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Spreadsheet of counts of patients with SNV/indel mutations in each gene

Association between ER/PR/HER2 defined groups and Indigenous American genetic ancestry including stage and region of residence as covariates

Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2+ tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07–1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2+ tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer.Significance:The positive association between Indigenous American genetic ancestry and HER2+ breast cancer suggests that the high incidence of HER2+ subtypes in Latinas might be due to population and subtype-specific genetic risk variants.

Gastric cancer is a leading cause of cancer mortality and health disparities in Latinos. We evaluated gastric intratumoral heterogeneity using multiregional sequencing of >700 cancer genes in 115 tumor biopsies from 32 patients, 29 who were Latinos. Analyses focused on comparisons with The Cancer Genome Atlas (TCGA) and on mutation clonality, druggability, and signatures. We found that only approximately 30% of all mutations were clonal and that only 61% of the known TCGA gastric cancer drivers harbored clonal mutations. Multiple clonal mutations were found in new candidate gastric cancer drivers such as EYS, FAT4, PCDHA1, RAD50, EXO1, RECQL4, and FSIP2. The genomically stable (GS) molecular subtype, which has the worse prognosis, was identified in 48% of our Latino patients, a fraction that was >2.3-fold higher than in TCGA Asian and White patients. Only a third of all tumors harbored clonal pathogenic mutations in druggable genes, with most (93%) GS tumors lacking actionable clonal mutations. Mutation signature analyses revealed that, in microsatellite-stable (MSS) tumors, DNA repair mutations were common for both tumor initiation and progression, while tobacco, POLE, and inflammation signatures likely initiate carcinogenesis. MSS tumor progression was likely driven by aging- and aflatoxin-associated mutations, as these latter changes were usually nonclonal. In microsatellite-unstable tumors, nonclonal tobacco-associated mutations were common. Our study, therefore, contributed to advancing gastric cancer molecular diagnostics and suggests clonal status is important to understanding gastric tumorigenesis. Our findings of a higher frequency of a poor prognosis associated molecular subtype in Latinos and a possible new aflatoxin gastric cancer etiology also advance cancer disparities research. Significance: Our study contributes to advancing our knowledge of gastric carcinogenesis, diagnostics, and cancer health disparities.

Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2+ tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07–1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2+ tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer. Significance: The positive association between Indigenous American genetic ancestry and HER2+ breast cancer suggests that the high incidence of HER2+ subtypes in Latinas might be due to population and subtype-specific genetic risk variants.

Helicobacter pylori have coevolved with mankind since its origins, adapting to different human groups. In America H. pylori has evolved in several subpopulations specific for regions or even countries. In this study we analyzed the genome of 163 Colombian strains along with 1,113 strains that represent worldwide H. pylori populations to better discern the ancestry and adaption to Colombian people. Population structure was inferred with FineStructure and chromosome painting identifying the proportion of ancestries in Colombian isolates. Phylogenetic relationship was analyzed using the SNPs present in the core genome. Also, a Fst analysis was done to identify the gene variants with the strongest fixation in the identified Colombian subpopulations in relation to their parent population hspSWEurope. Worldwide, population structure analysis allowed the identification of two Colombian subpopulations, the previously described hspSWEuropeColombia and a novel subpopulation named hspColombia. In addition, three subgroups of H. pylori were identified within hspColombia that follow their geographic origin. The Colombian H. pylori subpopulations represent an admixture of European, African and Native indigenous ancestry; although some genomes showed a high proportion of self-identity, suggesting a strong adaption to these mestizo Colombian groups. The Fst analysis identified 82 SNPs significantly fixed in 26 genes of the hspColombia subpopulation that encode mainly for outer membrane proteins and proteins involved in central metabolism. The strongest fixation indices were identified in genes encoding the membrane proteins HofC, HopE, FrpB-4 and Sialidase A. These findings demonstrate that H. pylori has evolved in Colombia to give rise to subpopulations following a geographical structure, evolving to an autochthonous genetic pool, drive by a positive selective pressure especially on genes encoding for outer membrane proteins.

Colombia es el segundo país con mayor cantidad de etnias Amerindias del continente gracias a su ubicación geográfica y a que se encuentra en el Noroccidente del continente Sur Americano tuvo que haber sido un corredor para las migraciones de los Amerindios. Pero debido a la mezcla amerindia, europea y africana, ocurrida en diferentes proporciones a lo largo del país hubo cambios en las dinámicas poblacionales. Ojetivo: se caracterizó molecularmente una muestra indígena proveniente de dos etnias – Pijao y Nasa Paez, - y otra muestra de individuos mestizos no relacionados del Tolima; con el fin de identificar heterocigocidad, frecuencias alélicas y distancias Fst, mediante el análisis de 100 marcadores informativos de ancestría (SNPs autosómicos). Metodología: Para la realización de este estudio se obtuvo ADN a partir de muestras de sangre tomadas en personas indígenas y mestizas de las regiones ya mencionadas, para tipificar 100 SNPs autosómicos o Marcadores de informativos de Ancestría (AIMs). Resultados: los análisis de la Heterocigocidad (Het) mostraron que los valores bajos se presentaban en las etnias indígenas Nasa (0,181) y Pijaos (0,250), mientras que los de Planadas (0,402) e Ibagué (0,415) presentaron los valores altos. Los análisis realizados de manera global mostraron que las poblaciones del Tolima son menos heterocigotas que las poblaciones ancestrales. Conclusiones: La población nativa Nasa, es la de mayor conservación de la variación nativa ancestral reflejada con los análisis de heterocigocidad y posee una mayor distancia genética con respecto a las poblaciones mestizas.

Introducción. El cáncer colorrectal es una carga para la salud pública en Colombia y el mundo. Estudios de asociación genética han identificado regiones cromosómicas asociadas a esta enfermedad, mostrando riesgo variable entre poblaciones, debido a la historia demográfica y la ancestría genética. Objetivo. Estudiar el riesgo que aportan 20 marcadores al cáncer colorrectal en Colombia, empleando 955 casos y 972 controles del consorcio CHIBCHA, analizando conjuntamente el efecto de la ancestría genética global y local. Metodología. Las muestras se genotipificaron usando microarreglos Axyom Affymetrix LAT y CUSTOME, para obtener los genotipos genómicos globales, incluyendo 20 SNPs de riesgo. Los análisis estadísticos se realizaron en PLINK (asociaciones), ADMIXTURE (ancestría global), Elai (ancestría local) y R (modelos logísticos). Resultados. Once regiones cromosómicas resultaron asociadas presentando ORs entre 1.14 y 1.41 (p

Objetivo: Caracterizar las características clínico-patológicas y algunos fenotipos moleculares del cáncer colorrectal (CCR), en 1278 pacientes de la región andina colombiana. Métodos: Se analizó una muestra de 1278 pacientes con CCR. Análisis de expresión de los genes MMR-Mismatch Repair-hMLH1, utilizando métodos inmunohistoquímicos (IHC). Para inestabilidad microsatelital-MSI se utilizó ADN de tejido tumoral-normal mediante PCR. Resultados: Promedio de edad 57,4 años, la enfermedad es más frecuente en el género femenino 53,2%. La frecuencia de pacientes menores de 50 años (26,5%) es mayor a la esperada, el CCR en estos casos se asoció a tipos histológicos agresivos -carcinoma mucinoso y carcinoma en anillo de sello- p=

Background More than 180 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified; these SNPs can be combined into polygenic risk scores (PRS) to predict breast cancer risk. Because most SNPs were identified in predominantly European populations, little is known about the performance of PRS in non-Europeans. We tested the performance of a 180-SNP PRS in Latinas, a large ethnic group with variable levels of Indigenous American, European, and African ancestry. Methods We conducted a pooled case-control analysis of US Latinas and Latin American women (4658 cases and 7622 controls). We constructed a 180-SNP PRS consisting of SNPs associated with breast cancer risk (P Results Of 180 SNPs tested, 142 showed directionally consistent associations compared with European populations, and 39 were nominally statistically significant (P Conclusions The 180-SNP PRS predicts breast cancer risk in Latinas, with similar performance as reported for Europeans. The performance of the PRS did not vary substantially according to Indigenous American ancestry.

Papillary thyroid cancer (PTC) is the second most commonly diagnosed malignancy in U.S. Latinas and in Colombian women. Studies in non-Latinos indicate that BRAF and TERT mutations are PTC prognostic markers. This study aimed to determine the prevalence and clinical associations of BRAF and TERT mutations in PTC Latino patients from Colombia. We analyzed mutations of BRAF (V600E) and TERT promoter (C228T, C250T) in tumor DNA from 141 patients (75 with classical variant PTC, CVPTC; 66 with follicular variant PTC, FVPTC) recruited through a multi-center study. Associations between mutations and clinical variables were evaluated with Fisher exact tests. Survival was evaluated with Kaplan–Meier plots. Double-mutant tumors (BRAF+/TERT+, n = 14 patients) were more common in CVPTC (P = 0.02). Relative to patients without mutations (n = 48), double mutations were more common in patients with large tumors (P = 0.03), lymph node metastasis (P = 0.01), extra-thyroid extension (P = 0.03), and advanced stage (P = 6.0 × 10−5). In older patients, TERT mutations were more frequent (mean age 51 years vs 45 years for wild type TERT, P = 0.04) and survival was lower (HR = 1.20; P = 0.017); however, given the small sample size, the decrease in survival was not statically significant between genotypes. Comparisons with published data in US whites revealed that Colombian patients had a higher prevalence of severe pathological features and of double-mutant tumors (10 vs 6%, P = 0.001). Mutations in both oncogenes show prognostic associations in Latinos from Colombia. Our study is important to advance Latino PTC precision medicine and replicates previous prognostic associations between BRAF and TERT in this population.

Background: Infection with Helicobacter pylori is recognized as the main risk factor for gastric cancer (GC); the clinical outcome of this infection is variable and partially depends on the virulence of the infective strain. This study characterizes H. pylori virulence genes in patients with diverse gastric lesions, from preneoplasia to GC, from a South American region with high GC mortality rates.Methods: We studied the virulence profiles of H. pylori strains to colonize the antrum of 318 patients with non-atrophic gastritis (NAG), 58 patients with preneoplastic lesions (PN), and 90 with GC from Ibagué, Colombia. The presence of 16S rDNA, the cagA and cagE genes, and the vacA s1, s2, m1, and m2 alleles were determined by PCR.Results: H. pylori infection was detected in 44% of all patients, 41.2% in NAG, 43.1% in PN and 54.4% of GC patients (p= 0.0813). cagA and cagE genes were significantly more frequent in and GC than in NAG (p= vacA s1m1 haplotype was significantly more frequent in PN (68%) and GC (65.3%) than in NAG (37.4%). The frequency of vacA s2m2 haplotype decreased significantly from NAG (42.7%) to PN (12%) and this to GC (4.1%). A total of 23 different genotypes were identified, with cagA+/cagE+/vacA s1m1 (84/205) as the more frequent in PN and GC and cagA-/cagE-/vacA s2m2 in NAG (49/205).Conclusions: In the population studied, vacA s2m2 was identified as a significant marker for protection against PN and GC, and genotype cagA+/cagE+/vacA s1m1 as a marker for increased GC risk. We also found that patients with PN and GC had a higher frequency of cagA+/cagE+/vacA s1m1 H. pylori strains known to be aggressive.

We present the complete genome sequences of three Helicobacter pylori strains isolated from patients who resided in Tolima Department, Colombia, diagnosed with chronic gastritis. The genomes present an average length of 1.6 Mbp and 1,546 genes and correspond to different H. pylori subpopulations.

Resumen Introducción. El cáncer de mama es un problema mundial de salud pública; entre el 5 y el 10 % de los casos presentan agregación familiar, lo que se explicaría por la presencia de mutaciones en genes de alto riesgo como el BRCA1 y el BRCA2. El origen fundador de la deleción BRCA1 3450del4 en Colombia ya fue reportado. Objetivo. Hacer un análisis descriptivo de seis familias del del Tolima y del Huila con la deleción BRCA1 3450del4 de la asociación de la mutación germinal, con el cáncer de mama y la agregación familiar. Materiales y métodos. Se hizo un estudio descriptivo y transversal de seis casos índice con cáncer de mama positivos para BRCA1 3450del4, que cumplían tres de los criterios establecidos por Jalkh, et al. A partir de la información de las entrevistas, se realizaron los árboles genealógicos (GenoPro™, versión 2016). Se tipificó la mutación en familiares sanos y afectados que aceptaron participar. Resultados. De los 78 individuos seleccionados por conveniencia en las seis familias, 30 presentaron la mutación BRCA1 3450del4; de ellos, seis tenían cáncer de mama, uno, cáncer de ovario, uno, cáncer de mama y ovario, y otro, cáncer de próstata; 21 no presentaban neoplasias. De los 30 individuos portadores de la variante patogénica, seis eran hombres y 24 mujeres, 13 de ellas menores de 30 años. Conclusiones. En este estudio se confirmó la asociación de la deleción BRCA1 3450del4 con el cáncer de mama de agregación familiar. Abstract Introduction: Breast cancer is a worldwide public health problem; between 5% and 10% of the cases present familial aggregation explained by genes of high risk such as BRCA1 and BRCA2. The founding origin of the deletion BRCA1 3450del4 in Colombia has been previously reported. Objective: To carry out in six families from Tolima and Huila departments a descriptive analysis of the presence of the BRCA1 3450del4 mutation associated with breast cancer and familial aggregation. Materials and methods: We conducted a descriptive and cross-sectional study of six index cases with breast cancer positive for BRCA1 3450del4 that fulfilled three of the criteria established by Jalkh, et al. The genealogical trees were made using the information of the interview data (GenoPro™, version 2016). The mutation was typified in healthy and affected relatives who agreed to participate. Results: Thirty of the 78 individuals selected by convenience in the six families presented the mutation BRCA1 3450del4 six of whom developed breast cancer, one, ovarian cancer, one ovarian and breast cancer, and one prostate cancer; 21 did not present any type of neoplasm at the time of the study. Of the 30 individuals carrying the pathogenic variant, six were men, 24 were women, and 13 of these were under 30. Conclusions: In this study of families with the deletion BRCA1 3450del4 in Tolima and Huila we confirmed its association with familial aggregation of breast cancer.

Based on epidemiological associations and experimentation, relationships between viruses and cancer have been established. For more than 14 million new cases of cancer per year, it is estimated that 15% are related to viral agents. Epithelial, hematolymphoid and mesenchymal malignancies related to different viruses have been document such as Epstein Barr, Kaposi’s sarcoma, hepatitis B and C, human lymphotropic type 1, Merkel’s carcinoma and human papilloma. New virus with oncogenic potential such as cytomegalovirus, JC polyoma virus and BK have been described. The interaction of the viruses with the host induces oncogene activation, inhibition of tumor suppressor genes and activation of miRNAs, as determining factors in the development of cancer. The pathology is initiated with the infection that induces the deregulation of cell signaling. The Epstein Barr virus is the oncogenic prototype, with 1% of the human cancers related to it.

We aimed to assess the current genetics practice to manage patients with Lynch syndrome (LS) across Latin America. A Latin American LS survey was sent out to 52 centres/registries, comprising a total of 12 countries from the region. Overall, 33 centres completed the survey, of which the oldest LS registry was established in 1992 in Sao Paulo (Brazil), and the youngest this year in San Jose (Costa Rica). In total, 87% (26/30) of the participating centres/registries belonging to the nine countries are performing genetic testing. Overall, 1352 suspected families were sequenced. Pathogenic variants were identified in 34% of the families, with slightly differing distribution of variants between females and males. Path_MLH1 variants were identified in 39% of females and 50% of males (p = 0.023), while path_MSH2 were identified in 37% of females and males, followed by path_PMS2 in 11% of females and 8% of males, path_MSH6 in 13% of females and 3% of males (p 0.001) and path_EPCAM in 0.3% of females and 2% of males. In Latin America, 9 of 12 (75%) participating countries had implemented healthcare for LS. LS screening is inconsistently applied within Latin America healthcare systems because of structural differences in the healthcare systems between the countries.

BackgroundOver 180 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified; these SNPs can be combined into polygenic risk scores (PRS) to predict breast cancer risk. Since most SNPs were identified in predominantly European populations, little is known about the performance of PRS in non-Europeans. We tested the performance of a 180-SNP PRS in Latinas, a large ethnic group with variable levels of Indigenous American, European, and African ancestry.MethodsWe conducted a pooled case-control analysis of U.S. Latinas and Latin-American women (4,658 cases, 7,622 controls). We constructed a 180-SNP PRS consisting of SNPs associated with breast cancer risk (p < 5 × 10−8). We evaluated the association between the PRS and breast cancer risk using multivariable logistic regression and assessed discrimination using area under the receiver operating characteristic curve (AUROC). We also assessed PRS performance across quartiles of Indigenous American genetic ancestry.ResultsOf 180 SNPs tested, 142 showed directionally consistent associations compared with European populations, and 39 were nominally significant (p < 0.05). The PRS was associated with breast cancer risk, with an odds ratio (OR) per standard deviation increment of 1.58 (95% CI 1.52 to 1.64) and AUCROC of 0.63 (95% CI 0.62 to 0.64). The discrimination of the PRS was similar between the top and bottom quartiles of Indigenous American ancestry.ConclusionsThe 180-SNP PRS predicts breast cancer risk in Latinas, with similar performance as reported for Europeans. The performance of the PRS did not vary substantially according to Indigenous American ancestry.

Familial nonmedullary thyroid cancer (NMTC) has not been clearly linked to causal germline variants, despite the large role that genetic factors play in risk. Recently, HABP2 G534E (rs7080536A) has been implicated as a causal variant in NMTC. We have previously shown that the HABP2 G534E variant is not associated with TC risk in patients from the British Isles. Hispanics are the largest and the youngest minority in the United States and NMTC is now the second most common malignancy in women from this population. In order to determine if the HABP2 G534E variant played a role in NMTC risk among Hispanic populations, we analyzed 281 cases and 1105 population-matched controls from a multicenter study in Colombia, evaluating the association through logistic regression. We found that the HABP2 G534E variant was not significantly associated with NMTC risk (P=0.843) in this Hispanic group. We also stratified available clinical data by multiple available clinicopathological variables and further analyzed the effect of HABP2 on NMTC presentation. However, we failed to detect associations between HABP2 G534E and NMTC risk, regardless of disease presentation (P≥0.273 for all cases). Therefore, without any significant associations between the HABP2 G534E variant and NMTC risk, we conclude that the variant is not causal of NMTC in this Hispanic population.

Context: A recent study reported the nonsynonymous G534E (rs7080536, allele A) variant in the HABP2 gene as causal in familial nonmedullary thyroid cancer (NMTC). Objective: The objective of this study was to evaluate the causality of HABP2 G534E in the TCUKIN study, a multicenter population-based study of NMTC cases from the British Isles. Design and Setting: A case-control analysis of rs7080536 genotypes was performed using 2105 TCUKIN cases and 5172 UK controls. Participants: Cases comprised 2105 NMTC cases. Patient subgroups with papillary (n = 1056), follicular (n = 691), and Hürthle cell (n = 86) thyroid cancer cases were studied separately. Controls comprised 5172 individuals from the 1958 Birth Cohort and the National Blood Donor Service study. The controls had previously been genotyped using genome-wide single nucleotide polymorphism arrays by the Wellcome Trust Case Control Consortium study. Outcome Measures: Association between HABP2 G534E (rs7080536A) and NMTC risk was evaluated using logistic regression. Results: The frequency of the HABP2 G534E was 4.2% in cases and 4.6% in controls. We did not detect an association between this variant and NMTC risk (odds ratio [OR] = 0.896; 95% confidence interval, 0.746–1.071; P = .233). We also failed to detect an association between the HABP2 G534E and cases with papillary (1056 cases; G534E frequency = 3.5%; OR = 0.74; P = .017), follicular (691 cases; G534E frequency = 4.7%; OR = 1.00; P = 1.000), or Hürthle cell (86 cases; G534E frequency = 6.3%; OR = 1.40; P = .279) histology. Conclusions: We found that HABP2 G534E is a low-to-moderate frequency variant in the British Isles and failed to detect an association with NMTC risk, independent of histological type. Hence, our study does not implicate HABP2 G534E or a correlated polymorphism in familial NMTC, and additional data are required before using this variant in NMTC risk assessment.

Gastric cancer is a leading cause of cancer mortality in Latinos, who are two times more likely to die of gastric cancer when compared to non-Latino Whites. Gastric cancer outcomes in this minority are poor as most tumors are detected in the metastatic setting, where five-year survival is less than 5%. Despite such a high mortality burden in Latinos and other minority populations, there are only three molecularly-guided therapies approved by the Food and Drug Administration to treat gastric cancer. To advance precision medicine in minority groups, the NCI Center to Reduce Cancer Health Disparities funded our University of California Minority Patient-Derived Xenograft (PDX) Development and Trial Center (UCaMP), which is currently creating and characterizing PDXs and patient-derived organoids from minority patients including those with gastric cancer. In this presentation, we will present an overview of recent advances in gastric cancer precision modeling using patient-derived organoids and xenografts from Latino patients. We will summarize the most promising druggable genes and pathways in gastric tumors and will present initial findings on the development of promising combinations using PIK3CA inhibitors. Citation Format: Hongyong Zhang, Nicole Coggins, Paul Lott, Ana Estrada, Guadalupe Polanco, Alexa Morales, Sienna Rocha, Amanda Kirane, Shiro Urayama, Javier Torres, Mabel Bohorquez, Magdalena Echeverry, UCaMP Consortium, Luis G. Carvajal-Carmona. Advancing gastric cancer precision medicine through minority patient derived modeling [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA13.

The goal of this study was to examine gastric (stomach) cancer mutational intratumoral heterogeneity (ITH) in Latinos using multiregion sequencing (MSEQ). Gastric cancer is the 2nd leading cause of cancer-related death worldwide. It is diagnosed in 25,000 Americans each year, with Latinos twice as likely to succumb as Whites. Treatment is currently limited to a few molecularly guided therapies, but TCGA data show that 70% of GC patients have a mutation in a gene targetable with existing drugs. Significant ITH has been identified in a variety of tumor types to date, although a GC study has yet to be published. ITH is an important consideration for personalized therapy. Driver gene mutations are frequently found to be nonclonal, a crucial factor when assessing effective druggability. In this study, two to five tumor biopsies and adjacent normal tissue were obtained from 33 Latino patients, totaling 120 tumor (T) biopsies and 33 normal (N) samples. DNA was extracted from the tissues and the coding regions of 762 cancer-related genes were sequenced using Agilent target enrichment and Illumina sequencing. For each biopsy, estimates were made of sample purity and ploidy, somatic mutations were called using joint analysis of all T and N sequence data for each patient, cancer cell fraction (CCF) was estimated for each mutation, and copy number variation (CNV) was called across the genome. Somatic mutations and copy number changes were analyzed for clonality in each patient. We found a high degree of heterogeneity, both intratumoral and interpatient, with the fraction of functional somatic mutations that are clonal ranging from 0 to 68%, the fraction private to one biopsy ranging from 32% to 100%, and the fraction shared between multiple but not all biopsies ranging from 0 to 42%. For 10 of the 33 samples there was at least one gene, containing a clonal functional mutation, for which there is an FDA-approved targeted therapy. In summary, our study is the first to assess ITH in GC. Our results are important to understand the genetic diversity and clonal architecture of these tumors and to improve molecular diagnostics. This abstract is also being presented as Poster D107. Citation Format: Ted Toal, Guadalupe P. Echeverry, Ruta Sahasrabudhe, Mabel Bohorquez, Javier Torres, Shiro Urayama, Amanda Kirane, Magdalena Echeverry, Luis G. Carvajal Carmona. Intratumoral heterogeneity in Latino gastric adenocarcinomas [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR15.

Gastric cancer (GC) is the 2nd leading cause of cancer-related death worldwide, with a five-year survival rate lower than 30%. GC is diagnosed in 25,000 Americans each year, with Latinos twice as likely to succumb compared to non-Hispanic whites. Treatment is currently limited to only two molecularly guided therapies. The Cancer Genome Atlas (TCGA) data show that 70% of GC patients have a mutation in a gene targetable with existing drugs. Significant spatial mutational intratumoral heterogeneity (ITH) has been identified in a variety of tumor types to date, although a GC ITH study has yet to be investigated. ITH is an important consideration for personalized therapy. Driver gene mutations are frequently found to be nonclonal, a crucial factor when assessing effective druggability. The goal of the present study was to examine GC ITH in Latino GC patients using targeted multiregional sequencing (MSEQ). Two to five biopsies from different tumor regions and adjacent normal tissue were obtained from 34 GC patients; DNA was extracted from the tumor and the normal tissues and the coding regions of 783 cancer genes were sequenced using Agilent enrichment and Illumina sequencing. Somatic mutations were called in each tumor sample, using joint analysis of all samples for each patient. Tumor cell fractions were estimated for each mutation in each sample, and phylogenetic trees were made for visualize each patient's somatic mutational patterns. We found a high degree of ITH, both intratumoral and interpatient, with the fraction of functional somatic mutations that are clonal ranging from 0 to 52%, the fraction private to one tumor sample ranging from 48% to 94%, and the fraction shared between multiple but not all samples ranging from 0 to 21%. There was at least one known drug interaction with a gene containing a clonal functional mutation for 11 of the 16 samples, and in 6 samples there were two or more known drug interactions. Our study is the first one to assess ITH in GC, and our results are important to understand the clonal architecture of these GCs and to improve molecular diagnostics. Citation Format: Ted Toal, Guadalupe M. Polanco-Echevery, Ruta Sahasrabudhe, Ana Estrada, Mabel Bohorquez, Magdalena Echeverry, Javier Torres, Luis G. Carvajal-Carmona. Gastric tumors from Latino patients show extensive intratumor heterogeneity [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 C030.

Background: Breast cancer is a partially heritable trait and over 180 common genetic variants have been associated with breast cancer in genome wide association studies (GWAS). We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25 with the protective minor allele originating from Indigenous American ancestry. Here we report on additional GWAS and replication in Latinas.Methods: We performed GWAS in 2385 cases and 7342 controls who were either U.S. Latinas or Mexican women. We replicated 2412 cases and 1620 controls of U.S Latina, Mexican, and Colombian women. In addition, we replicated the top novel variants in study of African American and African women and in one study of Chinese women. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model based approach.Results: We identified 3 SNPs (p=1.9×10-8 - 2.8×10-8) at 6q25 locus not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.75 (0.68-0.83). In a replication in women of Latin American origin, we also observed a consistent effect (OR: 0.88; 95% CI: 0.78-0.99; p=0.037). Since the minor allele was common in East Asians and African American but not European ancestry populations, we replicated in a meta-analysis of those populations and also observed a consistent effect (OR 0.94; 95% CI: 0.91 – 0.97; p=0.013).Conclusion: The effect size of this variant is relatively large compared to other common variants associated with breast cancer and adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.

Resumen:OBJETIVO:Reunir evidencias de la variación en la frecuencia de las mutaciones de BRCA1 y BRCA2 y la historia familiar en pacientes con cáncer de glándula mamaria (CGM) y cáncer de ovario (CO) de diferentes orígenes geográficos.MÉTODO:En este trabajo se realizó una revisión sistemática, siguiendo los parámetros del protocolo PRISMA, para estimar la prevalencia de mutaciones en los genes BRCA 1/2 en pacientes con CGM y CO, la incidencia de la historia familiar y la prevalencia observada en casos esporádicos en este tipo de cáncer.RESULTADOS:Se observa una heterogeneidad en la frecuencia de las mutaciones de estos genes en los estudios de historia familiar, con una variación entre 0.0 y 0.48 en pacientes y familiares con CGM y CO similares a los previamente reportados.DISCUSIÓN: Este amplio rango de la frecuencia se debe al origen de la población estudiada, el número de individuos analizados y la metodología de genotipificación utilizada. La revisión revela que el CGM y CO familiar es dos veces más frecuente, en comparación con los casos de esta misma patología con origen esporádico.CONCLUSIONES:Este tipo de estudios moleculares les permite a las personas que presentan historia familiar con CGM y CO realizarse análisis precoces y chequeos para prevenir en un futuro el desarrollo de alguna de estas neoplasias. Abstract:OBJECTIVE:Collect evidence about the frequency variation of BRCA1 and BRCA2 mutations and family history in patients with mammary gland cancer (MGC) and ovarian cancer (OC) from different geographical backgrounds.METHOD: This paper presents a systematic review using the PRISMA protocol parameters to estimate the prevalence of mutations in BRCA 1/2 genes in patients with MGC and OC, the incidence of family history and the observed prevalence in sporadic cases with this type of cancer.RESULTS:Heterogeneity is observed in the frequency of mutations of these genes in studies of family history ranging between 0.0 and 0.48 in patients and families with MGC and OC similar to those previously reported.DISCUSSION:This wide range of frequency is due to the origin of the studied population, the number of individuals analyzed and genotyping methodology used. The review reveals that the family MGC and OC is twice as common compared with cases of the same disease of a sporadic origin.CONCLUSIONS: This type of molecular studies allows other people who have family history of MGC and OC to perform early analysis and tests to prevent the future development of this neoplasia.

The G allele of the rs6983267 single-nucleotide polymorphism, located on chromosome 8q24, has been associated with increased risk of several cancer types. The association between rs6983267G and thyroid cancer (TC) has been tested in different populations, mostly of European ancestry, and has led to inconclusive results. While significant associations have been reported in the British and Polish populations, no association has been detected in populations from Spain, Italy and the USA. To further investigate the role of rs6983267G in TC susceptibility, we evaluated rs6983267 genotypes in three populations of different continental ancestry (British Isles, Colombia and Japan), providing a total of 3067 cases and 8575 controls. We detected significant associations between rs6983267G and TC in the British Isles (odds ratio (OR)=1.19, 95% CI: 1.11–1.27, P=4.03×10−7), Japan (OR=1.20, 95% CI: 1.03–1.41, P=0.022) and a borderline significant association of similar effect direction and size in Colombia (OR=1.19, 95% CI: 0.99–1.44, P=0.069). A meta-analysis of our multi-ethnic study and previously published non-overlapping datasets, which included a total of 5484 cases and 12 594 controls, confirmed the association between rs6983267G and TC (P=1.23×10−7, OR=1.13, 95% CI: 1.08–1.18). Our results therefore support the notion that rs6983267G is a bona fide TC risk variant that increases the risk of disease by ∼13%.

Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved. Colorectal cancer (CRC) is a major public health problem, and its incidence is rising in developing countries. However, studies characterizing CRC clinicopathological features in cases from developing countries are still lacking. The goal of this study was to evaluate clinicopathological and demographic features in one of the largest CRC studies in Latin America. The study involved over 1525 CRC cases recruited in a multicenter study in Colombia between 2005 and 2014 as part of ongoing genetic and epidemiological studies. We gathered clinicopathological data such as age at diagnosis, sex, body mass index, tobacco and alcohol consumption, family history of cancer, and tumor features including location, histological type, and stage. Statistical analyses were performed to test the association between age of onset, sex, and clinical manifestations. The average age at CRC diagnosis was 57.4 years, with 26.5% of cases having early-onset CRC (diagnosed by age 50 years). Most cases were women (53.2%; P=0.009), 49.2% were overweight or obese, 49.1% were regular alcohol drinkers, 52% were smokers/former smokers, and 12.2% reported relatives with cancer. Most tumors in the study were located in the rectum (42.7%), were adenocarcinomas (91.5%), and had advanced stage (T3-T4, 79.8%). Comparisons by sex found that male cases were more likely to be obese (36.5% vs 31.1%; P=0.001), less likely to have a family history of cancer (9.7% vs 15.3%; P=0.016), and more likely to have advanced-stage tumors (83.9% vs 76.1%; P=0.036). Comparisons by age of onset found that early-onset cases were more likely to be women (59.3% vs 51.0%; P=0.005) and report a family history of cancer (17.4% vs 10.2%; P=0.001). To our knowledge, our study is the largest report of clinicopathological characterization of Hispanic CRC cases, and we suggest that further studies are needed to understand CRC etiology in diverse Hispanic populations.

Up to 10% of cases of gastric cancer are familial, but so far, only mutations in CDH1 have been associated with gastric cancer risk. To identify genetic variants that affect risk for gastric cancer, we collected blood samples from 28 patients with hereditary diffuse gastric cancer (HDGC) not associated with mutations in CDH1 and performed whole-exome sequence analysis. We then analyzed sequences of candidate genes in 333 independent HDGC and non-HDGC cases. We identified 11 cases with mutations in PALB2, BRCA1, or RAD51C genes, which regulate homologous DNA recombination. We found these mutations in 2 of 31 patients with HDGC (6.5%) and 9 of 331 patients with sporadic gastric cancer (2.8%). Most of these mutations had been previously associated with other types of tumors and partially co-segregated with gastric cancer in our study. Tumors that developed in patients with these mutations had a mutation signature associated with somatic homologous recombination deficiency. Our findings indicate that defects in homologous recombination increase risk for gastric cancer. Fil: Sahasrabudhe, Ruta. University of California at Davis; Estados Unidos Fil: Lott, Paul. University of California at Davis; Estados Unidos Fil: Bohorquez, Mabel. Universidad del Tolima; Colombia Fil: Toal, Ted. University of California at Davis; Estados Unidos Fil: Estrada, Ana P.. Universidad del Tolima; Colombia Fil: Suarez, John J.. Universidad del Tolima; Colombia Fil: Brea Fernández, Alejandro. Ciber Enfermedades Raras; España Fil: Cameselle Teijeiro, José. Complejo Hospitalario Universitario de Santiago; España Fil: Pinto, Carla. Instituto Portugues de Oncologia de Francisco Gentil Porto; Portugal Fil: Ramos, Irma. Instituto Mexicano del Seguro Social; México Fil: Mantilla, Alejandra. Departamento de Patologia la Unidad Medica Alta Especialidad Oncologia; México Fil: Prieto, Rodrigo. Universidad del Tolima; Colombia Fil: Corvalan, Alejandro. Pontificia Universidad Católica de Chile; Chile Fil: Norero, Enrique. Pontificia Universidad Católica de Chile; Chile Fil: Alvarez, Carolina. Universidad Católica de Chile; Chile Fil: Tapia, Teresa. Pontificia Universidad Católica de Chile; Chile Fil: Carvallo, Pilar. Pontificia Universidad Católica de Chile; Chile Fil: Gonzalez, Luz M.. Instituto de Cancerologia, Las Americas; Colombia Fil: Cock-Rada, Alicia. Instituto de Cancerologia, Las Americas; Colombia Fil: Solano, Angela Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centro de Educaciones Médicas e Investigación Clínica ; Argentina. Universidad de Buenos Aires; Argentina Fil: Neffa, Florencia. Laboratorio Genia; Uruguay Fil: Della Valle, Adriana. Laboratorio Genia; Uruguay Fil: Yau, Chris. University of Oxford; Reino Unido Fil: Soares, Gabriela. Centro Hospitalar Do Porto; Portugal Fil: Borowsky, Alexander. University of California at Davis; Estados Unidos Fil: Hu, Nan. National Cancer Institute; Estados Unidos Fil: He, Li-Ji. Yangcheng Cancer Hospital; China Fil: Han, Xiao-You. Shanxi Cancer Hospital; China Fil: Taylor, Philip R.. National Institutes of Health; Estados Unidos Fil: Goldstein, Alisa M.. National Institutes of Health; Estados Unidos Fil: Torres, Javier. Instituto Mexicano del Seguro Social; México Fil: Echeverry, Magdalena. Universidad del Tolima; Colombia Fil: Ruiz-Ponte, Clara. Centro de Investigación Biomédica en Red de Enfermedades Raras; España Fil: Teixeira, Manuel R.. Universidad de Porto; Portugal Fil: Carvajal Carmona, Luis G.. University of California at Davis; Estados Unidos

Background: Several colorectal cancer susceptibility disease loci have been discovered through genome-wide association studies. However most of the variants were originally identified in Caucasian populations. Aim: To analyze the role of 20 known risk SNPs for colorectal cancer. Methods: Given that linkage disequilibrium is highly dependent on population demographic history and admixture background, we studied 20 risk SNPs in a pooled sample of 955 cases and 968 controls from admixed populations in Colombia. Results: The replication was reached for 11 out of 20 nominally associated SNPs; with allelic odds ratios (OR) ranging from 1.14 to 1.41, indicating a minimal increase in risk individually, however coinheritance of those SNPs resulted in an overall OR = 5.4 (95% CI: 3.052-9.731, P = 1.16E−08). Most of the variants followed a recessive model consistent with significant homozygous ORs distributed between 1.3 and 1.65. Among the most associated markers we found: rs4939827 (18q21.1, P = 7.35E−6), rs10411210 (19q13.11, P = 0.001), rs10795668 (10p14, P = 0.0024), rs4444235 (14q.2.2, P = 0.005), rs961253 (20p12.3, P = 0.006), rs16892766 (8q23.3, P = 0.011) and rs1050547 (8q24.21, P = 0.017). Conclusion: Our findings in Colombia have addressed the admixture and how this has influenced the risk associated with the known/unknown colorectal cancer regions, providing a comprehensive vision about several CRC-susceptibility SNPs identified in European populations, which also resulted, associated with an increased risk to CRC in the Colombian population, even though frequency and genetic structure differences accounted for those nonreplicated SNPs.

Papillary thyroid cancer (PTC) is the second most commonly diagnosed tumor in U.S. Hispanic women, representing ~9% of all incident female cancer cases in this minority. In Colombia, a country with a predominantly Hispanic population, PTC is the fifth most commonly diagnosed cancer in women. Several studies, predominantly in non-Hispanic whites (NHW), have associated the RAS-RAF gene and TERT promoter mutations with severe PTC clinical manifestations. We investigated associations between mutations in these genes and clinicopathologic data (age, gender, histologic type, tumor features and AJCC stage) in 143 Colombian cases (76 with classical variant PTC, CVPTC and 65 with follicular variant PTC, FVPTC). DNA from archival samples was isolated using standard methods and mutation status at hotspots in BRAF (V600E), NRAS (Q61R, Q61K), HRAS (Q61R, Q61K), and TERT (C228T, C250T) were assessed using Sanger sequencing. Clinicopathologic data between mutation carriers and noncarriers and with data from NHWs in the TCGA were carried out with t-tests and odds ratios (OR). BRAF V600E was detected in 59% of all cases, a rate that is similar to NHW (64%; P=0.29). When we stratified the data by subtype, we found a similar V600E frequency in CVPTC in Colombian cases than in NHWs (67% vs 68%; P=0.87) but a borderline significantly higher frequency of the mutation in FVPTC (49% vs 29%; P=0.06). TERT promoter mutations were found in 17% of all cases, a rate that is significantly higher than in NHW (10%, p= 0.03). 5% of cases had mutations in HRAS/NRAS, which is lower than in NHW (11%; P=0.04). Given the low RAS gene mutation frequency, comparisons with clinical data were carried out only with BRAF and TERT data. BRAF/TERT mutation-positive samples (BRAF+/TERT+, n=18) were compared to mutation-negative cases for either or both genes (n=123). BRAF+/TERT+ tumors were more common in CVPTC than in FVPTC (17% vs. 7%; OR=4.1; P=0.02), and in cases with tumors >2cm (20% vs. 6%; OR=4.0; P=0.03), with capsular invasion (18% vs. 5%; OR=5.6; P=0.02), with lymph node metastasis (19% vs. 6%; OR=7.1; P=0.006), with extrathyroidal extension (23% vs. 6%; OR=4.8; P=0.03), and advanced AJCC stage (29% vs. 4%; OR= 8.7; P=5.00 x 10-4). PTC is considered a relatively benign malignancy with good prognosis and survival in the U.S., but we found a high fraction of Colombian cases in advanced AJCC stage (32%) and with distant metastasis (6%), suggesting that most cases were not the result of incidental findings, a common phenomenon in developed countries where most PTCs are likely the result of overdiagnosis. In summary, we present the first report of BRAF/RAS/TERT mutations in Hispanics with PTC from Latin America, demonstrate the utility of these mutations to identify cases with severe disease, and generate a body of data that will be important for the establishment of PTC precision medicine in the region. Citation Format: Ana P. Estrada-Florez, Mabel E. Bohorquez, Carlos S. Duque, Jorge Donado, Gilbert Mateus, Fernando Bolaños, Alejandro Velez, Erika Estrada, Guadalupe Polanco-Echeverry, Ruta Sahasrabudhe, Elisha Garcia, Magdalena Echeverry, Luis G. Carvajal-Carmona. Associations between somatic mutations and clinical manifestations in South American Hispanic patients with papillary thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5233.

It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT. © 2010 Cancer Research UK. All rights reserved., published_or_final_version

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1,184 genotyped and imputed SNPs in 6,608 Caucasian cases and 37,925 controls, and 895 Asian cases and 1,968 controls, revealed the best signal of association for SNP rs11263763 (P=8.4×10(-14), OR=0.86, 95% CI=0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumour samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high to moderate LD as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression. ispartof: Human Molecular Genetics vol:24 issue:5 pages:1478-92 ispartof: location:England status: published

Gastric cancer (GC) is the third common cause of cancer related deaths worldwide and its risk is partially mediated by inherited factors. However, the majority of GC heritability remains to be discovered. The goal of this study was to identify novel GC genes. To identify novel GC genes, we undertook a multi-staged approach of whole exome sequencing (WES), followed by targeted sequencing and genotyping in germline DNA samples from hereditary diffuse GC (HDGC) and isolated GC cases recruited in Europe and Latin America. We also performed WES in 4 available tumor samples to analyze loss of heterozygosity and somatic mutation signature. Our study identified eleven cases with mutations in homologous recombination repair (HR) genes, including seven with PALB2 mutations, three with BRCA1 mutations and one with a RAD51C mutation. Out of 361 total unrelated GC cases analyzed, 6.45% of the HDGC cases (2 out of 31) and 2.7% (9 out of 330) of isolated/non-HDGC cases had mutations in PALB2, BRCA1 or RAD51C. Most of these mutations are known as pathogenic in other cancer types and three were shared by multiple Hispanic and European cases. None of these mutations were present in 1,170 population-matched controls (P=5.75x10-7). Tumor samples from four mutation carriers exhibited mutational signature indicative of defects in HR pathway. Our results suggest that mutations in HR genes are likely involved in GC susceptibility. Our findings have potential clinical implications as these cases and their families could benefit from risk reducing surveillance and possibly benefit from platinum or PARP inhibitor based therapies. Citation Format: Ruta Sahasrabudhe, Paul Lott, Mabel Bohorquez, Ted Toal, Ana Estrada, John Suarez, Alejandro Brea-Fernández, Jose Cameselle-Teijeiro, Carla Pinto, Irma Ramos, Alejandra Mantilla, Rodrigo Prieto, Alejandro Corvalan, Enrique Norero, Carolina Alvarez, Teresa Tapia, Pilar Carvallo, Luz Gonzalez, Alicia Cock-Rada, Angela Solano, Florencia Neffa, Adriana Della Valle, Chris Yau, Gabriela Soares, Alexander Borowsky, Xiao-You Han, Li-JI He, Phillip Taylor, Alisa Goldstein, Nan Hu, Javier Torres, Magdalena Echeverry, Clara Ruiz-Ponte, Manuel Teixeira, Luis G. Carvajal-Carmona. Germline mutations in PALB2, BRCA1 and RAD51C observed in gastric cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-158. doi:10.1158/1538-7445.AM2017-LB-158

The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5′ of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53–0.67, P=9 × 10−18), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21–0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49–0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations., Genome-wide association studies (GWAS) have revealed gene variants associated with breast cancer, but their association with breast cancer development in Latinas is not clear. Here, the authors carry out a GWAS of breast cancer in Latinas and identify a significant protective variant of Indigenous American origin in the 6q25 region.