<0.05). The Ki-67 positivity was also observed in 10.0% of cases with percentage positive cells varying from 2-24% with moderate and strong staining intensity. It was observed that with increase in the grade and score the number of cases showing positivity also increased but no statistical significance was seen with the same. Five cases (3.3%) were positive for both p53 and Ki-67. Of the 5 cases of prostatic carcinoma positive for both Ki-67 and p53, 4 were seen in high grade tumours (80.0%) and there was statistical significance observed with increase in grade and score ((p<0.05).(D) CONCLUSIONS: The present study highlighted that the immunohistochemical expression of Ki-67 and p53 in prostate carcinoma was lower when compared to other studies. They also permit development of prognostic factors as their expression increases with increase in the grade and score as well as offering of appropriate targeted treatment leading to increase in the survival time. It is hoped that research in unraveling biology of prostatic adenocarcinomas among patients of African Ancestry (AA) and Caucasian Ancestry (CA) using more biomarkers will be carried out in the future. Citation Format: Emmanuel Kunle Abudu, Agility Ukyi-Osuwa Obi-Ihesie, Ikwo Jonathan Kudamnya, Oluwasayo Omolara Abudu. Clinical, morphological, and immunohistochemical characterization of Nigerian prostatic adenocarcinomas: Current challenges and promising global initiatives [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C022.

Abstract C075: Socioeconomic status and genetic ancestry correlate with differences in clinical outcomes for colorectal cancer patients treated at a single tertiary cancer center

Abstract Intro: Lower socioeconomic status (SES) and African ancestry have been linked to poor overall survival (OS) in colorectal cancer (CRC). To better understand the interplay between these variables, we analyzed clinical and genomic real-world data from a large cohort of patients treated at a single tertiary center. Methods: Clinical annotations including sex, primary tumor location, age and stage at diagnosis were extracted from the electronic health record for 3,817 CRC patients who underwent clinical genomic sequencing at Memorial Sloan Kettering Cancer Center between 2014 and 2022. We also cataloged each patient’s type of primary health insurance (commercial, Medicare, Medicaid or self-pay). Socioeconomic status was assessed from each patient’s billing address using the Yost index (YI), which is a location-dependent percentile score based on household incomes, house values, rent, poverty, education, and employment statistics. Genetic ancestry was determined from DNA sequencing data using reference populations from the 1000 Genomes project, including European (EUR), African (AFR), East Asian (EAS), and Southeast Asian (SAS). Specific ancestries were assigned based on an ancestral fraction of >80%, otherwise patients were labeled as admixed (ADM). OS was measured from time of diagnosis to last follow-up. Results: Our cohort included 2,627 EUR, 195 EAS, 206 AFR, 61 SAS and 728 ADM patients. The median YI within our cohort was 18 [IQR: 30]. No significant associations were observed between YI and primary tumor location, age or stage at diagnosis. We observed significant differences in YI based on type of health insurance (median 15 for commercial vs. 29 for Medicaid, p<0.0001) and sex (median 15 in males vs. 17 in females, p=0.0113). YI was also strongly associated with genetic ancestry, with AFR patients exhibiting significantly higher YI values than other ancestries (median 45.5 vs. 14, p<0.0001). No significant differences in YI were observed among EUR, EAS and SAS patients. When all ancestries were analyzed together, patients within the bottom YI quartile (most affluent) had significantly longer OS than patients from the top YI quartile (most deprived) (median 52.3 vs. 61.6 months, p=0.023). No differences in OS were observed between EUR, EAS and SAS patients, but patients of AFR ancestry had significantly shorter OS than the rest (median 44.5 vs. 56.5 months, p= 0.016). When the analysis was restricted to patients of EUR, EAS and SAS ancestry, OS was still significantly shorter for patients within the top vs. bottom YI quartile (median 52.6 vs. 64.4 months, p=0.011). Conclusions: Patients of African ancestry exhibited lower socioeconomic status and shorter survival. Even when the analysis was restricted to other genetic ancestries, patients with the lowest socioeconomic status still had poorer clinical outcomes. The existence of these differences within a relatively homogeneous cohort of patients treated at the same institution highlights the need to better understand and address health disparities in CRC. Citation Format: Tejiri Agbamu, Xuechun Bai, Henry Walch, Michele Waters, Anisha Luthra, Kanika Arora, Christopher Fong, Doori Rose, Hannah Williams, Michael Berger, Karuna Ganesh, Julio Garcia-Aguilar, Nikolaus Schultz, Rona Yaegar, Walid Chatila, Francisco Sanchez-Vega. Socioeconomic status and genetic ancestry correlate with differences in clinical outcomes for colorectal cancer patients treated at a single tertiary cancer center [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C075.

Abstract C086: Prostate cancer: Integrative multi-omics profiling in patients of African descent

Abstract In the United States and globally, prostate cancer (PCa) mortality rates are highest among men of African descent. Previous studies suggested that tumor subtypes or gene expression profiles had the greatest influence on overall racial/ethnic survival accounting for 24% of the disparities in PCa and remains even when controlled for access to care and stage at presentation. Moreover, the tumor microenvironment plays an essential role in tumor progression, aggressiveness, therapeutic response, and patient outcomes. Additionally, the association of the genomic findings with patient ancestry and other characteristics, such as tumor biology and transcriptomic alterations, remains poorly understood. Here we performed a multi-Omics approach to unravel the complexity of tumor heterogeneity and understand disease progression & distinct tumor biology influenced by genetic ancestry. We performed Spatial NanoString high-plex GeoMx-DSP (Digital Spatial Profiler) at the protein and RNA levels for a total of 118 treatment-naive PCa patients (around 500 ROIs). Simultaneously, we ran matched genome-wide sequencing (whole transcriptome) for these patients. The cohort comprised 87 AAM, 3 unknown, and 28 EAM self-reported individuals. To verify the self-reported race, the genomic ancestry was qualified using genotype and Admixture analysis. To further validate differentially expressed genes at the protein level, we performed multi-plex histological staining of 40 markers to determine the spatial resolution and neighborhood clustering within the tumor and the microenvironment. In parallel, we performed scMultiOmics sequencing (scRNA & scATAC-Seq) at a single-cell resolution (6000 cells/sample at 25K reads per cell) from an additional 12 patients (9 AAM & 3 EAM). We will use the multi-omics integration method (CoGap) to build a structural, spatial map that reflects tissue/system phenotype and to understand the complementary role of multi-omics (genome, transcriptome, and metabolite) interrelation/influence on the disease processes. Our results demonstrate that patients who self-report as AAM or Nigerian are assigned to high African (> 70%) Ancestry with either Yoruba (Nigeria) and/or Bantu subpopulation in the Sub-Saharan area. Additionally, high African Ancestry patients are diagnosed at a younger age and show advanced pathology stages compared to patients with European Ancestry. Moreover, AAM with high African Ancestry has significantly (p-value 0.05) higher CD8 +ve cells infiltration. Interestingly, segmentation and gating of the immune cell populations showed increased expression of CD8+ve cells colocalization with PD-1 signaling within African Ancestry patients. Our study provides new insight into how genetic ancestry impacts immune signatures in AAM and contributes to PCa racial disparities. Our findings could lead to new therapeutic strategies using immune modulators drugs to decrease the global disease burden, especially among men at high risk for PCa, such as AAM of African descent. Citation Format: Isra Elhussin, Ezra Baraban, Tamara L. Lotan, Cathy Handy Marshall, Emmanuel Antonarakis, Moray J. Campbell, Melissa Davis, Michael Dixon, Isaac Kim, Stefan Ambs, Rick Kittles, Adam B. Murphy, Clayton Yates. Prostate cancer: Integrative multi-omics profiling in patients of African descent [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C086.

Abstract C047: Multiomics approaches to identify African-ancestry specific phenotypes of triple negative breast cancer

Abstract Despite recent convergence of breast cancer (BC) incidence among African American (AA) and European American (EA) women, BC mortality remains 40% higher among AA women. This disparity is driven partly by BC heterogeneity, where distinct subtypes have differing prognosis and treatment modalities, defined by presence of estrogen and/or progesterone receptor (HR+), overexpression of HER2, or lack of all three biomarkers (triple negative BC (TNBC)). TNBC is the most aggressive subtype, diagnosed as late-stage disease and lacking targeted therapeutic options. TNBC represents ~10% of annual diagnoses, however prevalence is significantly higher among AA women. Our work in the International Center for the Study of Breast Cancer Subtypes (ICSBCS) revealed significant association of west African (AFR) ancestry and TNBC, where we report that Ghanaian and AA women have increased frequency of TNBC, compared to Ethiopian and EA women, and that TNBC patients have higher percentages of quantified AFR ancestry. To characterize AFR ancestry-specific TNBC phenotypes, we have employed transcriptomics and whole genome sequencing (WGS) methods. Our recent publication from an AFR ancestry enriched TNBC transcriptomics cohort (n = 26) leveraged genetic ancestry to identify 600+ AFR and 2000+ AFR sub-continental ancestry associated genes. Pathway analysis showed enrichment of immune cell trafficking and indicates distinct AFR ancestry phenotypes that can be leveraged for future therapeutic opportunities. Recently, we have completed WGS on 80+ AFR ancestry patients with TNBC disease (n = 59) and HR+ disease (n = 23); representing AA (n = 71), Ethiopian (n = 8) and Ghanaian patients (n = 3). TP53 was the most mutated gene, more commonly mutated among TNBC cases (83%) compared to HR+ cases (35%) (p < 0.0001). HR+ had significantly more GATA3 (26%) and PIK3CA (30%) mutations compared to TNBC (0% and 9%, p < 0.05). Prevalence of COSMIC mutational signatures shows higher Signature 1 among HR+ cases, and higher Signature 3 among TNBC cases (both p < 0.05). Signature 3 is associated with DNA double-strand break repair and germline BRCA1/2 mutation status, where 9 TNBC cases have elevated homologous repair deficiency status. Our genomic work utilizes the reference genome, which is primarily sequenced from a single individual. With the African Pan Genome (APG), a set of 125,000+ contigs distinct from the reference genome, we have aligned RNAseq reads to the APG that failed to map to the reference genome. Successful APG alignment of a subset of reads indicates that genes are expressed from these distinct AFR sequences. We also identified CpG sites in contigs with gene expression, showing AFR ancestry specific regulatory regions in the previously unmapped genome. We are working to determine the significance of these in the tumor microenvironment. This work represents a comprehensive, AFR ancestry enriched cohort with multiple genomic data approaches that will allow us to further characterize TNBC disease and define actionable biomarkers and targets for women of African ancestry. Citation Format: Rachel Martini, Max Chao, Timothy Chu, Brian Stonaker, Ishmael Kyei, Ernest Adjei, Mahteme Bekele, Kofi Gyan, Olivier Elemento, Nicolas Robine, John Carpten, Lisa Newman, Melissa Davis. Multiomics approaches to identify African-ancestry specific phenotypes of triple negative breast cancer [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C047.

Whole-Genome Sequencing Reveals Distinct Mutational Signatures in Multiple Myeloma Patients with African Ancestry Compared with Those of Non-African Ancestry

INTRODUCTION: Improving health outcomes for patients with African ancestry (AA) is a key healthcare aim, but there is uncertainty in whether disparities arise predominantly from socioeconomic differences or from genetic differences in tumor biology. It remains an open question as to whether multiple myeloma (MM) occurring in AA patients has a similar or different spectrum of genomic abberations when compared to patients having European ancestry. To date, studies have suggested that AA have an excess of t(11;14) and a deficiency of TP53 mutations. We have established a series of 302 cases of MM precursor and newly diagnosed MM with whole-genome sequencing (WGS) available that is enriched for self-declared AA or diverse ethnic background. METHODS: In collaboration with the NYGC and Polyethnic-1000 consortium, we sequenced tumor samples to a depth of 60-80X and normal tissue to 30-40X. We a employed bioinformatics pipeline with a consensus mechanism for somatic variant calling, including Mutect2, Strelka2, and VarScan2 for SNVs; Mutect2, Strelka2, VarScan2, and SvABA for InDels; Battenberg and FACETS for CNVs; Manta, SvABA, DELLY2, and IgCaller for SVs. Additionally, an admixture workflow was used to estimate each individual's ancestral lineage using continentally-distinct references, comprising 23 regional populations within 5 super-populations from the 1000 Genomes Project (https://github.com/pblaney/mgp1000). Mutational signature were calculated using the R package mmsig (Rustad et al. Comm. Bio. 2021). RESULTS: Using admixture estimations from 302 patients with high-coverage WGS together with 941 patients from the CoMMpass trial, we identified five clusters corresponding to single dominant genetic ancestries (median proportion >75% assignment to reference super-population), together with a cluster characterized by highly admixed individuals with no dominant genetic ancestry (median proportion <50%). Of the total, 53.0% are in the European dominant (EUR) cluster, 26.5% African dominant (AFR), 8.6% American dominant (AMR), 7.9% highly admixed, 2.0% East Asian dominant (EAS) and South-East Asian dominant (SAS) clusters, respectively. Stratifying patients by their cluster assignment and calculating the frequency of subtype translocations, we show that t(11;14) occurred in 25.8% of EUR patients while in only 14.6% of AFR (p=0.045) and 7.7% of AMR (p=0.05) patients. The frequency of the t(4;14) was more closely distributed, with 15.7% in EUR, 11.5% in AMR, and 11% in AFR clusters. For the acquired somatic mutations, the tumor mutational burden (TMB) was lowest in the AFR cluster 2.21 (median, somatic mutations per Mb), significantly lower by comparison to the EUR cluster at 2.94 (FDR adj. P=4.3x10 -6). The most striking genomic difference was observed when comparing the mutational signatures landscape between AA and the other racial groups. Using WGS, AA had lower SBS1 and SBS5 absolute contribution compared to EUR, and this was largely responsible for the difference in TMB. SBS1 and SBS5 are known to be clock-like signatures, accumulating at a constant rate over time. Because no differences in age, cancer cell fraction, and coverage were observed between AA and EUR, this finding suggest different mutational clock-like rate between AA and EUR. The higher TMB observed in EUR was also driven by the higher APOBEC-mutational activity (SBS2 and SBS13) compared to AA (p=0.05). Interestingly, 72% of all EUR had APOBEC-activity evident, in contrast to 45% of the AA (p=0.001). This difference was confirmed after excluding the MM precursor patients, previously demonstrated to have lower APOBEC-activity (Oben et al. Natur Comm. 2021), and was validated on CoMMpass whole-exomes. CONCLUSIONS: Leveraging one of the largest series of diverse patients with WGS, and integrating genomic data with comprehensive ancestry information, AA MM emerged as biologically different in term of genomic drivers and mutational signatures, suggesting potential differences in etiology and genomic evolution over time. Further analysis will include molecular timing of clonal copy number gains, and reconstruction of phylogenetic trees, with view to improving our understanding of the etiology of MM development across patient genetic backgrounds. FIGURE: Genomic characteristics of myeloma across ancestries. A) Translocation percentage (number per cluster) and B) Tumor mutational burden across clusters.

Leveraging stories of cardiac amyloidosis patients of African ancestry or descent to support patient-derived data elements for efficient diagnosis and treatment

Leveraging stories of cardiac amyloidosis patients of African ancestry or descent to support patient-derived data elements for efficient diagnosis and treatment

Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer

IntroductionThe increase in incidence of colorectal cancer in young patients of African ancestry coupled with increased aggressiveness has warranted investigation of the heritable nature of these cancers. Only a limited number of published reports of hereditary colorectal cancer in indigenous African populations have been reported and no systematic screening of these groups has been performed previously. We aimed to investigate causative germline variants and to establish the incidence of pathogenic/likely pathogenic germline variants in the known colorectal cancer genes in indigenous African colorectal cancer patients using a next-generation sequencing (NGS) multigene panel.Materials and methodsPatients were selected from two hospitals in Cape Town and Johannesburg, South Africa. Patients with unresolved molecular diagnosis with an age of onset below or at 60 years were selected. Germline DNA samples were analyzed using a 14-gene NGS panel on the Ion Torrent platform. Variant calling and annotation were performed, and variants were classified according to the American College of Medical Genetics and Genomics guidelines. Observed variants were verified by Sanger sequencing and/or long-range PCR.ResultsOut of 107 patients, 25 (23.4%) presented with a pathogenic/likely pathogenic germline variant (PGV). Fourteen PGVs in at least one mismatch repair (MMR) gene were identified and verified in 12 patients (11.2%). Of these MMR gene variants, five were novel. The remaining 10 PGVs were in the APC, BMPR1A, MUTYH, POLD1, and TP53 genes.ConclusionThe high incidence of PGVs associated with early-onset colorectal cancer in indigenous African patients has important implications for hereditary colorectal cancer risk management. These findings pave the way for personalized genetic screening programs and cascade testing in South Africa. The next step would involve further screening of the unresolved cases using tools to detect copy number variation, methylation, and whole exome sequencing.

A feasible molecular diagnostic strategy for rare genetic disorders within resource-constrained environments

Timely and accurate diagnosis of rare genetic disorders is critical, as it enables improved patient management and prognosis. In a resource-constrained environment such as the South African State healthcare system, the challenge is to design appropriate and cost-effective assays that will enable accurate genetic diagnostic services in patients of African ancestry across a broad disease spectrum. Next-generation sequencing (NGS) has transformed testing approaches for many Mendelian disorders, but this technology is still relatively new in our setting and requires cost-effective ways to implement. As a proof of concept, we describe a feasible diagnostic strategy for genetic disorders frequently seen in our genetics clinics (RASopathies, Cornelia de Lange syndrome, Treacher Collins syndrome, and CHARGE syndrome). The custom-designed targeted NGS gene panel enabled concurrent variant screening for these disorders. Samples were batched during sequencing and analyzed selectively based on the clinical phenotype. The strategy employed in the current study was cost-effective, with sequencing and analysis done at USD849.68 per sample and achieving an overall detection rate of 54.5%. The strategy employed is cost-effective as it allows batching of samples from patients with different diseases in a single run, an approach that can be utilized with rare and less frequently ordered molecular diagnostic tests. The subsequent selective analysis pipeline allowed for timeous reporting back of patients results. This is feasible with a reasonable yield and can be employed for the molecular diagnosis of a wide range of rare monogenic disorders in a resource-constrained environment.

Will ChatGPT3 Substitute for us as Clozapine Experts?

ChatGPT3 is a new artificial intelligence program released on February 13, 2023. The authors tested ChatGPT3 on February 18, 2023, and repeated the test a week later. They used their expertise on the effects of ethnic ancestry in the stratification of clozapine dosing and the new idea that they published in March 2022 that African-Americans need higher clozapine doses because they have higher clozapine clearance. In the first interaction on February 18, ChatGPT3 provided reasonable and very up-to-date information, which included a comment that patients of African ancestry have higher clozapine metabolism. The other 4 interactions became progressively more concerning as we asked ChatGPT3 to provide references to justify the latter statement. ChatGPT3 provided non-existent "references" using articles from real journals, with real authors, false PubMed identifiers, and false titles. Moreover, ChatGPT3 said that the first author wrote in 2003 that African-Americans had higher CYP1A2 activity when that did not happen until 2022. One week later, the second author repeated the same set of questions. This time ChatGPT3 described the opposite, that African-Americans have "lower" CYP1A2 activity and "slower" metabolism. ChatGPT3 provided another set of articles to justify the information; some were real but did not comment on clozapine metabolism in African-Americans while others did not exist. ChatGPT3 provided a mixture of truth, twisted reality, and non-existent "facts." Within one week it defended opposite positions regarding a clinically relevant issue such as using higher or lower clozapine doses in African-Americans.

Role of the I416L Variant of Complement Factor I in Thrombotic Microangiopathy Among Patients of African Ancestry

Role of the I416L Variant of Complement Factor I in Thrombotic Microangiopathy Among Patients of African Ancestry

Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry

Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients. To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM. Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance. Presence of DCM. Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic). A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001). Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.

Unique Spectrum of Activating BRAF Alterations in Prostate Cancer.

Alterations in BRAF have been reported in 3% to 5% of prostate cancer, although further characterization is lacking. Here, we describe the nature of BRAF alterations in prostate cancer using a large cohort from commercially available tissue and liquid biopsies subjected to comprehensive genomic profiling (CGP). Tissue and liquid biopsies from patients with prostate cancer were profiled using FoundationOne CDx and FoundationOne Liquid CDx CGP assays, respectively. Tissue biopsies from non-prostate cancer types were used for comparison (n = 275,151). Genetic ancestry was predicted using a single-nucleotide polymorphism (SNP) based approach. Among 15,864 tissue biopsies, BRAF-activating alterations were detected in 520 cases (3.3%). The majority (463 samples, 2.9%) harbored class II alterations, including BRAF rearrangements (243 samples, 1.5%), K601E (101 samples, 0.6%), and G469A (58 samples, 0.4%). BRAF-altered prostate cancers were enriched for CDK12 mutations (OR, 1.87; 9.2% vs. 5.2%; P = 0.018), but depleted in TMPRSS2 fusions (OR, 0.25; 11% vs. 32%; P < 0.0001), PTEN alterations (OR, 0.47; 17% vs. 31%; P < 0.0001), and APC alterations (OR, 0.48; 4.4% vs. 8.9%; P = 0.018) relative to BRAF wild-type (WT) disease. Compared with patients of European ancestry, BRAF alterations were more common in tumors from patients of African ancestry (5.1% vs. 2.9%, P < 0.0001) and Asian ancestry (6.0% vs. 2.9%, P < 0.001). Activating BRAF alterations were detected in approximately 3% of prostate cancers, and most were class II mutations and rearrangements; BRAF V600 mutations were exceedingly rare. These findings suggest that BRAF activation in prostate cancer is unique from other cancers and supports further clinical investigation of therapeutics targeting the mitogen-activated protein kinase (MAPK) pathway.

Unique Genomic Alterations and Microbial Profiles Identified in Patients With Gastric Cancer of African, European, and Asian Ancestry: A Novel Path for Precision Oncology.

Here, we characterize differences in the genetic and microbial profiles of GC in patients of African (AFR), European, and Asian ancestry. Gastric cancer (GC) is a heterogeneous disease with clinicopathologic variations due to a complex interplay of environmental and biological factors, which may affect disparities in oncologic outcomes.. We identified 1042 patients with GC with next-generation sequencing data from an institutional Integrated Mutation Profiling of Actionable Cancer Targets assay and the Cancer Genomic Atlas group. Genetic ancestry was inferred from markers captured by the Integrated Mutation Profiling of Actionable Cancer Targets and the Cancer Genomic Atlas whole exome sequencing panels. Tumor microbial profiles were inferred from sequencing data using a validated microbiome bioinformatics pipeline. Genomic alterations and microbial profiles were compared among patients with GC of different ancestries. We assessed 8023 genomic alterations. The most frequently altered genes were TP53 , ARID1A , KRAS , ERBB2 , and CDH1 . Patients of AFR ancestry had a significantly higher rate of CCNE1 alterations and a lower rate of KRAS alterations ( P < 0.05), and patients of East Asian ancestry had a significantly lower rate of PI3K pathway alterations ( P < 0.05) compared with other ancestries. Microbial diversity and enrichment did not differ significantly across ancestry groups ( P > 0.05). Distinct patterns of genomic alterations and variations in microbial profiles were identified in patients with GC of AFR, European, and Asian ancestry. Our findings of variation in the prevalence of clinically actionable tumor alterations among ancestry groups suggest that precision medicine can mitigate oncologic disparities.

Analysis of Structural Variants Previously Associated With ALS in Europeans Highlights Genomic Architectural Differences in Africans.

Amyotrophic lateral sclerosis (ALS) is a degenerative condition of the brain and spinal cord in which protein-coding variants in known ALS disease genes explain a minority of sporadic cases. There is a growing interest in the role of noncoding structural variants (SVs) as ALS risk variants or genetic modifiers of ALS phenotype. In small European samples, specific short SV alleles in noncoding regulatory regions of SCAF4, SQSTM1, and STMN2 have been reported to be associated with ALS, and several groups have investigated the possible role of SMN1/SMN2 gene copy numbers in ALS susceptibility and clinical severity. Using short-read whole genome sequencing (WGS) data, we investigated putative ALS-susceptibility SCAF4 (3'UTR poly-T repeat), SQSTM1 (intron 5 AAAC insertion), and STMN2 (intron 3 CA repeat) alleles in African ancestry patients with ALS and described the architecture of the SMN1/SMN2 gene region. South African cases with ALS (n = 114) were compared with ancestry-matched controls (n = 150), 1000 Genomes Project samples (n = 2,336), and H3Africa Genotyping Chip Project samples (n = 347). There was no association with previously reported SCAF4 poly-T repeat, SQSTM1 AAAC insertion, and long STMN2 CA alleles with ALS risk in South Africans (p > 0.2). Similarly, SMN1 and SMN2 gene copy numbers did not differ between South Africans with ALS and matched population controls (p > 0.9). Notably, 20% of the African samples in this study had no SMN2 gene copies, which is a higher frequency than that reported in Europeans (approximately 7%). We did not replicate the reported association of SCAF4, SQSTM1, and STMN2 short SVs with ALS in a small South African sample. In addition, we found no link between SMN1 and SMN2 copy numbers and susceptibility to ALS in this South African sample, which is similar to the conclusion of a recent meta-analysis of European studies. However, the SMN gene region findings in Africans replicate previous results from East and West Africa and highlight the importance of including diverse population groups in disease gene discovery efforts. The clinically relevant differences in the SMN gene architecture between African and non-African populations may affect the effectiveness of targeted SMN2 gene therapy for related diseases such as spinal muscular atrophy.

#3155 APOL1 GENOTYPE IS A MAJOR DETERMINANT OF LUPUS NEPHRITIS SEVERITY IN PATIENTS OF AFRICAN ANCESTRY

Abstract Background and Aims Two polymorphisms of APOL1 gene, G1 and G2, exclusively found among patients of African ancestry, have been associated with chronic kidney disease (CKD) and end-stage kidney disease (ESKD)1. These high-risk polymorphisms have also been associated with collapsing glomerulopathy in various diseases. We aimed to evaluate the impact of APOL1 G1 and G2 polymorphisms on the clinical and pathological course LN which is already known to be more severe among patients of African ancestry2. Method We included patients from 6 hospitals in Paris and Marseille in France, between January 2017 and March 2020, with biopsy-proven LN, African ancestry and age &amp;gt;18 years at the time of inclusion. We excluded those with HIV infection. The data were retrospectively collected at LN diagnosis, 1 year after diagnosis and at last follow-up. APOL1 genotyping was performed and we divided patients in 2 groups: the high-risk genotype (HRG) group with 2 risk alleles and the low risk genotype (LRG) group with 1 or 0 risk allele. All patients signed a consent form for the genetic analysis and protocol approval was obtained from the ethic committee CERAPHP (Comité d'Ethique de la Recherche AP-HP Centre), registration number 00011928. Results Ninety-nine patients were included in the study, 13 in the HRG group and 86 in the LRG group. The median duration between LN diagnosis and inclusion in the study was 9.6 years [4.9-16.9]. At LN diagnosis, clinical and biological characteristics were similar except for kidney function that was lower in the HRG group compared to the LRG group with a median serum creatinine of 131μmol/L [69-687] versus 66μmol/L [52-133] (p = 0.0085). Patients in the HRG group were more likely to have a serum creatinine above 200 μmol/L compared to the LRG group (45.5% versus 10.5%, p = 0.0096, OR 7.1[1.8-28.6]), and required acute haemodialysis more frequently (30.8% versus 1.3% respectively, p = 0.0012, OR 34.7[3.5-345.1]). Collapsing glomerulopathy was more frequent in the HRG group (45.5% of patients, versus 4.5%, OR 17.5[3.3-91.9], p = 0.001). No significant difference was observed in the proportion of kidney response at 12 months, however, patients in the HRG group were more likely to develop CKD (33.3% versus 4.9%, OR 9.6[2.0-46.1]). Median follow-up from LN diagnosis to the end of study, ESKD or last follow-up was 7.9 years [3.4-13.3] and was similar between the 2 groups. At last follow-up, median eGFR was 22mL/min/1.73m2 [10-98] vs 99mL/min/1.73m2 [55-118] respectively, p = 0.0189. Survival without ESKD was poorer in the HRG group than in the LRG group with a hazard ratio (HR) of 5.0[1.6-15.8], p = 0.006, even after adjusting with the kidney response at 12 months (adjusted HR 6.24[1.8-21.6], p = 0.004) (Figure 1). Conclusion APOL1 genotype affects LN prognosis, resulting in a worse kidney function at diagnosis, development of collapsing glomerulopathy and higher risk of subsequent ESKD. Kidney survival remained significantly lower in the HRG group, after adjustment for kidney response at 12 months, suggesting that the prognosis of LN is heavily driven by APOL1 genotype regardless of the kidney response. APOL1 inhibitors are currently being developed, and could be used in the next future, for HRG patients with primary or secondary forms of collapsing glomerulopathy.

Abstract A045: Whole transcriptome analysis of paired African American prostate cancer cell lines

Abstract Recent investigations on patient race have begun to characterize biological differences in prostate cancer, particularly among patients of African ancestry. Despite clinical trends continuously demonstrating this health disparity, very few African American cell line models exist for downstream molecular investigations, and even fewer have undergone proper characterization of their expression profiles. Here, we characterize the transcriptome of the non-malignant RC-77 N/E and malignant RC-77 T/E prostate epithelial cell lines previously established from prostate specimens from the same African American patient with early-stage primary prostate cancer. Total RNA sequencing was performed on the paired cell lines using Illumina NextSeq 2000 P2 to build transcriptomic profiles that have previously been undetermined. Following data analysis and normalization, we identified 369 genes with significant upregulation in the RC-77 T/E cell line in comparison to its normal counterpart. Among the top 15 upregulated genes, half of them were previously characterized in prostate cancer but not in the context of patient race. We further compared the transcriptome of RC-77 T/E to that of the African American metastatic MDA-PCa-2b. Finally, we analyzed differential gene expression by race among prostate cancer patients in The Cancer Genome Atlas (TCGA) to correlate our transcriptomics findings on the cell line level with that on the population level. These findings may allow for more targeted assessments of genes that are dependent on race as molecular tools are established to narrow the health disparities gap in prostate cancer. Citation Format: Kristi Y. Lee, Erica L. Beatson, Cindy H. Chau, Douglas K. Price, William D. Figg. Whole transcriptome analysis of paired African American prostate cancer cell lines [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A045.

Abstract 1908: Clinical genomic profiling identifies lower frequency of therapeutically actionable alterations and lower prognostic value of APC inactivation in colorectal cancer patients of African ancestry

Abstract Intro. We compared molecular profiles and clinical outcomes in a large cohort of colorectal cancer (CRC) patients treated at a single tertiary center to investigate differences in the frequency of therapeutically targetable alterations and the prognostic value of somatic driver alterations across ancestry groups. Methods. We analyzed targeted DNA sequencing data from 4,441 CRC patients treated at Memorial Sloan Kettering between 2014 and 2022. Tumors were sequenced using MSK-IMPACT, a next-generation tumor-normal sequencing assay containing up to 505 genes. Genetic ancestry was estimated using reference populations from the 1000 Genomes Project, including European (EUR), African (AFR), East Asian (EAS), South Asian (SAS), and Native American (NAM). Patients were assigned specific ancestry labels when the predominant ancestry fraction was &amp;gt;80% and considered to have admixed ancestry (ADM) otherwise. Clinical actionability of individual genomic features was determined using the OncoKB knowledgebase. Results. Our cohort included 3,265 EUR, 263 EAS, 245 AFR, 89 SAS, and 15 NAM patients; 564 ADM patients were excluded from subsequent analyses. The AFR group had shorter overall survival (OS) from time of diagnosis (median 45.7 months vs. 67.1 months, p&amp;lt;0.0001). The fraction of patients who qualify for immunotherapy based on FDA guidelines, including microsatellite unstable (MSI) or highly mutated (TMB&amp;gt;10 mut/Mb), was lower in AFR vs. EUR (13.5% vs. 20.4%, p=0.008) patients. Among microsatellite stable (MSS) and not highly mutated (TMB&amp;lt;10 mut/Mb) patients, AFR patients had lower rates of clinically actionable alterations than EUR patients (5.6% vs 11.2%, p=0.01). This difference was driven by a depletion of actionable BRAF mutations in the AFR group (1.8% vs. 5.0%, p=0.04). Somatic APC alterations were associated with longer OS in MSS EUR patients (median 64.6 months in APC altered vs. 45.6 months in APC wildtype, p&amp;lt;0.0001), EAS patients (median 63.1 vs. 35.0 months, p=0.0015), and SAS patients (median not reached vs. 39.4 months, p=0.012). However, APC alterations exhibited no prognostic value for the AFR patients (median OS 45.0 vs. 45.9 months, p=0.91). Multivariate analyses accounting for sex, age, primary tumor location, and stage at diagnosis showed an association between APC status and OS in EUR patients (HR 0.64, CI 0.52-0.79, p&amp;lt;0.001), but not in AFR patients (HR 0.74, CI 0.31-1.7, p=0.492). Conclusions. AFR patients had fewer clinically actionable alterations than patients from other ancestries. The prognostic value of somatic APC alterations was also lower in AFR patients. Our findings provide novel insights into the genomic basis of racial disparities in CRC and highlight the need of ancestry stratification for the analysis of associations between molecular profiles and clinical outcomes. Citation Format: Henry Walch, Anisha Luthra, Kanika S. Arora, Michele Waters, Samantha Chin, Christopher J. Fong, Doori Rose, Hannah Williams, Jeese J. Smith, Nikolaus Schultz, Michael F. Berger, Karuna Ganesh, Julio Garcia-Aguilar, Rona Yaeger, Walid K. Chatila, Francisco Sanchez-Vega. Clinical genomic profiling identifies lower frequency of therapeutically actionable alterations and lower prognostic value of APC inactivation in colorectal cancer patients of African ancestry [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 1908.

Molecular profiling of a real-world breast cancer cohort with genetically inferred ancestries reveals actionable tumor biology differences between European ancestry and African ancestry patient populations

BackgroundEndocrine-resistant HR+/HER2- breast cancer (BC) and triple-negative BC (TNBC) are of interest for molecularly informed treatment due to their aggressive natures and limited treatment profiles. Patients of African Ancestry (AA) experience higher rates of TNBC and mortality than European Ancestry (EA) patients, despite lower overall BC incidence. Here, we compare the molecular landscapes of AA and EA patients with HR+/HER2- BC and TNBC in a real-world cohort to promote equity in precision oncology by illuminating the heterogeneity of potentially druggable genomic and transcriptomic pathways.MethodsDe-identified records from patients with TNBC or HR+/HER2- BC in the Tempus Database were randomly selected (N = 5000), with most having stage IV disease. Mutations, gene expression, and transcriptional signatures were evaluated from next-generation sequencing data. Genetic ancestry was estimated from DNA-seq. Differences in mutational prevalence, gene expression, and transcriptional signatures between AA and EA were compared. EA patients were used as the reference population for log fold-changes (logFC) in expression.ResultsAfter applying inclusion criteria, 3433 samples were evaluated (n = 623 AA and n = 2810 EA). Observed patterns of dysregulated pathways demonstrated significant heterogeneity among the two groups. Notably, PIK3CA mutations were significantly lower in AA HR+/HER2- tumors (AA = 34% vs. EA = 42%, P < 0.05) and the overall cohort (AA = 28% vs. EA = 37%, P = 2.08e−05). Conversely, KMT2C mutation was significantly more frequent in AA than EA TNBC (23% vs. 12%, P < 0.05) and HR+/HER2- (24% vs. 15%, P = 3e−03) tumors. Across all subtypes and stages, over 8000 genes were differentially expressed between the two ancestral groups including RPL10 (logFC = 2.26, P = 1.70e−162), HSPA1A (logFC = − 2.73, P = 2.43e−49), ATRX (logFC = − 1.93, P = 5.89e−83), and NUTM2F (logFC = 2.28, P = 3.22e−196). Ten differentially expressed gene sets were identified among stage IV HR+/HER2- tumors, of which four were considered relevant to BC treatment and were significantly enriched in EA: ERBB2_UP.V1_UP (P = 3.95e−06), LTE2_UP.V1_UP (P = 2.90e−05), HALLMARK_FATTY_ACID_METABOLISM (P = 0.0073), and HALLMARK_ANDROGEN_RESPONSE (P = 0.0074).ConclusionsWe observed significant differences in mutational spectra, gene expression, and relevant transcriptional signatures between patients with genetically determined African and European ancestries, particularly within the HR+/HER2- BC and TNBC subtypes. These findings could guide future development of treatment strategies by providing opportunities for biomarker-informed research and, ultimately, clinical decisions for precision oncology care in diverse populations.

P4 TRANSTHYRETIN–INDUCED CARDIAC AMYLOIDOSIS: A RARE MUTATION IN AN ITALIAN FAMILIAL CASE

Abstract A 65–year–old man came to our hospital for a subacute stroke of the left parietotemporal area. An aorto–coronary bypass for stable coronary artery disease and aortobisiliac bypass for infrarenal aortic aneurysm (with post–operative courses complicated by multiple atrial fibrillation paroxisms which were pharmacologically cardioverted) was reported. No undergoing anticoagulant therapy for CHADSVASc=1 was reported. Hypothesizing a cardioembolic origin of the stroke, echocardiographic analysis was performed which showed increased ventricular thickness and mass, inhomogeneous texture, reduced systolic function and strain with apical sparing, II degree diastolic dysfunction and severe left atrial dilatation. The strong suspicion of amyloidosis, raised by the echocardiographic findings, was confirmed by bone scintigraphy. The absence of free immunoglobulin chains in blood and urine and a normal protein electrophoretic pattern, would have instead excluded the diagnosis of AL amyloidosis. Thus we performed genetic testing to characterize the type of ATTR (transthyretin). An homozygous Val142Ile mutation in exon 4 of the TTR gene was found. This mutation, typically found in patients of African ancestry, is extremely rare in the Caucasian population. In fact, only 5 cases of patients with this mutation and with phenotypic manifestations very similar to the African ancestral ones have been so far reported, thus indicating that this mutation is not restricted to African ancestry but may be an underestimated Caucasian variant. The large GnomAD database estimates that this homozygous mutation is present in only 0.72% of the general population, while the remaining part of the carriers are heterozygous. Val142Ile leads to increased formation of amyloid fibrils and to the formation of a particularly unstable TTR tetramer. This variant is associated with a worse quality of life, a higher incidence of AF and a lower survival than the wild type TTR. In light of the worse clinical outcomes associated to this variant it is therefore essential to maintain a high level of clinical suspicion in order to perform an early diagnosis from a clinical and molecular point of view in order to be able to direct the patient as soon as possible to the current available therapies that can modify the course of the pathology and avoid premature fatal events.

APOL1 and the risk of adverse renal outcomes in patients of African ancestry with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) disproportionately affects individuals of African ancestry (AA) compared to European ancestry (EA). In the general population, high risk (HR) variants in the apolipoprotein L1 (APOL1) gene increase the risk of renal and hypertensive disorders in individuals of AA. Since SLE is characterized by an interferon signature and APOL1 expression is driven by interferon, we examined the hypothesis that APOL1 HR genotypes predominantly drive higher rates of renal and hypertensive-related comorbidities observed in SLE patients of AA versus those of EA. We performed a retrospective cohort study in patients with SLE of EA and AA using a genetic biobank linked to de-identified electronic health records. APOL1 HR genotypes were defined as G1/G1, G2/G2, or G1/G2 and low risk (LR) genotypes as 1 or 0 copies of the G1 and G2 alleles. To identify renal and hypertensive-related disorders that differed in prevalence by ancestry, we used a phenome-wide association approach. We then used logistic regression to compare the prevalence of renal and hypertensive-related disorders in EA and AA patients, both including and excluding patients with the APOL1 HR genotype. In a sensitivity analysis, we examined the association of end stage renal disease secondary to lupus nephritis (LN-related ESRD) with ancestry and the APOL1 genotype. We studied 784 patients with SLE; 195 (24.9%) were of AA, of whom 27 (13.8%) had APOL1 HR genotypes. Eighteen renal and hypertensive-related phenotypes were more common in AA than EA patients (p-value ≤ 1.4E-4). All phenotypes remained significantly different after exclusion of patients with APOL1 HR genotypes, and most point odds ratios (ORs) decreased only slightly. Even among ORs with the greatest decrease, risk for AA patients without the APOL1 HR genotype remained significantly elevated compared to EA patients. In the sensitivity analysis, LN-related ESRD was more prevalent in SLE patients of AA versus EA and AA patients with the APOL1 HR genotype versus LR (p-value < .05 for both). The higher prevalence of renal and hypertensive disorders in SLE patients of AA compared to those of EA is not fully explained by the presence of APOL1 high risk variants.