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Background Tumor biomarkers aid in the diagnosis, management, and prognosis in patients with cancer. In lung cancer, serum biomarkers are used at various timepoints. However, doubts remain about their accuracy for differential diagnosis and histological subtyping in patients with suspicious lung lesions. We conducted a diagnostic test study, selecting cases with malignant lung lesions and controls with benign lung lesions. Prior to lung biopsy, all patients had the following biomarkers measured in serum (Pro-GRP, NSE, CYFRA 21 − 1, SCC - Ag, CEA). Methods The predictive capacity of serum biomarkers evaluated to discriminate between lung cancer and benign pathology was measured using sensitivity, specificity, and Area Under the Curve (AUC). We also assessed their accuracy for distinguishing Small Cell Lung Cancer (SCLC) from Non-Small Cell Lung Cancer (NSCLC) and explored their ability to perform histological subtyping. Results A total of 93 patients were included, 60 with lung cancer and 30 with benign pathology. Serum levels of Pro-GRP and NSE were elevated in patients with SCLC (274 pg. / ml and 41.9 ng. / ml) compared to patients with NSCLC or nonmalignant lung disease (NMLD). The most accurate biomarkers for discriminating between malignant and benign pathology were CEA (AUC = 76.3%, sensitivity = 55.0% / specificity = 87.9%), and CYFRA 21 − 1(AUC = 76.2%, sensitivity = 55.1% / specificity = 87.9%). Pro-GRP had a poor predictive capacity alone for discriminating NSCLC from SCLC but increases in combination with CEA and CYFRA 21 − 1 (AUC = 80.4%, sensitivity = 70.6% / specificity = 81.8%). For SCLC the diagnostic efficacy of Pro-GRP increased by combining with other biomarkers such as NSE / CYFRA21–1 (AUC = 97.3%, sensitivity = 88.8% / specificity = 98.9%). Conclusions Individual biomarkers lacked the required sensitivity and specificity to perform a differential diagnosis or achieve histological subtyping on their own. They might be useful in parallel testing to aid the physician, but a tissue biopsy should not be delayed or postponed.

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.

Introduction: Triple negative breast cancer (TNBC), occurs in 10%-20% of all breast cancer and presents a higher frequency in Latinas compared to non-Hispanic white women. It is highly immunogenic and high levels of tumor infiltrating lymphocytes (TILs) have been associated with a better overall survival and higher probability to achieve pathological complete response (pCR). Objective: This is the first study in Colombian women aimed to explore stromal TILs (sTILs) level and composition as a prognostic and predictive biomarker in TNBC. Methods: A total of 195 TNBC tumor biospecimens from patients diagnosed between 2008-2016 in 3 Colombian health institutions were included. Stromal TILs (sTILs) was evaluated following the recommendations of the International TILs Working Group 2014 in hematoxylin & eosin slides from pre-treatment samples. The number of positive cells for CD4 and CD8 was evaluated by immunohistochemistry and digital image capture. Parametric and non-parametric tests were used to evaluate differences in clinic-pathological characteristics according to sTILs levels and composition. Differences in overall survival were analyzed using Kaplan-Meier curves and the log-rank test. Cox regression analysis was used to analyze sTILs as a prognostic marker for overall survival. A logistic regression model was applied to evaluate the association of sTILs with pCR. Results: Tumors with high sTILs levels were more likely to be early stage (64.4% stage I/II) compared to tumors with low sTILs levels (35.5%). Additionally, when compared patients with high sTILs vs. low sTILs, a higher percentage of patients with high sTILs didn’t receive neoadjuvant chemotherapy (NAC) (high:50% vs. low:32.7%, p=0.025) and received more conservative surgeries (high:60% vs. low:37.9%, p Citation Format: Carlos A. Huertas-Caro, Mayra A. Ramirez, Diego Felipe Ballen, Juan Carlos Mejía, Luz Fernanda Sua-Villegas, Alicia Cock-Rada, Jovanny Zabaleta, Laura Fejerman, María Carolina Sanabria-Salas, Silvia J. Serrano-Gomez. Tumoral infiltrating lymphocytes as a prognostic factor in triple negative breast cancer patients from Colombia [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PR007.

There are well-established disparities in cancer incidence and outcomes by race/ethnicity that result from the interplay between structural, socioeconomic, socio-environmental, behavioural and biological factors. However, large research studies designed to investigate factors contributing to cancer aetiology and progression have mainly focused on populations of European origin. The limitations in clinicopathological and genetic data, as well as the reduced availability of biospecimens from diverse populations, contribute to the knowledge gap and have the potential to widen cancer health disparities. In this review, we summarise reported disparities and associated factors in the United States of America (USA) for the most common cancers (breast, prostate, lung and colon), and for a subset of other cancers that highlight the complexity of disparities (gastric, liver, pancreas and leukaemia). We focus on populations commonly identified and referred to as racial/ethnic minorities in the USA—African Americans/Blacks, American Indians and Alaska Natives, Asians, Native Hawaiians/other Pacific Islanders and Hispanics/Latinos. We conclude that even though substantial progress has been made in understanding the factors underlying cancer health disparities, marked inequities persist. Additional efforts are needed to include participants from diverse populations in the research of cancer aetiology, biology and treatment. Furthermore, to eliminate cancer health disparities, it will be necessary to facilitate access to, and utilisation of, health services to all individuals, and to address structural inequities, including racism, that disproportionally affect racial/ethnic minorities in the USA. Fil: Zavala, Valentina A.. University of California; Estados Unidos Fil: Bracci, Paige M.. University of California; Estados Unidos Fil: Carethers, John M.. University of Michigan; Estados Unidos Fil: Carvajal Carmona, Luis. University of California at Davis; Estados Unidos Fil: Coggins, Nicole B.. University of California at Davis; Estados Unidos Fil: Cruz Correa, Marcia R.. Universidad de Puerto Rico; Puerto Rico Fil: Davis, Melissa. No especifíca; Fil: de Smith, Adam J.. University of California; Estados Unidos Fil: Dutil, Julie. Ponce Research Institute; Puerto Rico Fil: Figueiredo, Jane C.. Cedars Sinai Medical Center; Estados Unidos Fil: Fox, Rena. University of California; Estados Unidos Fil: Graves, Kristi D.. University Of Georgetown; Estados Unidos Fil: Gomez, Scarlett Lin. University of California; Estados Unidos Fil: Llera, Andrea Sabina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Neuhausen, Susan L.. No especifíca; Fil: Newman, Lisa. No especifíca; Fil: Nguyen, Tung. University of California; Estados Unidos Fil: Palmer, Julie R.. National Institutes of Health; Estados Unidos Fil: Palmer, Nynikka R.. University of California; Estados Unidos Fil: Pérez Stable, Eliseo J.. National Institutes of Health; Estados Unidos Fil: Piawah, Sorbarikor. University of California; Estados Unidos Fil: Rodriquez, Erik J.. National Institutes of Health; Estados Unidos Fil: Sanabria Salas, María Carolina. Instituto Nacional de Cancerología; Colombia Fil: Schmit, Stephanie L.. University of Southern California; Estados Unidos Fil: Serrano Gomez, Silvia J.. Instituto Nacional de Cancerología; Colombia Fil: Stern, Mariana Carla. University of Southern California; Estados Unidos Fil: Weitzel, Jeffrey. No especifíca; Fil: Yang, Jun J.. St. Jude Children’s Research Hospital; Estados Unidos Fil: Zabaleta, Jovanny. No especifíca; Fil: Ziv, Elad. University of California; Estados Unidos Fil: Fejerman, Laura. University of California; Estados Unidos

PURPOSE OF THE REVIEW: Breast cancer incidence and mortality rates are lower in some Hispanic/Latino subpopulations compared to Non-Hispanic White women. However, studies suggest that the risk of breast cancer-specific mortality is higher in US Hispanics/Latinas. In this review we summarized current knowledge on factors associated with breast cancer incidence and risk of mortality in women of Hispanic/Latino origin. RECENT FINDINGS: Associative studies have proposed a multiplicity of factors likely contributing to differences in breast cancer incidence and survival between population groups, including socioeconomic/sociodemographic factors, lifestyle choices as well as access to and quality of care. Reports of association between global genetic ancestry overall as well as subtype-specific breast cancer risk among Hispanic/Latinas suggest that incidence and subtype distribution could result from differential exposure to environmental and lifestyle related factors correlated with genetic ancestry as well as germline genetic variation. SUMMARY: Hispanic/Latino in the United States have been largely underrepresented in cancer research. It is important to implement inclusive programs that facilitate the access of this population to health services and that also include education programs for the community on the importance of screening. In addition, it is important to continue promoting the inclusion of Hispanics/Latinos in genomic studies that allow understanding the biological behavior of this disease in the context of all human genetic diversity.

Breast cancer is the most frequent cancer in women worldwide. It is classified into intrinsic subtypes characterized by different molecular profiles and prognosis. The prevalence of the different intrinsic subtypes varies between population groups. IHC surrogates based on the expression of the estrogen receptor, progesterone receptor, and HER2 have been widely used to study the distribution of intrinsic subtypes in non-Hispanic whites and African Americans, but data are limited for Hispanic/Latina women. Similarly, most studies analyzing gene expression profiles only include women of European descent. This review focuses on studies that describe the distribution of breast cancer subtypes in Hispanic/Latina women and highlights the need for more research in this population. Cancer Epidemiol Biomarkers Prev; 27(1); 3–10. ©2017 AACR.

Nischarin (Nisch) is a key protein functioning as a molecular scaffold and thereby hosting interactions with several protein partners. To explore the physiological importance of Nisch, here we generated Nisch loss-of-function mutant mice and analyzed their metabolic phenotype. Nisch-mutant embryos exhibited delayed development, characterized by small size and attenuated weight gain. We uncovered the reason for this phenotype by showing that Nisch binds to and inhibits the activity of AMP-activated protein kinase (AMPK), which regulates energy homeostasis by suppressing anabolic and activating catabolic processes. The Nisch mutations enhanced AMPK activation and inhibited mechanistic target of rapamycin signaling in mouse embryonic fibroblasts as well as in muscle and liver tissues of mutant mice. Nisch-mutant mice also exhibited increased rates of glucose oxidation with increased energy expenditure, despite reduced overall food intake. Moreover, the Nisch-mutant mice had reduced expression of liver markers of gluconeogenesis associated with increased glucose tolerance. As a result, these mice displayed decreased growth and body weight. Taken together, our results indicate that Nisch is an important AMPK inhibitor and a critical regulator of energy homeostasis, including lipid and glucose metabolism.

The National Institutes of Health defines precision medicine as “An emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.” Without adequate representation of patient diversity, precision medicine based on data derived largely from Americans of northern European ancestry may actually exacerbate health disparities. Breast cancer is a highly prevalent, molecularly heterogeneous group of malignancies that remains a cause of significant morbidity and mortality worldwide. Much is known about the molecular landscape of breast cancers, their mutational and gene expression profiles. Molecular tests are widely used in the clinic to estimate breast cancer risk and its recurrence in patients treated for breast cancer. However, these tests are based on studies conducted in populations that at present include very small numbers of Latinas. As of December 2018, only 37 out of 3650 molecular profiles of breast cancer from The Cancer Genome Atlas are from women who reported Hispanic/Latina ethnicity, and no race or ethnicity information is associated with a majority of the cases (2735). Hence, the clinical usefulness of molecular breast cancer tests in Latinas of different ancestry admixtures remains to be established. Patients who are identified as Hispanic/Latino are characterized by highly variable ancestry admixtures, which makes genetic and gene–environment interaction studies particularly challenging. Our group has investigated the molecular portraits of breast cancers in a cohort of Colombian women and identified a high prevalence of luminal B subtype tumors characterized by high expression of proliferation-related genes and other clinically relevant genes. Furthermore, we have uncovered clinically relevant genes whose expression is significantly associated with Native American ancestry. Additional studies are needed to validate these findings in other Hispanic/Latina populations and to examine the gene sets included in popular molecular tests.

Breast cancer is the most common cancer and leading cause of cancer death for Latina women in the United States. Latinos are the fastest-growing minority group in the nation, encompassing individuals from multiple countries and cultures and with a wide range of genetic ancestry influences including Indigenous American, European, African, and to a lesser extent, Asian. Breast cancer risk, characteristics, and outcomes differ between populations and among individuals in the same population group according to nationality, place of birth, and genetic ancestry, with the added intersection of socioeconomic status. Most of the observed differences are explained by barriers in access to health care, lifestyle, and health-related behaviors. However, there is evidence that underlying genetic differences might also contribute to the observed heterogeneity. This article summarizes what is known about breast cancer incidence, tumor characteristics, and survival in women of Latin American origin, with emphasis on the heterogeneous nature of this group of individuals usually identified with the categories of Hispanics or Latinos.

Breast cancer (BC) is the most common malignancy in women worldwide. Different risk factors are associated with the disease which is classified into several intrinsic subtypes according to expression of hormone receptors (estrogen and progesterone) and human epidermal growth factor receptor 2 (HER2). The advent of high throughput techniques has allowed the molecular classification of BC and development of diagnostic/prognostic tools to predict disease outcome and progression. However, most molecular classifications and diagnostic/prognostic tools were developed using samples from European/Caucasian women. Hispanic/Latino describes an admixed group of individuals with different fractions of European, African, and Indigenous American ancestries. We determined the frequency of the different intrinsic subtypes of BC in Colombia and their association with genetic ancestry and found that luminal B subtype was the most prevalent in Colombian women with BC. We found that African ancestry was associated with more aggressive forms of BC. We then used next-generation sequencing techniques to determine the underlying markers of luminal B subtype of BC in Colombia. We found 67 genes differentially expressed between luminal A and luminal B subtypes, and of those, six were common between patients with high European/low Indigenous American ancestries. Interestingly, three genes (ERBB2, MIEN1, and GRB7) form a genomic “block” in chromosome 17 from which ERBB2 and GRB7 are co-expressed. The expression of ERBB2 was independent of HER-2 labeling. Our results suggest a major role of ethnicity in the modulation of these genes in BC in Hispanic/Latina women and may be the basis for future larger studies to investigate the role of ethnicity in BC susceptibility in minority groups.

The incidence of Human Epidermal Growth Factor Receptor 2 positive (HER2+) breast cancer is higher in Latinas, both in the U.S. and in Latin America. Preliminary analyses of the Peruvian Genetics and Genomics of Breast Cancer (PEGEN-BC) study data set showed a strong association between the Indigenous American (IA) component of ancestry and HER2 status independently of stage at diagnosis and other factors. The aim of this study was to identify genetic loci associated with genetic ancestry and HER2+ breast cancer in patients with high IA ancestry. To achieve this aim we used admixture mapping and gene-expression guided fine mapping. Breast cancer patients were recruited at the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru. A total of 1,850 patients have been recruited to date. DNA samples are currently available for a total of 1,380 patients. Genome wide genotypes were obtained with the Affymetrix Precision Medicine Research Array. After quality control, genome wide genotype data was available for 1,312 patients. After LD pruning and exclusion of SNPs with minor allele frequency Admixture mapping analysis revealed two regions associated with IA ancestry in two chromosomal regions: 2q11-2q12 (OR=0.6, p=0.00009) and 3p14 (OR=1.5, p= 0.0004). Of the 44 genes within the 2q region, TGFBRAP1, member of the heat shock protein 90 family, was the only gene with suggestive differential expression by HER2 status (p=0.032). Of the 28 genes within the 3p14 region, we found significant differential expression for FLNB (lower expression in HER2+ tumours, 5%FDR= 0.03), which has been shown to supress tumour growth and metastasis. Combining admixture mapping and transcriptomics is a promising approach to discover candidate genes associated with subtype-specific breast cancer risk. We are currently working to replicate suggestive findings and expand our sample size to increase power. Citation Format: Valentina Zavala, Katie M. Marker, Tatiana Vidaurre, Jeannie Navarro-Vasquez, Sandro Casavilca, Mónica Calderon, Julio Abugattas, Henry Gómez, Hugo Fuentes, Ruddy Liendo-Picoaga, Jose M. Cotrina, Silvia P. Neciosup, Carlos A. Castaneda, Zaida Morante, Fernando Valencia, Silvia J. Serrano-Gomez, Jovanny Zabaleta, Laura Fejerman. Admixture mapping and gene expression analysis to identify candidate genes associated with HER2 positive breast cancer in Latinas [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 4615.

Background: Breast cancer incidence is lower in foreign-born Latina women compared to U.S.-born Latinas, and the risk increases with younger age at migration. It is only partially known what factors contribute to these risk patterns. Several explanations have been proposed (e.g., changes in reproductive factors, diet, or environmental pollutants), but risk remains higher in U.S.-born Latinas after adjusting for established breast cancer risk factors. The goal of the present study was to find new risk factors that could explain how the migration experience, with its concomitant environmental and lifestyle-changes, affects the risk of breast cancer. Small reactive molecules have long been suspected of causing cancer by binding DNA and causing mutations. Protein adducts result from the presence of these reactive molecules but have the advantage of being easier to measure than DNA adducts. Methods: We measured levels of a panel of 23 human serum albumin (HSA)-Cys34 adducts by high-resolution mass spectrometric methods in selected samples of Latina women from the San Francisco Bay Area Breast Cancer Study for whom serum was available (146 controls and 146 cases, 45% foreign-born). Genetic ancestry was estimated from genome-wide genotypes. To identify adducts that were predictive of foreign-born status and breast cancer diagnosis, we used bootstrapped regularized logistic regression and random forest to rank all adducts and additional covariates such as percent of Indigenous American (IA) ancestry in terms of prediction importance, and then selected variables with higher prediction importance. As a measure of the prediction accuracy of selected variables for the binary outcomes, we calculated a cross-validated area under the receiver operating curve (AUC) estimate using the set of selected adducts and covariates, as well as a corresponding 95% confidence intervals. Results and Conclusions: In a model that included foreign-born status as the dependent variable, all adducts and demographic variables, two adducts were selected as predictors: mass to charge ratio (m/z)=849.07 (addition of S2O3H) and m/z=847.10 (S-methylsulfonylation). Adduct 849.07 had an associated random forest variable importance that was considerably greater than that of any other adduct. This adduct had lower levels in foreign-born Latinas and in Latinas with high IA ancestry. Additionally, adduct 849.07 was the top-ranking variable when breast cancer status was analyzed as the dependent variable. Other variables, including body mass index (BMI), African and IA ancestry, were also selected by the regularized regression as predictive, and together all five variables had a cross-validated AUC estimate of 0.61, 95% CI=(0.55,0.68) when predicting foreign-born status. Our results suggest that adduct 849.07 may be associated with the increased risk of breast cancer observed in U.S-born vs. foreign-born Latinas. More studies are needed to replicate our findings and identify the precursor molecule(s) for this adduct. Citation Format: Silvia J. Serrano-Gómez, Courtney Schiffman, Hasmik Grigoryan, Henrik Carlsson, Sandrine Dudoit, Esther M. John, Stephen M. Rappaport, Laura Fejerman. Breast cancer risk in U.S-born Latina women: potential role of reactive electrophiles [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 C065.

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.

The last 10 years witnessed an acceleration of our understanding of what genetic factors underpin the risk of breast cancer. Rare high- and moderate-penetrance variants such as those in the BRCA genes account for a small proportion of the familial risk of breast cancer. Low-penetrance alleles are expected to underlie the remaining heritability. By now, there are about 180 genetic polymorphisms that are associated with risk, most of them of modest effect. In combination, they can be used to identify women at the lowest or highest ends of the risk spectrum, which might lead to more efficient cancer prevention strategies. Most of these variants were discovered in populations of European descent. As a result, we might be failing to discover additional polymorphisms that could explain risk in other groups. This review highlights breast cancer genetic epidemiology studies conducted in Latin America, and summarizes the information that they provide, with special attention to similarities and differences with studies in other populations. It includes studies of common variants, as well as moderate- and high-penetrance variants. In addition, it addresses the gaps that need to be bridged in order to better understand breast cancer genetic risk in Latin America.

Breast cancer is the most common cancer in Latina women. Although they have a lower incidence of the disease when compared with other population groups such as non-Hispanic white and African-American women, some studies have shown that Latina women have a higher risk of mortality when compared with non-Hispanic white women. This phenomenon can be explained in part by the higher prevalence of aggressive subtypes in Latina women, particularly the triple negative. Such differences in breast cancer–intrinsic subtype distribution between population groups might be a consequence of a variety of risk factors differentially present among population groups. Here, we provide a full description of risk factors that might be associated with the high prevalence of the triple-negative subtype in Latina women. We assessed demographic (socioeconomic status), modifiable (reproductive patterns, obesity, and physical activity), and nonmodifiable (family history, germline BRCA mutations, and genetic ancestry) risk factors. The observed inconsistencies among different epidemiologic studies in Latinas warrant further research focused on breast cancer subtype–specific risk factors in this population.

Background: Breast cancer is the most frequent malignancy in women worldwide. Distinct intrinsic subtypes of breast cancer have different prognoses, and their relative prevalence varies significantly among ethnic groups. Hispanic/Latino (H/L) populations are a genetically admixed and heterogeneous group, with variable levels of European, Native American and African ancestries. Breast cancer in H/L patients is understudied from a molecular standpoint, and most studies reported so far include limited numbers of H/L patients and assign ethnicity based on self-reported data rather than ancestry. This is the first study to explore the prevalence of breast cancer intrinsic subtypes in Colombia and their association with clinicopathological data and genetic ancestry. Methods: Immunohistochemistry surrogates from the 2013 St. Gallen International Expert Consensus were applied to classify breast cancer into intrinsic subtypes in 301 patients diagnosed between 2008 and 2012 at the Colombian National Cancer Institute. We analyzed the distribution of subtypes by age, histologic type, node status, margins at surgery, AJCC stage, tumor size, Bloom-Richardson grade, histologic features, administration and response to neoadjuvant therapy, adjuvant therapy and recurrence. Genetic ancestry was estimated from a panel of 80 ancestry-informative markers (AIM). Results: Luminal B breast cancer subtype was the most prevalent in our population (47.5%), followed by luminal A (23.9%), non-basal triple negative (9.3%), basal-like (8.6%), HER2-enriched (8%), and unknown (2.6%). The average of age at diagnosis was 55 and the average tumor size was 4.08 cm. We found statistical significant differences in age at diagnosis, Bloom-Richardson grade, histologic features, adjuvant chemotherapy and recurrence according to intrinsic subtype. Consistent with North American and European observations, basal-like and non-basal triple negative were poorly differentiated tumors and more likely to be diagnosed at younger ages compared to luminal tumors. Patients diagnosed with HER2-enriched, basal and non-basal triple negative breast cancer had the highest African ancestry. Conclusions: Luminal B tumors, a high risk subset of ER-positive breast cancer, occur with remarkably higher prevalence in Colombian women with breast cancer compared to North American and European populations. Triple-negative subtypes and HER2-enriched tumors appeared to be more frequent among patients with African ancestry, as observed in North American cohorts. Future studies analyzing the molecular profiles of breast cancer in Colombian women will help us understand the molecular basis of this subtype distribution and compare the molecular characteristics of the different intrinsic subtypes in Colombian Hispanic/Latina patients. Citation Format: Serrano-Gomez SJ, Sanabria MC, Hernández-Suarez GA, Garcia O, Silva C, Romero A, Mejía JC, Fejerman L, Antonia T, Miele L, Zabaleta J. Increased prevalence of luminal B subtype in Colombian women with breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-08-09.

Background: Breast cancer is the most common cancer in Colombian women. Five intrinsic subtypes have been described based on gene expression profiles and genetic signatures, such as PAM50, have been developed to classified tumors with different prognosis. In Colombia, we have previously reported that the most prevalent breast cancer subtype was luminal B based on immunohistochemistry (IHC) surrogates, which are routinely used in the clinical practice. We analyzed the concordance between IHC surrogates and PAM50 classification in luminal tumors from Colombian women and explored gene expression differences that may account for the observed differences. Methods: We performed whole-transcriptome RNA-seq analysis in 46 breast cancer samples from Colombian women diagnosed with estrogen receptor positive tumors (27 luminal A and 21 luminal B) at the Colombian National Cancer Institute. Genefu package from R was used to perform PAM50 classification, and the DESeq2package was used to test differential gene expression between discordant cases between PAM50 and IHC. Genes with adjusted p value less than 0.05 were considered statistical significant. Results: We found that 23 patients (50%) were discordant between both methodologies (IHC and PAM50). For the 27 luminal A tumors assessed by IHC, 10 (37%) were re-classified as luminal B by PAM50 and 3 (11.11%) as normal-like. On the other hand, for the 21 tumors classified as luminal B by IHC, 4 (19.04%) were re-assigned as HER2-enriched, 4 (19.04%) as luminal A and 2 (9.5%) as normal-like. Next, we tested differential expression in discordant vs. concordant cases with PAM50 within each luminal subtype assessed by IHC. For luminal B IHC-tumors, we found 67 differentially expressed genes. Some of the top differentially expressed genes are part of the ERBB2 signaling pathway (ERBB2, padj < 0.01, log2FC = 2.5; GRB7, padj < 0.01, log2FC = 2.95), which is consistent with the re-assignment of luminal A tumors to luminal B. Moreover, we found overexpression of ARID5B (padj< 0.01, log2FC=1.72) a histone modifier gene that has been described mutated in breast cancer. This result might suggest that an epigenetic mechanism may be involved in defining the luminal profile of these tumors. On the other hand, for luminal A IHC-tumors, we found 12 differentially expressed genes. The gene with the highest fold-change was DSCAM-AS1 (padj = 0.030, log2FC=3.43) which is very interesting as it is a estrogen-regulated long noncoding RNA (lncRNA) that has been recently associated with tumor progression and tamoxifen resistance. Conclusions: Our results suggest that epigenetic mechanisms such as histone modifications and the lncRNAs might be associated with luminal tumors in Colombian women and might also define the fate of the luminal profile of these tumors. Citation Format: Silvia J. Serrano-Gomez, Maria Carolina Sanabria-Salas, Jone Garay, Juan C. Mejia, Oscar Garcia, Jovanny Zabaleta, Laura Fejerman. Understanding transcriptomic profiles that might explain discordance of the PAM50 and immunohistochemistry classification methods in luminal tumors from Colombian women [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 460.

// Jone Garay 1 , M. Blanca Piazuelo 2 , Lizbeth Lopez-Carrillo 3 , Yelda A. Leal 4 , Sumana Majumdar 1 , Li Li 1 , Nataly Cruz-Rodriguez 1, 5, 6 , Silvia J. Serrano-Gomez 1, 5, 6 , Carlos S. Busso 7 , Barbara G. Schneider 2 , Alberto G. Delgado 2 , Luis E. Bravo 8 , Angela M. Crist 9 , Stryder M. Meadows 9 , M. Constanza Camargo 10 , Keith T. Wilson 2, 11 , Pelayo Correa 2 and Jovanny Zabaleta 1, 12 1 Stanley S. Scott Cancer Center, LSUHSC, New Orleans, LA, USA 2 Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA 3 Instituto Nacional de Salud Publica, Cuernavaca, Morelos, Mexico 4 Unidad de Investigacion Medica Yucatan de la Unidad Medica de Alta Especialidad (UMAE) del Instituto Mexicano del Seguro Social (IMSS), Yucatan, Mexico 5 Pontificia Universidad Javeriana, Bogota, Colombia 6 Grupo de Investigacion en Biologia del Cancer, Instituto Nacional de Cancerologia, Bogota, Colombia 7 Department of Otorhinolaryngology, LSUHSC, New Orleans, LA, USA 8 Department of Pathology, Universidad del Valle, Cali, Colombia 9 Department of Cell and Molecular Biology Tulane University, New Orleans LA, USA 10 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA 11 Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA 12 Department of Pediatrics, LSUHSC, New Orleans, LA, USA Correspondence to: Jovanny Zabaleta, email: jzabal@lsuhsc.edu Keywords: precancerous gastric lesions, DMBT1 , H. pylori , inflammation, gastric cancer Received: October 25, 2016 Accepted: March 16, 2017 Published: April 03, 2017 ABSTRACT Helicobacter pylori infection triggers a cascade of inflammatory stages that may lead to the appearance of non-atrophic gastritis, multifocal atrophic, intestinal metaplasia, dysplasia, and cancer. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by binding to pathogens. Initial studies showed its deletion and loss of expression in a variety of tumors but the role of this gene in tumor development is not completely understood. Here, we examined the role of DMBT1 in gastric precancerous lesions in Caucasian, African American and Hispanic individuals as well as in the development of gastric pathology in a mouse model of H. pylori infection. We found that in 3 different populations, mucosal DMBT1 expression was significantly increased (2.5 fold) in individuals with dysplasia compared to multifocal atrophic gastritis without intestinal metaplasia; the increase was also observed in individuals with advanced gastritis and positive H. pylori infection. In our animal model, H. pylori infection of Dmbt1-/- mice resulted in significantly higher levels of gastritis, more extensive mucous metaplasia and reduced Il33 expression levels in the gastric mucosa compared to H. pylori -infected wild type mice. Our data in the animal model suggest that in response to H. pylori infection DMBT1 may mediate mucosal protection reducing the risk of developing gastric precancerous lesions. However, the increased expression in human gastric precancerous lesions points to a more complex role of DMBT1 in gastric carcinogenesis.

Breast cancer is the most frequent malignancy in women worldwide. Distinct intrinsic subtypes of breast cancer have different prognoses, and their relative prevalence varies significantly among ethnic groups. Little is known about the prevalence of breast cancer intrinsic subtypes and their association with clinicopathological data and genetic ancestry in Latin Americans. Immunohistochemistry surrogates from the 2013 St. Gallen International Expert Consensus were used to classify breast cancers in 301 patients from Colombia into intrinsic subtypes. We analyzed the distribution of subtypes by clinicopathological variables. Genetic ancestry was estimated from a panel of 80 ancestry informative markers. Luminal B breast cancer subtype was the most prevalent in our population (37.2%) followed by luminal A (26.3%), non-basal triple negative (NBTN) (11.6%), basal like (9%), human epidermal growth factor receptor 2 (HER2) enriched (8.6%) and unknown (7.3%). We found statistical significant differences in distribution between Colombian region (P = 0.007), age at diagnosis (P = 0.0139), grade (P < 0.001) and recurrence (P < 0.001) according to intrinsic subtype. Patients diagnosed with HER2-enriched, basal-like and NBTN breast cancer had the highest African ancestry. Future studies analyzing the molecular profiles of breast cancer in Colombian women will help us understand the molecular basis of this subtype distribution and compare the molecular characteristics of the different intrinsic subtypes in Colombian patients.

Background: Studies in Latinas have reported a high prevalence of ER/PR/HER2-negative (TNBC) and HER2-enriched breast tumors. In our ongoing study of breast cancer molecular characteristics of Colombian women (N=301), more than 20% of the tumors were classified as TNBC. Molecular analyses of this aggressive subtype of breast cancer in women of European ancestry have revealed additional molecular heterogeneity, which is associated with treatment response and survival. The goal of the present study was to explore the molecular profile of TNBC in a sample of Latin American women from Colombia and assess if genetic ancestry modified the gene expression profile. Methods: We performed whole-transcriptome RNA-seq analysis in 48 TNBC tumors that were classified into intrinsic subtypes by immunohistochemistry (IHC) following St. Gallen 2015 surrogates. Genetic ancestry was estimated from a panel of 80 ancestry-informative markers (AIM). We categorized patients with TNBC according to the median of Indigenous ancestry (low Indigenous ancestry group: ancestry proportion below the median; high Indigenous ancestry: ancestry proportion above the median). We used top differentially expressed genes from Lehmann et al. (2011) (n=128) to explore the distribution of TNBC subtypes in our samples and to explore differences in the expression of these genes according to genetic ancestry. Results: Unsupervised hierarchical clustering analysis did not show any clear clustering of the Colombian samples into defined subtypes based on expression of the 128 top differentially expressed genes reported by Lehmann et al. Subsequently, we selected genes that clustered together according to the definitions of TNBC subtypes of Lehmann, leaving a total of 35 genes for the analysis. Unsupervised hierarchical clustering using this list of genes identified two clusters, one predominantly observed for woman of high Indigenous American ancestry (average Indigenous American ancestry for this group was 45%) and another more common in women of low Indigenous ancestry (average Indigenous American ancestry for this group was 36%, p=0.04). The cluster that included most of the women with high Indigenous ancestry proportions was characterized by lower gene expression for the 35 genes compared to the cluster that included women with low Indigenous ancestry proportions. Conclusions: Our results suggest differential expression of genes within TNBC breast cancer subtype according to genetic ancestry; nevertheless, we could not identify clear TNBC subtypes previously defined by Lehmann et al. in our study. Further analyses are needed to identify TNBC subtypes in Hispanic/Latina samples. Citation Format: Silvia J. Serrano-Gomez, Maria Carolina Sanabria-Salas, Jone Garai, Melody C. Baddoo, Gustavo Hernandez-Suarez, Juan Carlos Mejia, Oscar Garcia, Lucio Miele, Laura Fejerman, Jovanny Zabaleta. Identification of triple-negative breast cancer subtypes in Colombian patients [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A38.

The epithelial to mesenchymal transition (EMT) is a biological process in which a non-motile epithelial cell changes to a mesenchymal phenotype with invasive capacities. This phenomenon has been well documented in multiple biological processes including embryogenesis, fibrosis, tumor progression and metastasis. The hallmark of EMT is the loss of epithelial surface markers, most notably E-cadherin, and the acquisition of mesenchymal markers including vimentin and N-cadherin. The downregulation of E-cadherin during EMT can be mediated by its transcriptional repression through the binding of EMT transcription factors (EMT-TFs) such as SNAIL, SLUG and TWIST to E-boxes present in the E-cadherin promoter. Additionally, EMT-TFs can also cooperate with several enzymes to repress the expression of E-cadherin and regulate EMT at the epigenetic and post- translational level. In this review, we will focus on epigenetic and post- translational modifications that are important in EMT. In addition, we will provide an overview of the various therapeutic approaches currently being investigated to undermine EMT and hence, the metastatic progression of cancer as well.

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 < 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.

Background. Acute lymphoblastic leukemia (ALL) in Hispanic populations represents a public health problem that requires priority attention because its incidence and mortality increase annually. Intensive chemotherapeutic schemes in the last decade in the United States and other countries and have led to higher rates of durable remissions. However, these schemes have shown disappointing results in Hispanic populations. In Colombia, for example, the median overall survival (OS) is less than 11.3 months, the event-free survival (EFS) is 7.34 months, and only 61% of patients achieve complete remission (CR). Therefore, it is interesting to explore the underlying molecular characteristics of the disease in Hispanic patients. Previously we identified a gene expression signature associated with response to induction treatment and outcome of adult Hispanic patients with B-ALL. These ID1, ID3 and IGJ seem to be involved in many tumorigenic processes. The goal of our study is identify the role of these genes in B-ALL and its relevance in the prognosis and progression of disease in an in vitro model. Methods. CRISPR-Cas9 Gene Engineering and expression-ready ORF cDNA clones were used to either down-regulate or over-express, respectively, the expression of ID1, ID3 and IGJ genes in the adult B-ALL cell line NALM6. We used TaqMan to quantify the levels of mRNA expression of ID1/ID3/IGJ genes after over-expression. Protein expression by Flow Cytometry was used to verify silencing and over-expression of our 3-genes signature. Cell viability and proliferation were determined by anexin V-PI and MTT assay, respectively at 0, 24, 48, 72 and 96 hours after modulation. Cell cycle analysis was performed using BrdU and 7-AAD. Separately, increasing doses of cyclophosphamide, doxorubicin and cytarabine were used to determine the role of ID1, ID3, and IGJ genes in chemo resistance at 24, 48, 72, 96, and 144 hours. Total RNA from leukemic cells was isolated using Trizol method. We used microarray analysis to identify genes differentially expressed after silencing/overexpression. We performed Immunophenotype analysis of 43 B-ALL adult Hispanic patient Bone Marrow samples using the panel of antibodies recommended and standardized by the European consortium Euroflow. Correlation analysis were used to establish the association between our 3-Gene expression signature and the expression of surface markers currently used for diagnostic and follow-up of B-ALL patients. Results. We observed that both overexpression and silencing of ID1, ID3 and IGJ modulated B-ALL cells cell cycle. ID1/ID3/IGJ overexpression resulted in a loss of S phase and arrest of the cells in the G0/G1 phase of the cell cycle. On the contrary, ID1/ID3/IGJ silencing induced a loss of G0/G1 phase and gain in the number of cells in G2/M and S phases. Gain-of-expression and loss-of-expression analyses using incremental doses of chemotherapy agents currently used in the B-ALL treatment, demonstrate that ID1/ID3/IGJ signature promotes drug resistance of the NALM6 B-ALL cell line. Clinically, patients with higher ID1/ID3/IGJ expression have high expression of CD20 and CD10 markers (aberrantly expressed in immature cells) and shorter OS and EFS. In addition, more than 2,000 genes that are differentially expressed in the cells with modulation of the expression of ID1/ID3/IGJ suggesting a complex network of biological processes implicated in the drug resistance and poor prognosis present in the patients with this 3-gene signature. Conclusions. Our data identify the ID1/ID3/IGJ signature as possible modulator of molecular events during B-ALL differentiation, proliferation and drug resistance. These results highlight the potential role of this gene signature both as a risk stratification tool and as a candidate therapeutic target in Hispanic population. Citation Format: Nataly Cruz-Rodriguez, Alba Lucia Combita, Jone Garai, Leonardo Jose Enciso, Sandra Milena Quijano, Silvia Serrano-Gomez, Li Li, Jovanny Zabaleta. Biological and clinical significance of ID1/ID3/IGJ expression signature modulation in B-Acute lymphoblastic leukemia. [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 B36.