e17631 Background: Endometrial cancer is the most common gynecological malignancy in the United States. Endometrial cancer disproportionately affects black women in terms of incidence and survival despite advancement in treatment, and preventive strategies. Identifying distinct tumor markers in patients with African ancestry will help distinguish biological determinants underlying the disparities in endometrial cancer. In this study, we investigated the genetic alterations in endometrial cancer in individuals of African (AFR) ancestry using The Cancer Genome Atlas (TCGA). Methods: The genomic and clinical data of TCGA PanCancer Atlas uterine corpus endometrial carcinoma (UCEC) were explored using CBioportal (http://www.cbioportal.org/). We utilized The Cancer Genome Ancestry Atlas (TCGAA) and LAMP for estimates of genetic ancestry and quantitative ancestral composition. This dataset contains 529 patients, including 357 self-reported whites and 107 blacks. For each case the proportion of European, West African, East Asian, Native American ancestry was estimated. The dominant ancestry was defined as ≥50% of admixture from one reference population. Differences in gene mutation frequency were analyzed based on AFR ancestry proportion. The Kaplan-Meier curves were generated, and Cox regression analyses were performed. Results: Global genetic ancestry analysis identified 115 AFR ancestry cases with mean ancestry of 80.4%. The dominant AFR ancestry subject matched the self-reported race with 94% accuracy. We identified 23 subjects with ≥90% AFR ancestry, 43 subjects with 80-90% AFR ancestry, 34 subjects with 70-80% AFR ancestry, and 15 subjects with 50-70% AFR ancestry. TP53 was the most frequently mutated gene in patients with AFR ancestry(49.5%). ≥90% AFR ancestry had the highest rate of TP53 mutations (52.2%) compared with 80-90% AFR ancestry (51.2%), 70-80% AFR ancestry (43.8%), and 50-70% AFR ancestry (41.7%). PTEN was less commonly mutated in patients with higher proportion of AFR ancestry (47.8% in ≥90% AFR ancestry, 39.0% in 80-90% AFR ancestry, 59.4% in 70-80% AFR ancestry, and 66.7% in 50-70% AFR ancestry). PIK3CA mutation frequency was almost identical in all AFR ancestry groups studied. No significant differences in overall survival was observed between AFR ancestry groups. Conclusions: We aimed to investigate the etiology of endometrial cancer disparities by analyzing the effect of ancestry on genetic alterations in endometrial cancer. This study demonstrated differences in the mutation frequency among patients with AFR ancestry. We have shown that TP53 mutations were seen more frequently in patients with higher AFR ancestry, which may confer a poorer prognosis. Nonetheless, to validate the findings of this study, future studies should be conducted with larger sample sizes and more diverse ancestral groups to explore how genetic ancestry impacts tumorigenesis and cancer progression.

e15086 Background: Genomic mutations play an important role in cancer pathogenesis and can be used as targeted agents for treatment. Cancer related biomarkers in body fluids and tissues are being used to identify specific target genes. They also help in predictive and prognostic assessment related to the disease. Various platforms like guardant 360, foundation act, oncotype are commercially available. Specific genomic aberrations have enhanced the field of Precision Medicine in individualizing treatment protocols. Methods: Prospective data was collected from 45 African American patients at our institution using the commercially available Genomic Enabled Medicine ExTra cancer panel (Ashion Analytics). Sample include 18 types of cancer (10 breast, 9 colorectal, 5 endometrium, 4 prostate, 3 uterine, 2 cervical, 1 pancreas, 1 gallbladder, 1 melanoma, 1 larynx, 1 gastric, 1 carcinoid, 1 carcinosarcoma, 1 lymphoma, 1 ovary, 1 bladder, 1 thyroid). Both tumor and normal DNA were collected from year 2019 through 2020. For comparison, clinical and genomic, The Cancer Genome Atlas (TCGA) data for 1,065 African American adults with solid tumors were downloaded from the NCI Genome Data Common portal. The two data sets were eventually compared for identifying common genetic mutations and possible new targets for cancer management. Results: Of the 45 patients, 38 patients (84%) had at least one genomic alteration, and 38 known driver mutations were identified. Their median age was 56 years (range, 37 – 94). TP53 mutations were most common, identified in 44% of patients versus 37% in African Americans in TCGA. PIK3CA and KRAS mutations were next most common (22% and 20%, respectively) compared to TCGA African American samples (13% and 12%, respectively). The most frequent mutations on PIK3C were H1047R in 4 patients (8.8%), followed by E545K in 3 patients (6.6%). Oncogenic mutations were observed in APC, PTEN, ARID1A, FBXW7, NF1, PIK3R1, RNF43, ATM, CCNE1. Conclusions: In our study, we found higher prevalence of oncogenic driver gene mutations (including TP53, PIK3CA, KRAS, APC, PTEN, ARID1A) in African American cancer patients compared to TCGA African American cancer patients. It is important to note that high percentage of our patients had actionable oncogenic drivers that may be useful in treatment decision-making. Our aim is to continue to build on our database on African American patients for identifying specific and common gene mutations to enhance development of targeted agents.

3621 Background: Colorectal cancer is the second leading cause of cancer deaths in the world to affect both men and women. Racial disparities have been known to affect the disease diagnosis and progression, and proliferative genomic studies have been undertaken to elucidate their relationship. In this study, we investigate the tumor mutation profile in colorectal adenocarcinoma (COAD) based on genetic ancestry using The Cancer Genetic Ancestry Atlas (TCGAA). Methods: 59 AA (African American) individuals in TCGAA COAD dataset were identified. To account for and eliminate the biases introduced by self-identification of races, we utilized TCGAA genomic analysis to accurately estimate the ancestral genomic composition of each individual. For each individual, percentages of European (EA), West African (WA), East Asian (EAA), and Native American (NA) ancestry were identified based on Local Ancestry in adMixed Populations (LAMP). Individuals were screened for dominant WA ancestry (≥50% based on LAMP) and assigned to three groups, ≥90%, 80-89%, and 50-79%. Differences in gene mutation frequency and overall survival were compared among the three subgroups of individuals with WA ancestry. Results: Based on genomic ancestry analysis, 58 individuals with dominant WA ancestry (Range 53%-100%) were identified. We classified them into three groups based on percentage of WA ancestry: ≥90% (n = 17), 80-89% (n = 26), and 50-79% (n = 15). APC was the most frequently mutated gene in all groups except ≥90% WA ancestry, which had the most mutation frequency in TP53. ≥90% WA ancestry showed the highest rate of mutation of 81.3% in TP53 compared to 70.8% (80-90% WA ancestry) and 40.0% (50-79% WA ancestry). Interestingly, ≥90% WA ancestry had the highest average rate of mutation (33%) for 7 tumor suppressor genes ( AMER1, APC, ARID1, FBXW7, TCF7L2, TGFBR2, and TP53), compared to 29% and 22% in 80-89% WA ancestry and 50-79% WA ancestry, respectively. In addition, ≥90% WA ancestry had a lower rate (19%) of mutation in 6 oncogenes ( BRAF, NRAS, KRAS, PIK3CA, SMAD4, and SOX9) compared to 24% in both 80-89% and 50-79% WA ancestry. Although not statistically significant, a higher percentage of WA ancestry in an individual was correlated with a downward trend in the overall survival rate (median survival 56.3 months in ≥90% WA ancestry vs 61.8 months in 80-89% WA ancestry). Conclusions: In this study, we analyzed different gene mutations correlated with African ancestry and their potential relationship to the etiology, progression, and prognosis of COAD. The mutation profile of these genes will allow us to investigate altered pathways associated with African ancestry and draw insight into colon cancer pathogenesis in various ancestry groups. Further studies are warranted to elucidate the role of genetic ancestry in tumorigenesis and disease progression and to identify potential therapeutic targets specific to groups disproportionately affected by cancer.

8516 Background: Racial disparities in lung cancer are well-known with African Americans disproportionally affected by lung cancer in terms of incidence and survival. Previous comparative analyses of molecular features of lung cancer revealed racial differences in genomic profiles, which supports somatic differences arising from genetic ancestry. Using The Cancer Genome Atlas (TCGA), we investigated the genetic alterations in lung adenocarcinomas (LUAD) on individuals of African (AFR) ancestry. Methods: The genomic and clinical data of TCGA PanCancer Atlas LUAD were downloaded through the GDC Data Portal. Given that substantial proportion of the US population consist of genetically admixed populations, we utilized The Cancer Genome Ancestry Atlas (TCGAA) and LAMP for estimates of genetic ancestry and quantitative ancestral compositions. This dataset contains 518 samples, including 393 self-reported whites and 52 African Americans. For each case the proportion of European, AFR, East Asian, native American ancestry was estimated. The dominant ancestry was defined as ≥50% of admixture from one reference population. Differences in gene mutation frequency were analyzed based on AFR ancestry proportion. The Kaplan-Meier curves were generated, and Cox regression analyses were performed. Results: Global ancestry analysis identified 50 AFR ancestry cases with mean ancestry of 78.3%. The dominant AFR ancestry group matched the self-reported race with 96% accuracy. We identified 9 subjects with ≥90% AFR ancestry, 22 subjects with 80-90% AFR ancestry, 12 subjects with 70-80% AFR ancestry, and 7 subjects with 50-70% AFR ancestry. TP53 was the most frequently mutated gene, and ≥90% AFR ancestry had the highest rate of mutations (77.8%) compared with 80-90% AFR ancestry (68.2%), and 70-80% AFR ancestry (66.8%). We evaluated classic driver gene mutations (EGFR, KRAS, NRAS, PIK3CA, ALK) and found only 33% of ≥90% AFR ancestry subjects carry a known driver mutation, compared to 58-77% in lower proportion of AFR ancestry subjects. Higher AFR ancestry was associated with worse overall survival (OS) and progression free survival (PFS). Median OS was 14.5 months for ≥90% AFR ancestry compared to 71.47 months in 70-80% AFR ancestry (P = 0.048). ≥90% AFR ancestry had median PFS of 12.8 months compared to 33.5 months in 80-90% AFR ancestry, and 47.1 months in 70-80% AFR ancestry (P = 0.002). Conclusions: This study demonstrates the power of genomic study to investigate the etiology of health disparities by analyzing the effect of ancestry on genetic alterations in LUAD. Our results reveal different mutation loads even among AFR ancestry patients. We observed that AFR ancestry is associated with worse OS, suggesting possible influence of germline ancestry in subsequent somatic alterations. Further work is needed to explore how genetic ancestry impacts tumorigenesis and cancer progression to eliminate lung cancer disparities.

e20554 Background: Significant progress has been made in the screening, diagnosis, and treatment of squamous cell carcinomas of the lung (LUSC). Despite the advancements, African American populations continue to experience worse disease burden and poorer overall survival, even after controlling for patient and tumor characteristics. While the interplay of various social determinants of health is well known to contribute to racial disparities in cancers, the molecular basis of racial disparity is less understood. Given the diversity of the US population that comprise of genetically admixed groups, understanding the role of ancestry and its influence on biology of cancers that drive incidence and prognosis is paramount to reducing racial disparities. Therefore, in this study, we aimed to investigate the influence of African (AFR) ancestry in genetic mutations of LUSC. Methods: We utilized The Cancer Genome Ancestry Atlas (TCGAA) to obtain data on the genetic ancestry and ancestral composition of 504 LUSC patients. The dataset contained 459 self-reported whites, 32 blacks, and 11 Asians. The percentage of each patient’s ancestral composition (European, AFR, Asian, and Native American) was revealed via the LAMP technique. The dominant ancestry was defined as those with genetic composition of ≥50% from one of four ancestral backgrounds. Genetic alteration profiles and clinical data of patients were obtained from LUSC TCGA PanCancer Atlas through GDC data portal. Of those with AFR dominant ancestry, we analyzed the differences in the gene mutation frequency based upon the proportion of AFR ancestry. Results: Ancestry analysis uncovered 30 AFR ancestry dominant cases with a mean AFR composition of 78.4%. We found 14 subjects with > 80% AFR ancestry and 16 subjects with 50-80% AFR ancestry. Two patients from the > 80% were excluded from the mutational analyses due to absence of genetic profiles in the data portal. TP53 was the most frequently mutated gene with a rate of 91.7% and 87.5% in > 80% and 50-80% AFR groups, respectively. Evaluation of the classic genetic mutations that drive disease pathology in LUSC (EGFR, ALK, PIK3CA, NRAS, KRAS) revealed 25% of > 80% AFR ancestry subjects carried mutations in at least one of these genes compared to 6.3% in the 50-80% AFR ancestry subjects. Also, a trend towards worse overall survival (OS) was seen in those with greater proportion of AFR ancestry (median OS of 27.2 months in > 80% group vs 43.9 months in 50-80% group). Conclusions: Despite the limited sample size, our study highlights substantial heterogeneity in tumor biology even within those of AFR ancestry and that genetic ancestry may impact tumor and host biology that contribute to disparities. Moving forward, engagement of the African American community into clinical trials and genomic studies are needed to explore ancestral influence on tumorigenesis, and to facilitate discovery of new actionable targets to help eradicate racial disparities in lung cancer.