RESUMO

Breast cancer (BC) is one of the most frequent cancer types in women worldwide. About 7% is diagnosed in young women (YBC) less than 40 years old. In Mexico, however, YBC reaches 15% suggesting a higher genetic susceptibility. There have been some reports of germline variants in YBC across the world. However, there is only one report from a Mexican population, which is not restricted by age and limited to a panel of 143 genes resulting in 15% of patients carrying putatively pathogenic variants. Nevertheless, expanding the analysis to whole exome involves using more complex tools to determine which genes and variants could be pathogenic. We used germline whole exome sequencing combined with the PeCanPie tool to analyze exome variants in 115 YBC patients. Our results showed that we were able to identify 49 high likely pathogenic variants involving 40 genes on 34% of patients. We noted many genes already reported in BC and YBC worldwide, such as BRCA1, BRCA2, ATM, CHEK2, PALB2, and POLQ, but also others not commonly reported in YBC in Latin America, such as CLTCL1, DDX3X, ERCC6, FANCE, and NFKBIE. We show further supporting and controversial evidence for some of these genes. We conclude that exome sequencing combined with robust annotation tools and further analysis, can identify more genes and more patients affected by germline mutations in cancer.

RESUMO

Genomic characterization of patients with myeloproliferative neoplasms (MPN) may lead to better diagnostic classification, prognostic assessment, and treatment decisions. These goals are particularly important in myelofibrosis (MF). We performed target Next Generation Sequencing for a panel of 255 genes and Chromosome Microarray Analysis (CMA) in 27 patients with MF. Patients were classified according to genomic findings and we compared the performance of a personalized prognostication system with IPSS, MIPSS70 and MIPSS70 + v2. Twenty-six patients presented mutations: 11.1% had single driver mutations in either JAK2, CALR or MPL; 85.2% had mutations in non-restricted genes (median: 2 per patient). CMA was abnormal in 91.7% of the 24 cases with available data. Copy-Number-Neutral Loss-of-Heterozygosity was the most common finding (66.7%). Del13q was the most frequent copy number variation, and we could define a 2.4 Mb minimally affected region encompassing RB1, SUCLA2 and CLLS2 loci. The largest genomic subgroup consisted of patients with mutations in genes involved with chromatin organization and splicing control (40.7%) and the personalized system showed better concordance and accuracy than the other prognostic systems. Comprehensive genomic characterization reveals the striking genetic complexity of MF and, when combined with clinical data, led, in our cohort, to better prognostication performance.

Assuntos

Variações do Número de Cópias de DNA , Genômica , Transtornos Mieloproliferativos/genética , Mielofibrose Primária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Proteínas de Ligação ao Cálcio/genética , Calreticulina/genética , Moléculas de Adesão Celular/genética , Estudos de Coortes , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Janus Quinase 2/genética , Perda de Heterozigosidade/genética , Masculino , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Mutação , Transtornos Mieloproliferativos/classificação , Mielofibrose Primária/classificação , Prognóstico

RESUMO

BACKGROUND: Although rare in the United States, gallbladder cancer (GBCA) is a common cause of cancer death in some parts of the world. To investigate regional differences in pathogenesis and outcomes for GBCA, tumor mutations were analyzed from a sampling of specimens. METHODS: Primary tumors from patients with GBCA who were treated in Chile, Japan, and the United States between 1999 and 2016 underwent targeted sequencing of known cancer-associated genes. Fisher exact and Kruskal-Wallis tests assessed differences in clinicopathologic and genetic factors. Kaplan-Meier methods evaluated differences in overall survival from the time of surgery between mutations. RESULTS: A total of 81 patients were included. Japanese patients (11 patients) were older (median age, 72 years [range, 54-81 years]) compared with patients from Chile (21 patients; median age, 59 years [range, 32-73 years]) and the United States (49 patients; median age, 66 years [range, 46-87 years]) (P = .002) and had more well-differentiated tumors (46% vs 0% for Chile/United States; P < .001) and fewer gallstone-associated cancers (36% vs 67% for Chile and 69% for the United States; P = .13). Japanese patients had a median mutation burden of 6 (range, 1-23) compared with Chile (median mutation burden, 7 [range, 3-20]) and the United States (median mutation burden, 4 [range, 0-27]) (P = .006). Tumors from Japanese patients lacked AT-rich interaction domain 1A (ARID1A) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, whereas Chilean tumors lacked Erb-B2 receptor tyrosine kinase 3 (ERBB3) and AT-rich interaction domain 2 (ARID2) mutations. SMAD family member 4 (SMAD4) was found to be mutated similarly across centers (38% in Chile, 36% in Japan, and 27% in the United States; P = .68) and was univariately associated with worse overall survival (median, 10 months vs 25 months; P = .039). At least one potentially actionable gene was found to be altered in 80% of tumors. CONCLUSIONS: Differences in clinicopathologic variables suggest the possibility of distinct GBCA pathogenesis in Japanese patients, which may be supported by differences in mutation pattern. Among all centers, SMAD4 mutations were detected in approximately one-third of patients and may represent a converging factor associated with worse survival. The majority of patients carried mutations in actionable gene targets, which may inform the design of future trials.

Assuntos

Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Carcinoma Adenoescamoso/patologia , Neoplasias da Vesícula Biliar/patologia , Mutação , Adenocarcinoma/genética , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoescamoso/genética , Carcinoma Adenoescamoso/cirurgia , Chile , Demografia , Feminino , Seguimentos , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Estados Unidos

RESUMO

More than 200 cancer susceptibility syndromes (CSS) have been recognized through performing classic epidemiologic studies and genetic linkage analysis. In most CSSs clinical conditions of the patients have been identified as well as their hereditary patterns and the predisponent genes to cancer development. Cancer hereditary identification is a useful condition, since cancer family integrants may benefit of efficient strategies in early screening and in tumor prevention strategies; this consultation is performed by oncogenetic molecular medical consultants who must be scientifically competent for Human Genetics and Cancer molecular biology domains. The oncogenetic molecular consult of patients and family relatives of cancer predisposition families is a medical service in health programs of developed and developing countries; in our country this type of medical service needs to be organized and settled to be part of the integral oncology medical service. The oncogenetic molecular consultation is a structural process of assessment and communication of the associated integral problems of the cancer inherited susceptibility in familial cancer.

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Se han descrito más de 200 síndromes de susceptibilidad hereditaria humana para desarrollar cáncer (SSHDC), los cuales han sido identificados a partir de estudios clásicos epidemiológicos y de análisis de ligamiento genético. En la mayoría de los SSHDC se han identificado las condiciones clínicas de los pacientes, sus patrones de herencia y los genes que predisponen al desarrollo del cáncer. La identificación de cánceres hereditarios es de gran utilidad, ya que los familiares de los pacientes podrán beneficiarse de medidas eficaces no solo en la detección precoz, sino también en la prevención de los tumores; esta identificación se realiza por medio de la consulta de especialistas en oncogenética molecular, quienes deben ser competentes en las áreas de genética humana y biología molecular del cáncer. La consulta oncogenética molecular de los pacientes y de los integrantes de familias con predisposición al cáncer es un servicio de atención médica en países desarrollados y en algunos en vías de desarrollo que se realiza desde hace más de una década; en nuestro país, este tipo de consulta requiere organizarse y establecerse para formar parte de la atención médica integral oncológica. La consulta oncogenética es un proceso estructurado de evaluación y comunicación de los problemas integrales asociados con la susceptibilidad hereditaria de padecer cáncer.

Assuntos

Aconselhamento Genético/métodos , Predisposição Genética para Doença , Síndromes Neoplásicas Hereditárias/genética , Adulto , Biomarcadores Tumorais/genética , Feminino , Marcadores Genéticos , Testes Genéticos , Humanos , Masculino , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/terapia

RESUMO

Approximately 10% of all cancers are considered hereditary and are primarily caused by germline, high penetrance mutations in cancer predisposition genes. Although most cancer predisposition genes are considered molecularly heterogeneous, displaying hundreds of different disease-causing sequence alterations, founder mutations have been identified in certain populations. In some Latin American countries, founder mutations associated with increased risk of breast and other cancers have been described. This is particularly interesting considering that in most of these countries, populations are highly admixed with genetic contributions from native populations and from the in-flux of several distinct populations of immigrants. In this article, we present a review of the scientific literature on the subject and describe current data available on founder mutations described in the most common breast cancer predisposition genes: BRCA1, BRCA2 and TP53.