Higher European Ancestry Research Articles

Ancestry and somatic profile predict acral melanoma origin and prognosis.

Acral melanoma, which is not ultraviolet (UV)-associated, is the most common type of melanoma in several low- and middle-income countries including Mexico. Latin American samples are significantly underrepresented in global cancer genomics studies, which directly affects patients in these regions as it is known that cancer risk and incidence may be influenced by ancestry and environmental exposures. To address this, here we characterise the genome and transcriptome of 128 acral melanoma tumours from 96 Mexican patients, a population notable because of its genetic admixture. Compared with other studies of melanoma, we found fewer frequent mutations in classical driver genes such as BRAF, NRAS or NF1. While most patients had predominantly Amerindian genetic ancestry, those with higher European ancestry had increased frequency of BRAF mutations and a lower number of structural variants. These BRAF-mutated tumours have a transcriptional profile similar to cutaneous non-volar melanocytes, suggesting that acral melanomas in these patients may arise from a distinct cell of origin compared to other tumours arising in these locations. KIT mutations were found in a subset of these tumours, and transcriptional profiling defined three expression clusters; these characteristics were associated with overall survival. We highlight novel low-frequency drivers, such as SPHKAP, which correlate with a distinct genomic profile and clinical characteristics. Our study enhances knowledge of this understudied disease and underscores the importance of including samples from diverse ancestries in cancer genomics studies.

Assessing the Risk Stratification of Breast Cancer Polygenic Risk Scores in a Brazilian Cohort

Polygenic risk scores (PRSs) for breast cancer have a clear clinical utility in risk prediction. PRS transferability across populations and ancestry groups is hampered by population-specific factors, ultimately leading to differences in variant effects, such as linkage disequilibrium and differences in variant frequency (allele frequency differences). Thus, locally sourced population-based phenotypic and genomic data sets are essential to assess the validity of PRSs derived from signals detected across populations. This study assesses the transferability of a breast cancer PRS composed of 313 risk variants (313-PRS) in a Brazilian trihybrid admixed ancestries (European, African, and Native American) whole-genome sequenced cohort, the Rare Genomes Project. 313-PRS was computed in the Rare Genomes Project (n=853) using the UK Biobank (UKBB; n=264,307) as reference. The Brazilian cohorts have a high European ancestry (EA) component, with allele frequency differences and to a lesser extent linkage disequilibrium patterns similar to those found in EA populations. The 313-PRS distribution was found to be inflated when compared with that of the UKBB, leading to potential overestimation of PRS-based risk if EA is taken as a standard. However, case controls lead to equivalent predictive power when compared with UKBB-EA samples with area under the receiver operating characteristic curve values of 0.66 to 0.62 compared with 0.63 for UKBB.

Exploring the relationship between admixture and genetic susceptibility to attention deficit hyperactivity disorder in two Latin American cohorts

Contemporary research on the genomics of Attention Deficit Hyperactivity Disorder (ADHD) often underrepresents admixed populations of diverse genomic ancestries, such as Latin Americans. This study explores the relationship between admixture and genetic associations for ADHD in Colombian and Mexican cohorts. Some 546 participants in two groups, ADHD and Control, were genotyped with Infinium PsychArray®. Global ancestry levels were estimated using overall admixture proportions and principal component analysis, while local ancestry was determined using a method to estimate ancestral components along the genome. Genome-wide association analysis (GWAS) was conducted to identify significant associations. Differences between Colombia and Mexico were evaluated using appropriate statistical tests. 354 Single-nucleotide polymorphisms (SNPs) and Single-nucleotide variants (SNVs) related to some genes and intergenic regions exhibited suggestive significance (p-value < 5*10e−5) in the GWAS. None of the variants revealed genome-wide significance (p-value < 5*10e−8). The study identified a significant relationship between risk SNPs and the European component of admixture, notably observed in the LOC105379109 gene. Despite differences in risk association loci, such as FOXP2, our findings suggest a possible homogeneity in genetic variation’s impact on ADHD between Colombian and Mexican populations. Current reference datasets for ADHD predominantly consist of samples with high European ancestry, underscoring the need for further research to enhance the representation of reference populations and improve the identification of ADHD risk traits in Latin Americans.

Abstract 2729: Cell infiltration prediction of breast cancer tissues identifies basophils as potentially important immune cells in the tumor microenvironment

Abstract Background: Breast cancer (BC) is the most common and deadliest cancer in women worldwide. Hormone receptor (HR) positive tumors (luminal) are the most frequent while HER-2 overexpressing (HR-, HER2+) and triple negative (TNBC, HR-/HER2-) are most deadly. HR+ subtypes are more common in non-Hispanic White women while HER-2 and TNBC present either higher prevalence or risk of mortality in minority groups. Hispanic/Latinos (H/L) is the largest and fastest growing minority in the U.S.A. However, H/L women have been underrepresented in BC studies. We reported that luminal B is the most common BC subtype in a group of H/L and that ERBB2, GRB7 and MIEN1 genes have increased expression in women with higher Indigenous American ancestry. Immune infiltration of tumors has become a hallmark for the prediction of outcome. However, contrary to TNBC, luminal tumors have been considered low immunogenic. Immune infiltration of luminal B tumors in H/L has not yet been investigated. Our goal was to predict immune infiltration of luminal B tumors based on RNA-seq data and according to the levels of body mass index (BMI) and ancestral fractions (West African, European, Indigenous American). Methods: We performed RNA-seq in 70 luminal B tumors of H/L from Puerto Rico. Ancestry was estimated by genotyping on the Affymetrix U.K. Biobank array and global ancestry proportions determined with Admixture Software v1.3, using 1000 Genomes reference population for anchoring. BMI, age at diagnosis and tumor size were extracted from the Electronic Medical Records. We used Partek Flow for the RNA-seq analysis based on ancestry fraction and BMI. Prediction of cell populations was done in xCell. Correlation analysis was done in GraphPad Prism v7.05. Results: We found an inverse correlation between Indigenous American and γδ-T cell infiltration (R2= -0.3; p=0.03) while BMI was associated with increased infiltration of basophils (R2=0.3; p=0.026). Among women with high BMI, those with low European ancestry had increased levels of basophils infiltration R2=0.66; p=0.17) and those with high European ancestry had reduced infiltration of naïve CD8+ T cells (R2= -0.53; p=0.008) and reduced plasmacytoid dendritic cells (pDC, R2=-0.51; p=0.01). Conclusions: We found that luminal B tumors have infiltration of immune cells that may contribute to differences in the response to treatment and outcome. To the best of our knowledge, the role of infiltrating basophils into breast cancer tissues has not been described. However, circulating basophils and predicted infiltration of basophils into ovarian and colorectal cancer tissues have been correlated with survival. Our findings have to be confirmed in a larger set of samples and by additional methods, including immunohistochemistry. Citation Format: Jone Garai, Julie Dutil, Douglas W. Cress, Victoria Seewaldt, Jamie K. Teer, Laura Fejerman, Lucio Miele, Jovanny Zabaleta. Cell infiltration prediction of breast cancer tissues identifies basophils as potentially important immune cells in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2729.

Abstract P075: Genetic European Ancestry And Incident Diabetes Mellitus In Black Individuals-Insights From The SPRINT Trial

Background: A metabolic paradox of lower triglyceride (TG) and higher high-density lipoprotein cholesterol (HDL-C) levels but a higher incidence of diabetes has been described in Blacks. We evaluated the association of genetic ancestry-related variants with the risk of incident diabetes in self-identified Black individuals in the Systolic Blood Pressure (BP) Intervention Trial (SPRINT). Methods: The genetic European ancestry proportions were estimated using 106 biallelic genotype markers in non-diabetic Black participants. Participants were stratified into tertiles (T1-T3) of European ancestry proportions. Multivariable-adjusted association of baseline metabolic syndrome indices (fasting plasma glucose [FPG], TG, HDL-C, body mass index [BMI], and BP) with the ancestry proportion was assessed. Multivariable-adjusted Cox regression was used to assess the risk of incident diabetes (FPG ≥126 mg/dL or self-reported diabetes treatment) across tertiles. Results: In 2,466 participants with median European ancestry 19% (13 - 27%), those in T1 were relatively younger, with lower Framingham risk score, and worse renal function (p&lt;0.05 for all). At baseline, higher European ancestry proportion was associated with higher TG and lower HDL-C levels after controlling for clinical and demographic factors (p&lt;0.05 for both). FPG, BMI, and BP were not significantly associated with ancestry proportion. Compared with T1, those in second (HR: 0.64 [95% CI: 0.45-0.90]) and third tertiles (HR: 0.61 [0.44-0.89]) had a lower risk of incident diabetes after controlling for covariates. Specifically, a 5% increment in European ancestry was associated with a 29% lower risk of incident diabetes (HR: 0.71 [0.55-0.93]). No interaction was observed between intensive BP control strategy and European ancestry proportion tertiles on incident diabetes. Conclusions: Genetic factors may account for racial differences in TG and HDL-C levels. The higher risk of incident diabetes in Blacks may similarly be genetically determined.

ADIPOQ and LEP variants on asthma and atopy: Genetic association modified by overweight.

Asthma and atopy are considered condition associated with obesity, being affected by genetic and environmental factors. The LEP and ADIPOQ genes, responsible for the expression and secretion of leptin and adiponectin, respectively, and polymorphisms in such genes have been linked to both diseases, independently, and also with the obesity-associated asthma phenotype in populations with high European ancestry and high-income countries. However, in mixed populations, there are few studies evaluating the impact of these variants in genes associated with the phenotype of asthma and obesity. Thus, the aim of this study was to investigate variants in LEP and ADIPOQ associated with asthma and atopy, and whether overweight modifies that effect. The study involved 203 asthmatics children and 813 control subjects (between 5 and 11years old), with or without overweight, from the SCAALA (Asthma and Allergy Social Changes in Latin America) program. Among them, 831 had data for allergy markers, being 258 atopic and 573 non-atopic. Genotyping was performed using a commercial panel Omnium Illumina 2.5. Logistic regression was performed to identify associations expected by using PLINK 1.09 and three genetic models: additive, dominant and recessive adjusted for sex, age, helminth infection, BMI and Principal Components (PC) 1 and 2, for ancestry, in order to control the confounding factor by population structure. For asthma, G allele of rs822396, in ADIPOQ, was positively associated in additive model (OR 1.4, 95% CI 1.08-1.83) and T allele of rs1063537 in dominant model (OR 1.52, 95% CI 1.01-2.30). In LEP, rs11763517 (C allele) and rs11760956 (A allele) were both negatively associated with asthma in the additive model (OR 0.70, 95% CI 0.54-0.91; OR 0.66, 95% CI 0.50-0.89) respectively, and the A allele of rs2167270 in dominant model (OR 0.71, 95% CI 0.51-0.98). The G allele of rs12706832 showed a positive association with asthma in the recessive model (OR 1.66, 95% CI 1.06-2.61). When the population was stratified by the BMI / Age Z-Score, the protection observed for asthma between the variants rs11760956, rs11763517 and rs2167270 was lost overweight individuals; The protection observed for atopy was lost in all variants (rs16861205, rs2167270 and rs17151919) in the overweight group. These results suggest that SNPs on the LEP and ADIPOQ genes may have an impact on atopy and asthma. Furthermore, we also show that the asthma and atopy protection attributed to variants on LEP and ADIPOQ genes is lost in individuals exposed to overweight.

Haplotype analysis of the internationally distributed BRCA1 c.3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia

BackgroundThe BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry.MethodsBC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia.ResultsThe haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was ~ 100 generations in Iberia and that it was introduced to South America early during the European colonization period.ConclusionsOur results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening.

Abstract 1212: Quantitative ancestry analysis in Hispanic uveal melanoma patients reveals novel disease susceptibility loci

Abstract Uveal Melanoma (UM) is the most common eye cancer in adults and leads to metastatic death in up to half of patients. The molecular landscape of UM has been extensively characterized, and this information is now widely used in clinical management. Research interest in UM has expanded dramatically in the past decade, with landmark genomic studies highlighting its unique and deadly clinical and molecular characteristics however this pool of genetic data has been performed almost entirely in white non-Hispanic patients of European ancestry. Hispanics are the second most common ethnic group affected by UM, and one of the fastest growing ethnic groups in the U.S. Individuals who self-identify as Hispanic. This study included 141 patients with posterior uveal melanomas, 72 who self identified as White non-Hispanic, 61 as Hispanic, 4 as Black non-Hispanic, 2 as Asian non-Hispanic, and 2 as Other/Multiracial non-Hispanic. In order to by-pass ethnic and cultural variables that influence self reporting demographic information, global and local ancestry was assessed. Leukocyte DNA from each patient was genotyped, generating whole genome single nucleotide polymorphism (SNP) profiles. Quality control was performed keeping only bi allelic SNPs and SNP call rate of &amp;gt;98%. Global ancestral estimates, using greater than 100,000 SNPs, were calculated against reference samples from West African, East Asian, European, and Native American ancestral populations. ADMIXTURE was used to estimate the ancestral proportions among the UM patients. Greater than 500,000 SNPs were phased and local ancestral calls were calculated on each patient. The genetic structure of individual patient samples revealed a diverse ancestral admixture among self-reported Hispanic patients with UM. Significant differences in global European ancestry were shown between Class 1A and Class 1B patients, where Class 1B patients were more European (P = 0.0087). Kruskal-Wallis test showed a significant difference between the three groups' european ancestry showing that Class 1A, Class 1B, and Class 2 distributions are not all the same (P=0.035). Patients with higher European ancestry are also more likely to be PRAME-positive (P=0.02). For local ancestry analysis, a linear regression was performed at each haplotype. A significance threshold of 0.000694 was established after correction for the mean number of ancestral switches in the cohort. Two regions on chr20 reached genome wide significance (P&amp;lt;0.0006) with an enrichment of European ancestry in more aggressive malignancies. These findings present an exciting opportunity for studying ancestral genetic determinants on patient outcome in UM. The results show that genetic ancestry may influence the occurrence and clinical significance of prognostic biomarkers and patient outcomes in UM. Utilizing genetic ancestry may aid in our understanding and guide future management of ocular pathologies in admixed individuals. Citation Format: Daniel Alexander Rodriguez, Margaret I. Sanchez, Christina L. Decatur, J. William Harbour. Quantitative ancestry analysis in Hispanic uveal melanoma patients reveals novel disease susceptibility loci [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1212.

Abstract C035: Relationship between ancestry fractions and gene expression in triple-negative breast cancer in Hispanic/Latina women

Abstract Background: Breast cancer is the most frequently diagnosed form of invasive cancer in women and the second leading cause of cancer death. Triple-negative breast cancer (TNBC) accounts for 10-20% of the disease. This aggressive subtype lacks receptors for estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2), drastically reducing treatment options. Hispanic/Latinas, who derive ancestry from European, African, and Native origins, are at least 30% more likely to be diagnosed with TNBC compared to non-Hispanic White women. However, little is known about the genomic architecture of TNBCs in Hispanic/Latinas. The goal of our study was to test the association between genetic ancestry and gene expression in TNBC samples from Hispanics/Latinas to help identify potential therapeutic targets. Methods and Results: We obtained 41 TNBC tissues through collaboration with the National Cancer Institute in Colombia along with demographic and clinical information. Genetic ancestry proportions were estimated using a panel of 106 Ancestry Informative Markers (AIMs). RNA was extracted from FFPE tissues, qualified using Agilent chips, and used for RNA sequencing at the Translational Genomics Core at the Stanley S. Scott Cancer Center. We used an online tool (http://cbc.mc.vanderbilt.edu/tnbc/) to validate TNBC status, and 33 of the 41 samples were confirmed. Quality control procedures ensured that the samples were of acceptable quality for further analysis. Individuals were classified as having high or low genetic ancestry proportions for each of the ancestral components, based on mean ancestry proportions overall. Differential gene expression between individuals in each ancestry category was estimated utilizing DESeq2 in R-Studio. Average genetic ancestry proportions for the 33 samples analyzed were 0.52 European (18 individuals were in the high European ancestry group, 14 in the low European ancestry group), 0.36 Indigenous American (15 high, 17 low) and 0.1 African (8 high, 24 low). We observed that 91 genes were differentially expressed between high vs. low European ancestry, 21 for the Native and 12 for the African. Interestingly, 5 genes were common between the European and Native ancestries. LGALS9C and MESP1 had significant differences in normalized counts between high and low ancestry for both the Europeans and Natives, though the subgroups displayed opposite correlation patterns. These results were validated by real-time PCR. Using cBioPortal, we found that MESP1 and LGALS9C were associated with amplification in 2.8% and 1.5% of breast cancer cases, respectively. LGALS9C expression displays an inverse correlation with disease outcome in several cancers, including breast. Conclusions: Our data suggest that expression levels of several genes, most notably MESP1 and LGALS9C, may be ancestry specific in TNBC patients from Colombia. Confirmation and further understanding of these findings are of outmost importance given that they could be therapeutic targets. Citation Format: Laura Carrasquilla, Jone Garai, Silvia J. Serrano-Gomez, Maria C. Sanabria-Salas, Melody C. Baddoo, Laura Fejerman, Jovanny Zabaleta. Relationship between ancestry fractions and gene expression in triple-negative breast cancer in Hispanic/Latina women [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C035.

Comprehensive Molecular Profiling of Idiopathic Erythrocytosis By Genetic Ancestry

Introduction: Idiopathic erythrocytosis (IE) is characterized by a persistently elevated hemoglobin, equivocal erythropoietin (EPO) levels, absence of janus kinase 2 (JAK2) mutations suggestive of polycythemia vera (PV) and no secondary cause. One study used a targeted 21 gene next-generation sequencing panel and identified novel variants in known erythrocytosis-related genes as well as novel genes associated with the oxygen-sensing pathway. However, expanded sequencing of blood and matched tissue samples in a large ethnically diverse group of IE patients has not been performed. Methods: All patients signed informed consent to participate in an observational study approved by the Institutional Review Board; they provide blood and buccal mucosa samples at study entry and at 24-month follow-up. Patients were enrolled if JAK2 testing and a complete work up for secondary causes was negative. They were required to have hemoglobin levels greater than 16 g/dL on two occasions or greater than 15 g/dL if undergoing phlebotomy. Our initial sequencing of 20 IE patients was performed utilizing high resolution whole-exome sequencing of circulating blood samples (disease) at a mean coverage of 390x and matched normal (buccal) samples at mean coverage of 300x. To stratify samples by genetic ancestry, we performed a population stratification principle component analysis (PCA) and STRUCTURE using Ancestry Informative Markers derived from 1K Genome Phase1_v3 Exome database. The primary in-silico analysis was performed on the baseline samples from treatment-naïve patients. The whole-exome data was generated in accordance to GATK's best practices with same filters applied as described by Exome Aggregation Consortium. The additional downstream in-silico paired analysis was performed using MutSig2.0 (Mutation Significance) algorithm to determine significant mutations and GISTIC (The Genomic Identification of Significant Targets in Cancer) to identify the significant copy number events, IPA (Ingenuity Pathway Analysis) to determine pathways along with other computational . Results: Median age at baseline was 52 years (range 35-71). Six patients (30%) were female and 14 (70%) were male. Median values and ranges for laboratory parameters at baseline were as follows: WBC 6.6 x 109/L (5-9.7), Hgb 17 g/dL (15.5-19.8), Plt 218 x 109/L (86-374), and EPO level 9.8 IU/L (2-14.3). Three patients had a personal history of malignancy, including 2 with lymphoma. Two patients had a family history of myeloid malignancy (chronic myeloid leukemia and PV). Our ancestry analysis of initial 20 patients with IE identified 6 patients with high European percent ancestry (EUR), 1 patient with high Asian percent ancestry (EAS) and 13 patients with high percent Ad Mixed ancestry (AMR). In our cohort, 60% (12/20) of patients had been also diagnosed with a liver disorder (11 with fatty liver, 1 with cirrhosis) that was not significantly different across populations. We identified, on average, 42 non-silent somatic mutations (not present in the buccal samples) in whole blood across our cohort with no statistical difference (p=0.671) in mutation burden between ancestry groups or between patients with and without liver disease. Age, gender, and ethnicity were not associated with mutation burden. Utilizing MutSig algorithm, we identified a novel candidate gene, CHAF1A, with high mutation prevalence of 30% in patients with IE. Further analysis of mutation landscape identified somatic nonsilent mutations in 25 known oncogenes which were present in at least 10% of patients. Our mutation signatures in IE identified a significant association with failure of double stranded DNA repair. Only one patient had a mutation in TET2. Further analysis of copy number indicated copy number loss in genes such as SETD3 and GSH associated with chromatin assembly which may suggest alterations in chromatin assembly and changes in the epigenome. Our analysis also identified a high number of 9p and 13q gains in patients with IE. Conclusion: In this study, we utilized high-resolution next generation sequencing in association with comprehensive clinical annotation to determine potential molecular drivers of IE in a multi-ethnic population. We identified somatic mutations in a subset of patients which may represent clonal hematopoiesis. Long term follow up of outcomes in this cohort may clarify the significance of these mutations in the pathogenesis of IE. Disclosures No relevant conflicts of interest to declare.

Abstract 2419: A polygenic risk score predicts breast cancer risk in Latinas

Abstract Background: Genome-wide association studies (GWAS) have identified over 180 single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Polygenic risk scores (PRS) represent the combined effects of multiple SNPs and have been consistently shown to improve the performance of existing risk models. Most SNPs were discovered in women of European ancestry. Thus, there are limited data on how PRS perform in Latinas, whose ancestry is a mixture of European and Indigenous American. We therefore sought to validate the performance of a 184-SNP PRS in Latinas. Methods: We conducted a pooled analysis of U.S. Latina and Mexican participants from 6 existing studies. Our analysis included 3,441 women with breast cancer and 7,773 women without breast cancer. We constructed a PRS containing 184 SNPs associated with breast cancer in prior GWAS, p &amp;lt; 5 x 10-8. We used multivariable logistic regression to evaluate the associations between the PRS and breast cancer, adjusting for genetic ancestry and study of origin. To assess discrimination, we calculated the area under the receiver operating characteristic curve (AUROC). To test the performance of the PRS by genetic ancestry, we stratified our analysis by quartiles of Indigenous American genetic ancestry. Results: The PRS was associated with breast cancer, with an odds ratio (OR) per standard deviation increment of 1.51 (95% CI 1.44-1.59). The PRS showed intermediate discrimination for cases vs. controls, with an AUROC of 0.62 (95% CI 0.60-0.63). When we stratified the analysis by genetic ancestry, the PRS performed worse in women with higher Indigenous American/lower European ancestry. Specifically, the discrimination of the PRS was least in the top quartile of Indigenous American ancestry and greatest in the bottom quartile, with AUROC of 0.60 (95% CI 0.57-0.62) vs. 0.65 (95% CI 0.62-0.67), respectively (p = 0.01). The corresponding ORs per standard deviation of the PRS were 1.40 (95% CI 1.29-1.53) for the top quartile and 1.70 (95% CI 1.52-1.89) for the bottom quartile of Indigenous American ancestry (p = 0.006). Conclusions: A 184-SNP PRS predicts breast cancer in Latinas, with the AUROC of 0.62 in our study being comparable to previous estimates in Europeans. However, the performance of the PRS varied according to genetic ancestry. While our results suggest the PRS may be used as-is in Latinas with higher European ancestry, future efforts should focus on refining the PRS in Latinas of higher Indigenous American ancestry through discovery and replication of novel predictive SNPs in this subgroup. Citation Format: Yiwey Shieh, Laura Fejerman, Sarah D. Sawyer, Donglei Hu, Scott Huntsman, Esther M. John, Lawrence H. Kushi, Gabriela Torres-Mejia, Jeffrey N. Weitzel, Christopher A. Haiman, Elad Ziv, Susan L. Neuhausen. A polygenic risk score predicts breast cancer risk in Latinas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2419.

Genetic admixture patterns in Argentinian Patagonia.

As in other Latin American populations, Argentinians are the result of the admixture amongst different continental groups, mainly from America and Europe, and to a lesser extent from Sub-Saharan Africa. However, it is known that the admixture processes did not occur homogeneously throughout the country. Therefore, considering the importance for anthropological, medical and forensic researches, this study aimed to investigate the population genetic structure of the Argentinian Patagonia, through the analysis of 46 ancestry informative markers, in 433 individuals from five different localities. Overall, in the Patagonian sample, the average individual ancestry was estimated as 35.8% Native American (95% CI: 32.2–39.4%), 62.1% European (58.5–65.7%) and 2.1% African (1.7–2.4%). Comparing the five localities studied, statistically significant differences were observed for the Native American and European contributions, but not for the African ancestry. The admixture results combined with the genealogical information revealed intra-regional variations that are consistent with the different geographic origin of the participants and their ancestors. As expected, a high European ancestry was observed for donors with four grandparents born in Europe (96.8%) or in the Central region of Argentina (85%). In contrast, the Native American ancestry increased when the four grandparents were born in the North (71%) or in the South (61.9%) regions of the country, or even in Chile (60.5%). In summary, our results showed that differences on continental ancestry contribution have different origins in each region in Patagonia, and even in each locality, highlighting the importance of knowing the origin of the participants and their ancestors for the correct interpretation and contextualization of the genetic information.

FLG loss of function mutations R501X and R2447X in Puerto Rico: Association of genetic ancestry with Atopic Dermatitis and Ichthyosis Vulgaris

In Puerto Rico, we do not have many studies of Loss of function (LoF) mutations but using the data from the 1000 Genome Project we identified several polymorphisms that predicted to eliminate protein function. In this research, we work with two single nucleotide polymorphisms that produce premature stop codons in the FLG gene. They are known as R501X and R2447X. Both are associated to skin conditions such as ichthyosis vulgaris and atopic dermatitis; they also have been associated to asthma and allergies. The 1000 Genome Project data is based on the analysis of 104 Puerto Ricans only, and we wanted to test if the frequencies in it were accurate for the Puerto Rican population. We genotyped 736 individuals for the mutation R501X and 292 for R2447X using real time PCR. From the 736 individuals, we found 21 heterozygotes for the SNP R501X, this mutation in the FLG gene having an allele frequency of 0.0142. This allele frequency compared to the one previously reported, shows a difference of 0.0114 suggesting that the mutation in Puerto Rico is not rare. This mutation has been identified mainly in 3 geographical regions of Puerto Rico with high European ancestry. We started working with the mutation R2447X and genotyped 292 individuals; and 3 heterozygotes were found. From this samples the mutation shows an allelic frequency of 0.005; and it appears to be localized in the east region of the island. Now, we expect to genotype the same individuals for both mutations and compare their distribution, prevalence and relation between both.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Social-group identity and population substructure in admixed populations in New Mexico and Latin America.

We examined the relationship between continental-level genetic ancestry and racial and ethnic identity in an admixed population in New Mexico with the goal of increasing our understanding of how racial and ethnic identity influence genetic substructure in admixed populations. Our sample consists of 98 New Mexicans who self-identified as Hispanic or Latino (NM-HL) and who further categorized themselves by race and ethnic subgroup membership. The genetic data consist of 270 newly-published autosomal microsatellites from the NM-HL sample and previously published data from 57 globally distributed populations, including 13 admixed samples from Central and South America. For these data, we 1) summarized the major axes of genetic variation using principal component analyses, 2) performed tests of Hardy Weinberg equilibrium, 3) compared empirical genetic ancestry distributions to those predicted under a model of admixture that lacked substructure, 4) tested the hypotheses that individuals in each sample had 100%, 0%, and the sample-mean percentage of African, European, and Native American ancestry. We found that most NM-HL identify themselves and their parents as belonging to one of two groups, conforming to a region-specific narrative that distinguishes recent immigrants from Mexico from individuals whose families have resided in New Mexico for generations and who emphasize their Spanish heritage. The “Spanish” group had significantly lower Native American ancestry and higher European ancestry than the “Mexican” group. Positive FIS values, PCA plots, and heterogeneous ancestry distributions suggest that most Central and South America admixed samples also contain substructure, and that this substructure may be related to variation in social identity. Genetic substructure appears to be common in admixed populations in the Americas and may confound attempts to identify disease-causing genes and to understand the social causes of variation in health outcomes and social inequality.

Paraguay: Unveiling migration patterns with ancestry genetic markers

Before the arrival of Spanish settlers, the East region of Paraguay, was inhabited by Guarani people. After the Paraguayan war in 1870, which ended in loss of a high percentage of the male population, the migration to the country was encouraged. Immigration data indicate a high input of Eurasians to the territory. Also, since 1960s, a large number of Brazilians and Argentineans arrived in Paraguay. Samples from the eastern provinces of Paraguay were sequenced for the mtDNA control region and 88% presented native American haplogroups. A preliminary study on the same samples using AIMs indicates a high autosomal contribution from Europe and native America. The comparison of both type of markers showed that the European ancestry for autosomes is higher than expected when averaging mtDNA and the Y chromosome. This result supports recent admixture between Paraguayans and other populations probably already admixed, where the men contributed with high European ancestry.

Genomewide analysis of admixture and adaptation in the Africanized honeybee.

Genetic exchange by hybridization or admixture can make an important contribution to evolution, and introgression of favourable alleles can facilitate adaptation to new environments. A small number of honeybees (Apis mellifera) with African ancestry were introduced to Brazil ~60years ago, which dispersed and hybridized with existing managed populations of European origin, quickly spreading across much of the Americas in an example of a massive biological invasion. Here, we analyse whole-genome sequences of 32 Africanized honeybees sampled from throughout Brazil to study the effect of this process on genome diversity. By comparison with ancestral populations from Europe and Africa, we infer that these samples have 84% African ancestry, with the remainder from western European populations. However, this proportion varies across the genome and we identify signals of positive selection in regions with high European ancestry proportions. These observations are largely driven by one large gene-rich 1.4-Mbp segment on chromosome 11 where European haplotypes are present at a significantly elevated frequency and likely confer an adaptive advantage in the Africanized honeybee population. This region has previously been implicated in reproductive traits and foraging behaviour in worker bees. Finally, by analysing the distribution of ancestry tract lengths in the context of the known time of the admixture event, we are able to infer an average generation time of 2.0years. Our analysis highlights the processes by which populations of mixed genetic ancestry form and adapt to new environments.

Abstract PR05: Ancestry as a potential modifier of gene expression in luminal B tumors among Colombian women

Abstract Background: Differences in outcome of breast cancer according to race/ethnicity have been reported. African American women have higher breast cancer-specific mortality rates compared to non-Hispanic White women (NHW). Although these differences have been attributed to the high prevalence of basal-like subtype among African Americans, these women have also less favorable outcome in less aggressive tumors when compared to NHW. Hispanic/Latino (H/L) populations are a genetically admixed and heterogeneous group, with variable levels of European, Native American and African ancestries. Some studies suggest that breast cancer-specific mortality is higher in U.S. Latinas compared to NHW even after adjustment for socioeconomic status and education. The molecular profile of breast cancer has been widely described in NHWs but knowledge is lacking in Latinas. We have previously reported that the most prevalent breast cancer intrinsic subtype in Colombian women was Luminal B. In this study we explored ancestry-associated differences in molecular profiles of luminal B tumors among these highly admixed women. Methods: To identify ancestry-associated differentially expressed genes in Luminal B tumors, we performed a whole-transcriptome RNA-seq analysis in 42 luminal tumors (21 Luminal A and 21 Luminal B) from Colombian women. Genetic ancestry was estimated from a panel of 80 ancestry-informative markers (AIM). We categorized patients according to luminal subtype and to the proportion of European ancestry (Low European ancestry group: ancestry proportion below the median; High European ancestry: ancestry proportion above the median).. We compared luminal B against luminal A tumors according to the assigned ancestry groups. We used DESeq2 package form R to test differential gene expression between the two tumor subtypes and by ancestry category. Genes with adjusted pvalue less than 0.05 were considered statistical significant. Results: We found 30 differentially expressed genes (pvalue &amp;lt; 0.05) by genetic ancestry among Luminal B tumors from which 27 were differentially expressed in the less European luminal B tumors and 3 in the more European group. Tests of interaction suggest that ancestry is a statistically significant modifier of expression for the following genes for Low European Ancestry group: CENPF, SNORA54, AIF1L, TNFSF13, LRRC1, ARHGAP33, ONECUT2, CDK12, BUB1, NTRK2, HES1); and FDXACB1, RAB26, ATP8B3 for the High European Ancestry group. An exploratory analysis of these genes reveals enrichment of pathways associated to ERBB signaling in the Low European Ancestry group. Conclusions: Our results suggest that the proportion of European genetic ancestry in Colombian women might modify gene expression in luminal B tumors. Further analysis will be needed to confirm these findings. Citation Format: Silvia J. Serrano-Gomez, Carolina Sanabria, Melody C. Baddoo, Nataly Cruz-Rodriguez, Jone Garai, Gustavo Hernandez-Suarez, Juan Carlos Mejia, Lucio Miele, Chindo Hicks, Laura Fejerman, Jovanny Zabaleta. Ancestry as a potential modifier of gene expression in luminal B tumors among Colombian women. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr PR05.

Social Identity in New Mexicans of Spanish-Speaking Descent Highlights Limitations of Using Standardized Ethnic Terminology in Research

In this study, we evaluated the extent to which regional history has shaped the social identity nomenclature in New Mexicans of Spanish-speaking descent (NMSD). We asked 507 NMSD to list the social-identity terms they used to describe themselves and their parents, and we examined the correspondence between these choices and family ties to the region, birthplace, and continental ancestry. NMSD frequently identified using the regional terms "Nuevomexicano/a" (15%) and "Spanish" (12%). These individuals reported family ties to the region that predate New Mexican statehood. They and their parents were frequently born in New Mexico, frequently chose the other of the two terms as a secondary descriptor, and frequently ascribed one of the two terms to their parents. About 10% of NMSD identified as "Mexican American" and "Mexican." About 25% of these individuals, and more than half of their parents, were born in Mexico. They also frequently chose the other of the two terms as a secondary descriptor and frequently ascribed one of the two terms to their parents. Compared to NMSD who identified as "Mexican" and "Mexican American," individuals who identified as "Nuevomexicano/a" and "Spanish" had higher European ancestry and lower Native American and African ancestry. Our results also suggest that the term "Hispanic," frequently chosen as both a primary and secondary social identity term by NMSD, may, as it continues to rise in prominence, mask more deeply rooted and potential socially relevant aspects of social identity in New Mexico. More broadly, these results indicate that regional history influences social identity nomenclatures in ways that are potentially incompatible with US Office of Management and Budget standards. This incompatibility may adversely affect the ability of researchers in the social sciences to assess the causes of social inequality and health disparities in individuals of Spanish-speaking descent in different regions of the United States. We argue that future studies would benefit from more fine-grained, region-specific analyses of social identity.

FASN, dietary fat intake, and risk of uterine leiomyomata in the Black Women's Health Study

To replicate results from a previous genome-wide association study of European ancestry women, in which a positive association was found between uterine leiomyomata (UL) and rs4247357, a single-nucleotide polymorphism located near the fatty acid synthase (FASN) gene. Prospective cohort study. Not applicable. African-American women aged 23-50years, who were premenopausal and had an intact uterus in1997. None. We genotyped rs4247357 among 2,301 incident UL cases and 3,005 controls from the Black Women's Health Study (1997-2011). Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression with control for age, geographic region of residence, and percent European ancestry using a panel of validated ancestry informative markers. Overall, rs4247357 was not associated with UL risk. Relative to the CC genotype, ORs were 1.04 (95% CI 0.92-1.19) for the AC genotype and 1.09 (95% CI 0.93-1.29) for the AA genotype. A positive association was found, however, among those with higher European ancestry (≥40%). Relative to the CC genotype, ORs were 2.03 (95% CI 1.12-3.69) for the AC genotype and 2.44 (95% CI 1.20-4.96) for the AA genotype. Dietary fat intake also appeared to modify the FASN-UL association. Although there was little overall association between rs4247357 and UL risk, a positive association was observed among women with ≥40% European ancestry. Direct sequencing of this genomic region might be warranted to determine whether rs4247357, or some other variant, is causally related to UL.

Abstract PR08: The role of genetic structure in Colombian coastal and Andean populations on disparities in colorectal adenomas and cancer risk

Abstract Background: Latin-Americans have different proportions of Amerindian, African and European genetic ancestry. Particularly, in Colombia the degree of admixture varies across the country as a result of very complex demographic events taken place since 16th century (colonization) and sex-bias gene flow effects. Colorectal cancer (CRC) mortality rates are heterogeneous across Colombian territory and this variation could be explained by regional differences in Colombian genetic background. Methods: To evaluate the association of genetic ancestry and colorectal adenomas and cancer risk, we genotyped 813 samples from Colombian coastal and andean regions, including 349 controls, 292 CRC cases and 172 adenomatous polyps (AP). Autosomal and X-chromosome individual ancestries were estimated using ADMIXTURE software with 556 AIMS (Fst &amp;gt; 0.5 among HAPMAP reference populations; k=3) and differences in ancestry proportions were assessed using a t-test. Multinomial logit model analysis between phenotype and ancestry proportions (covariates: sex, age, NSAIDs consumption, city of provenance and educational level) were conducted in R. Results: We found statistical differences (p &amp;lt; 0.05) between African, European and Asian (as a measure of Amerindian) ancestry means of autosomes versus X-chromosome (sex bias). As expected, ancestry means were different between the coast versus andean regions (African 0.27 vs 0.09; European 0.44 vs 0.57 and Asian/Amerindian 0.29 vs 0.35, respectively), reflecting differences among cities. For controls, AP and CRC the respective ancestry means were: African (0.17, 0.18 and 0,20), European (0.50, 0.53 and 0.48) and Asian/Ameridian (0.33, 0.29, 0.32). Univariate analysis showed that European ancestry was associated with an increased risk of AP (p &amp;lt; 0.05) and that African ancestry was associated with an increased risk of CRC (p &amp;lt; 0.05); no differences were found for phenotype among cities. After running full multinomial model, the association between European ancestry and the risk of AP remained (OR 8.50; 95%CI 1.65-43.78; p = 0.011); on the other hand, the association between African ancestry and CRC risk had the same direction but was not significant (OR 1.06; 95%CI 1.00-1.13, p = 0.065). On the full model, we also found that Colombians with no education have more CRC than those with at least high school degree, and this was consistent with univariate analysis. No differences were seeing between educational level and AP, neither in the univariate nor in the multivariate analysis, even though multinomial model of education by ancestry (corrected by city), showed that Colombians with high European ancestry are more likely to hold advance education degree. Conclusions: Colombian regions have differences in the degree of admixture as a consequence of the highly asymmetric pattern of mating of European men with Native American women and the African slavery trade in the coasts since the colonization period, according to this study and others on Y-chromosome and mtDNA. There was no signal of sampling bias in our study (no differences in phenotypes by city). The association of CRC risk and African ancestry did not remain in the full model, probably due to a small effect, small sample size or the fact that people without education (low socioeconomical status) have less access to health system. The association of AP risk with European ancestry remained after controlling with covariates (including educational level); this probably indicates that there are European genetic factors (ej: SNPs) modifying the risk of AP in Colombians. Our results highlight the importance of performing Local Admixture Inference analysis in order to estimate the ancestry of specific chromosomal regions in admixed individuals in the study of human evolutionary history and genetic association studies. This abstract is also presented as Poster C37. Citation Format: Maria Carolina Sanabria-Salas, Gustavo Adolfo Hernández-Suárez, Adriana Umaña-Pérez, Martha Lucía Serrano-Pérez, Myriam Sánchez de Gómez, Martha Patricia Rojas, Jovanny Zabaleta, Konrad Rawlik, Albert Tenesa. The role of genetic structure in Colombian coastal and Andean populations on disparities in colorectal adenomas and cancer risk. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr PR08.