In Latin America (LA), cancer is the second leading cause of death, and little is known about the capacities and needs for the development of research in the field of cancer genomics. In order to evaluate the current capacity for and development of cancer genomics in LA, we collected the available information on genomics, including the number of next-generation sequencing (NGS) platforms, the number of cancer research institutions and research groups, publications in the last 10 years, educational programs, and related national cancer control policies. Currently, there are 221 NGS platforms and 118 research groups in LA developing cancer genomics projects. A total of 272 articles in the field of cancer genetics/genomics were published by authors affiliated to Latin American institutions. Educational programs in genomics are scarce, almost exclusive of graduate programs, and only few are concerning cancer. Only 14 countries have national cancer control plans, but all of them consider secondary prevention strategies for early diagnosis, opportune treatment, and decreasing mortality, where genomic analyses could be implemented. Despite recent advances in introducing knowledge about cancer genomics and its application to LA, the region lacks development of integrated genomic research projects, improved use of NGS platforms, implementation of associated educational programs, and health policies that could have an impact on cancer care.
Triple-negative breast cancer (TNBC) presents a marked diversity at the molecular level, which promotes a clinical heterogeneity that further complicates treatment. We performed a detailed whole exome sequencing profile of 29 Mexican patients with long follow-up TNBC to identify genomic alterations associated with overall survival (OS), disease-free survival (DFS), and pathologic complete response (PCR), with the aim to define their role as molecular predictive factors of treatment response and prognosis. We detected 31 driver genes with pathogenic mutations in TP53 (53%), BRCA1/2 (27%), CDKN1B (9%), PIK3CA (9%), and PTEN (9%), and 16 operative mutational signatures. Moreover, tumors with mutations in BRCA1/2 showed a trend of sensitivity to platinum salts. We found an association between deficiency in DNA repair and surveillance genes and DFS. Across all analyzed tumors we consistently found a heterogeneous molecular complexity in terms of allelic composition and operative mutational processes, which hampered the definition of molecular traits with clinical utility. This work contributes to the elucidation of the global molecular alterations of TNBC by providing accurate genomic data that may help forthcoming studies to improve treatment and survival. This is the first study that integrates genomic alterations with a long follow-up of clinical variables in a Latin American population that is an underrepresented ethnicity in most of the genomic studies.
In triple-negative breast cancer (TNBC), only 30% of patients treated with neoadjuvant chemotherapy achieve a pathological complete response after treatment and more than 90% die due to metastasis formation. The diverse clinical responses and metastatic developments are attributed to extensive intrapatient genetic heterogeneity and tumor evolution acting on this neoplasm. In this work, we aimed to evaluate genomic alterations and tumor evolution in TNBC patients with aggressive disease. We sequenced the whole exome of 16 lesions from four patients who did not respond to therapy, and took several follow-up samples, including samples from tumors before and after treatment, as well as from the lymph nodes and skin metastases. We found substantial intrapatient genetic heterogeneity, with a variable tumor mutational composition. Early truncal events were MCL1 amplifications. Metastatic lesions had deletions in RB1 and PTEN, along with TERT, AKT2, and CCNE1 amplifications. Mutational signatures 06 and 12 were mainly detected in skin metastases and lymph nodes. According to phylogenetic analysis, the lymph node metastases occurred at an early stage of TNBC development. Finally, each patient had three to eight candidate driving mutations for targeted treatments. This study delves into the genomic complexity and the phylogenetic and evolutionary development of aggressive TNBC, supporting early metastatic development, and identifies specific genetic alterations associated with a response to targeted therapies.
Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant disease that represents approximately 5-10% of all patients with breast cancer. This syndrome is mainly associated to high risk pathogenic alleles in BRCA1/2 genes, but only for 25% of HBOC cases. More than 25 genes have been associated with familial breast and/or ovarian cancer and still more are expected to emerge. In the Mexican population there have been some efforts to analyze this syndrome, but they are limited to BRCA genes. This work aims to find new pathogenic alleles in exonic and splice sites in a panel of 143 cancer-predisposing genes in 309 Mexican cancer patients with suspicion of HBOC and 27 non-cancer patients with a severe family history of cancer, using massive parallel sequencing technology. In the group of cancer patients 14.6% (45/309) had pathogenic variants, 23.9% (74/309) harbored variants with unknown clinical significance (VUS) and 61.5% (109/309) were negative. The genes most frequently affected with pathogenic variants were BRCA2 24.4% (11/45), BRCA1 8.9% (4/45), MSR1 4.4% (2/45), ATM 4.4% (2/45), PDE11A 4.4% (2/45) and FANCI 4.4% (2/45). The non-cancer group had a 18.5% (5/27) of patients with pathogenic variants and 81.5% (22/27) were negative. In this group pathogenic variants were found in BRCA2, FANCF, PDE11A, POLH and WRN. Private or ultra-rare variants defined as VUS (ClinVar, deleterious in SIFT/Polyphen2, less than 0.001% in ExAC/1KG/ESP6500) were found in 53 genes. This study demonstrates that there is a higher contribution of pathogenic alleles in other susceptibility cancer genes (66.7%) than BRCA1/2 (33.3%), confirming that clinical sequencing of expanded gene panels will identify new, rare and private, variants and eventually will translate in better molecular diagnosis and personalized risk assessment in carriers. Clinical impact of the VUS identified here must be further evaluated. This work was supported by the National Autonomous University of Mexico, PAPIIT (IA204215). Citation Format: Felipe Vaca-Paniagua, Rosalía Quezada-Urban, Clara Díaz-Velásquez, Rina Gitler, Gabriela Torres-Mejia, Maria Patricia Rojo-Castillo, Max Sirota-Toporek, Andrea Figueroa-Morales, Oscar Moreno-García, Ivan Delgado-Enciso, Victor Hugo Garzón-Barrientos, Nayeli Lizbeth García-Esquivel, Ernesto Arturo Rojas-Jiménez, Héctor Gregorio-Martínez, Luis Ignacio Terrazas. Pathogenic germline variants in Mexican patients with hereditary breast and ovarian cancer syndrome [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 4275. doi:10.1158/1538-7445.AM2017-4275
Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant disease that represents approximately 5-10% of all patients with breast cancer. This syndrome is mainly associated to high-risk pathogenic alleles in BRCA1 and BRCA2 genes, but only for 25% of HBOC cases. This work aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 31 non-cancer patients with a severe family history of cancer, using massive parallel sequencing. We found 15% (45/300) patients with pathogenic variants in the group of cancer patients; 12% (35/300) harbored variants with unknown clinical significance (VUS) and 73% (220/300) were negative. The non-cancer group had a 32% (10/31) of patients with pathogenic variants, 3% (1/31) had VUS and 65% (20/31) were negative. Moreover, the most recurrent mutation was the Mexican founder deletion of exons 9-12 in BRCA1, found in 5 of 16 cancer patients with alterations in this gene. Private or rare VUS variants with potential impact at protein level were found in 22 genes, being CHEK2 the one with most VUS (6/39). Noteworthy, our results show for the first time in the Mexican population an equal contribution of pathogenic alleles in other susceptibility cancer genes (50%) as in BRCA1/2 (50%). This highlights the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to broader gene panels. Further studies need to be conducted to define the clinical impact of the pathogenic alleles and VUS identified. Citation Format: Felipe Vaca-Paniagua, Rosalía Quezada-Urban, Clara E. Díaz-Velásquez, Rina Gitler, María P. Rojo-Castillo, Max Sirota-Toporek, Andrea Figueroa-Morales, Oscar Moreno-García, Lizbeth García Esquivel, Gabriela Torres-Mejía, Michael Dean, Ivan Delgado-Enciso, Héctor Ochoa-Díaz-López, Fernando Rodriguez-León, Virginia Jan, Victor H. Hugo Garzón-Barrientos, Pablo Ruiz-Flores, Perla K. Espino-Silva, Jorge Haro-Santa Cruz, Héctor Martínez-Gregorio, Ernesto Rojas-Jiménez, Rosa M. Álvarez-Gómez, Luis A. Herrera, Isabelle Romieu, Luis I. Terrazas, Yolanda I. Chirino, Cecilia Frecha, Javier Oliver, Sandra Perdomo. Comprehensive analysis of germline variants in Mexican patients with hereditary breast and ovarian cancer susceptibility [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 1240.
Breast cancer is the neoplastic disease with the highest incidence and mortality worldwide and nearly 10% of the cases are due to inherited pathogenic alleles in cancer predisposing genes such as BRCA1 and BRCA2. However, the spectrum of inherited breast cancer susceptibility not caused by BRCA1/2 pathogenic alleles has not been explored in the Mexican population. In this work we evaluated the presence of germline pathogenic alleles in the coding sequence and splice sites of 143 cancer susceptibility genes in 69 Mexican female patients with cancer that were selected for family cancer history. Inclusion criteria followed the guidelines of the National Comprehensive Cancer Network for Genetic/Familial High-Risk Assessment of Breast and Ovarian Cancer. Data from international databases of normal populations and cancer patients, as well as annotation information and technical parameters were used to define pathogenic variants. The genes with the highest frequency of pathogenic alleles (stopgain/loss, frameshift indels) were BRCA1 (8.7%, 6/69), BRCA2 (2.9%, 2/69), FANCC (2.9%), MSR1 (2.9%), FANCL (1.4%, 1/69), SDHB (1.4%) and TSC2 (1.4%). New or rare missense variants with unknown clinical significance (VUS), but defined as pathogenic in ClinVar or by algorithms assessing evolutionary conservation and deleterious structural changes at protein level, were found in single patients in the genes AIP, ANTXR1, APC, ATR, CD96, CYP21A2, ERCC3, ERCC6, FANCA, FANCB, FANCE, LIG4, LYST, MSH6, MSR1, MTAP, PDE11A, PDGFRA, PMS2, POLE, PTCH1, RAD50, RHBDF2, RUNX1 and WRN. These patients did not have pathogenic alleles, suggesting a potential contribution of these VUS to disease susceptibility. This work contributes to identify new susceptibility alleles that can predispose to hereditary breast cancer in the Mexican population. Further studies need to be conducted to define the clinical impact of the VUS identified here, which together with international efforts will better define genetic susceptibility to breast cancer. This work was supported by the National Autonomous University of Mexico, PAPIIT (IA204215). Citation Format: Felipe Vaca-Paniagua, Rosalía Quezada-Urban, Clara Estela Díaz-Velásquez, Rina Gitler, María Patricia Rojo-Castillo, Max Sirota-Toporek, Andrea Figueroa-Morales, Oscar Moreno-García, Fernando Mainero-Ratchelous, Lizzette Sabrina De Hoyos-Arévalo, Ivan Delgado-Enciso, Victor Hugo Garzón-Barrientos, Luis Ignacio Terrazas. Identification of germline pathogenic alleles in 143 cancer predisposing genes in Mexican patients with hereditary breast cancer by massive parallel sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2545.
In Latin American (LA) countries cancer is the second most frequent cause of death after cardiovascular disease. Disease patterns have changed from infectious to chronic, the population is increasing and becoming elderly, and countries lack planning to respond adequately to this epidemiological and socio-demographic transition. By 2025 and increment of nearly 30% of new cases and 35% of deaths from cancer are predicted. Genomic studies have profoundly changed cancer management from improved cancer diagnosis to reformulating cancer prognosis and treatment. However, all these key advances have been mainly concentrated in highly developed nations and little is known about the capacities and needs of cancer genomics in the LA context. In order to evaluate the capacity and development of cancer genomics in LA, we collected available information for all countries in Central, South America and Cuba. Data reviewed included: number of NGS platforms, number of cancer research institutions, research groups working in cancer genetics, publications on cancer genetics and genomics in the last 10 years, educational programs on genomics and related national cancer control policies. Currently, there are a total of 212 NGS platforms in LA. Mexico and Brazil are the countries with more users, and Peru and Ecuador have the fewest. 118 research groups in South America have been working in cancer genetics and started developing cancer genomics related projects. No data on research groups was available for countries in Central America. In the last 10 years, 231 articles in cancer genetic/genomic related topics were published by authors affiliated to LA institutions. Educational programs in genomics are scarce, almost exclusive of graduate programs and few applied to cancer. Twelve countries in LA have national cancer control plans (NCCP). All NCCPs reviewed consider secondary prevention strategies for early diagnosis, opportune treatment and decrease of mortality, areas where genomic analysis could be implemented. Only 5 NCCPs include cancer research as an action plan to increase cancer prevention strategies and reduce both incidence and mortality. Despite the recent advances in introducing cancer genomics knowledge and application in LA, the region lacks development of integrated genomic research projects, improved use of platforms, associated educational programs and health policies that might focus on the most frequent cancers and could impact cancer care. Citation Format: Sandra Perdomo, Angela Torres, Javier Olivier, Cecilia Frecha, Rosalía Quezada-Urban, Clara Estela Díaz-Velasquez, Felipe Vaca. Is Latin America ready for the use of genomics in cancer care and control [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 3263. doi:10.1158/1538-7445.AM2017-3263
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