RESUMEN
Increased genetic risk for melanoma can occur in the context of germline pathogenic variants in high-penetrance genes, such as CDKN2A and CDK4, risk variants in low- to moderate-penetrance genes (MC1R and MITF), and possibly due to variants in emerging genes, such as ACD, TERF2IP, and TERT. We aimed to identify germline variants in high- and low- to moderate-penetrance melanoma risk genes in Brazilian patients with clinical criteria for familial melanoma syndrome. We selected patients with three or more melanomas or melanoma patients from families with three tumors (melanoma and pancreatic cancer) in first- or second-degree relatives. Genetic testing was performed with a nine-gene panel (ACD, BAP1, CDK4, CDKN2A, POT1, TERT, TERF2IP, MC1R, and MITF). In 36 patients, we identified 2 (5.6%) with germline pathogenic variants in CDKN2A and BAP1 and 4 (11.1%) with variants of uncertain significance in the high-penetrance genes. MC1R variants were found in 86.5%, and both red hair color variants and unknown risk variants were enriched in patients compared to a control group. The low frequency of germline pathogenic variants in the high-penetrance genes and the high prevalence of MC1R variants found in our cohort show the importance of the MC1R genotype in determining the risk of melanoma in the Brazilian melanoma-prone families.
Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Brasil/epidemiología , Predisposición Genética a la Enfermedad , Melanoma/epidemiología , Melanoma/genética , Melanoma/patología , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Pruebas Genéticas , Mutación de Línea Germinal , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Receptor de Melanocortina Tipo 1/genéticaRESUMEN
Genetic predisposition accounts for nearly 10% of all melanoma cases and has been associated with a dozen moderate- to high-penetrance genes, including CDKN2A, CDK4, POT1 and BAP1. However, in most melanoma-prone families, the genetic etiology of cancer predisposition remains undetermined. The goal of this study was to identify rare genomic variants associated with cutaneous melanoma susceptibility in melanoma-prone families. Whole-exome sequencing was performed in 2 affected individuals of 5 melanoma-prone families negative for mutations in CDKN2A and CDK4, the major cutaneous melanoma risk genes. A total of 288 rare coding variants shared by the affected relatives of each family were identified, including 7 loss-of-function variants. By performing in silico analyses of gene function, biological pathways, and variant pathogenicity prediction, we underscored the putative role of several genes for melanoma risk, including previously described genes such as MYO7A and WRN, as well as new putative candidates, such as SERPINB4, HRNR, and NOP10. In conclusion, our data revealed rare germline variants in melanoma-prone families contributing with a novel set of potential candidate genes to be further investigated in future studies.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Melanoma/genética , Mutación/genética , Neoplasias Cutáneas/genética , Adolescente , Adulto , Anciano , Brasil , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Linaje , Penetrancia , Secuenciación del Exoma/métodos , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: BRCA1 associated-protein 1 (BAP1) tumor predisposition syndrome is associated with an increased risk for malignant mesotheliomas, uveal and cutaneous melanomas, renal cell carcinomas, and singular cutaneous lesions. The latter are referred to as BAP1-inactivated melanocytic tumors (BIMTs). When multiple BIMTs manifest, they are considered potential markers of germline BAP1 mutations. CASE PRESENTATION: Here, we report a novel pathogenic BAP1 germline variant in a family with a history of BIMTs, cutaneous melanomas, and mesotheliomas. We also describe singular pathological aspects of the patient's BIMT lesions and their correlation with dermoscopic and reflectance confocal microscopy findings. CONCLUSIONS: This knowledge is crucial for the recognition of BIMTs by dermatologists and pathologists, allowing the determination of appropriate management for high-risk patients, such as genetic investigations and screening for potentially aggressive tumors.
Asunto(s)
Melanoma/genética , Melanoma/patología , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genética , Adulto , Anciano , Anciano de 80 o más Años , Dermoscopía/métodos , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Masculino , Microscopía Confocal/métodos , Persona de Mediana Edad , Linaje , Pronóstico , Melanoma Cutáneo MalignoRESUMEN
AIM: This work evaluates a possible causative role for germline copy number variants (CNVs) in melanoma predisposition. PATIENTS & METHODS: A total of 41 melanoma-prone Brazilian patients were investigated for CNVs using 850K single nucleotide polymorphism arrays. RESULTS: Ten rare CNVs were identified in nine patients, comprising 54 known genes, mostly related to cancer. In silico analyses revealed gene enrichment for cellular development and growth, and proliferation, highlighting five genes directly associated with the melanoma phenotype (ANGPT1, IDH1, PDE5A, HIST1H1B and GCNT2). CONCLUSION: Patients harboring rare CNVs exhibited a decreased age of disease onset, in addition to an overall higher skin cancer predisposition. Our findings suggest that rare CNVs contribute to melanoma susceptibility, and should be taken into account when investigating cancer risk factors.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Adulto , Femenino , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios RetrospectivosRESUMEN
Lymphovascular invasion (LVI) and histologic grade are clinical parameters of high prognostic value in breast cancer and indicate the level of tumor aggressiveness. Many studies have focused on the association of breast cancer subtypes with gene expression and chromosomal profiles, but considerably less genomic information is available regarding traditional prognostic factors such as histologic grade and LVI. We studied by array-CGH a group of 57 invasive ductal carcinomas of the breast to outline the DNA copy number aberration (CNA) profile linked to high histologic grades and LVI. Selected CNAs were validated using real-time quantitative PCR (qPCR). Furthermore, gene expression analysis was performed in a subset of 32 of these tumors, and findings were integrated with array-CGH data. Our findings indicated an accumulation of genomic alterations in high-grade breast tumors compared to low-grade samples. Grade III tumors showed higher number of CNAs and larger aberrations than low-grade tumors and displayed a wide range of chromosomal aberrations, which were mainly 5p, 8q, 10p, 17q12, and 19 gains, and 3p, 4, 5q proximal, 9p, 11p, 18q, and 21 losses. The presence of LVI, a well-established prognostic marker, was not significantly associated with increased genomic instability in comparison to breast tumors negative for LVI, considering the total number of chromosomal alterations. However, a slightly increase in the frequency of specific alterations could be detected in LVI-positive group, such as gains at 5p, 16p, 17q12, and 19, and losses at 8p, 11q, 18q, and 21. Three newly reported small-scale rearrangements were detected in high-risk tumors (LVI-positive grade III) harboring putative breast cancer genes (amplicons at 4q13.3 and 11p11.2, and a deletion at 12p12.3). Furthermore, gene expression analysis uncovered networks highlighting S100A8, MMP1, and MED1 as promising candidate genes involved in high-grade and LVI-positive tumors. In summary, a group of genomic regions could be associated with high-risk tumors, and expression analysis pinpointed candidate genes deserving further investigation. The data has shed some light on the molecular players involved in two highly relevant prognostic factors and may further add to the understanding of the mechanisms of breast cancer aggressiveness.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma/genética , Carcinoma/patología , Aberraciones Cromosómicas , Femenino , Genómica/métodos , Humanos , Metástasis Linfática , Invasividad Neoplásica , Estudios Retrospectivos , Eliminación de SecuenciaRESUMEN
AIM: Cytogenetic data of hepatoblastomas, a rare embryonal tumor of the liver, mostly consist of descriptions of whole-chromosome aneuploidies and large chromosome alterations. High-resolution cytogenetics may provide clues to hepatoblastoma tumorigenesis and indicate markers with clinical significance. PATIENTS & METHODS: We used array-CGH (180K) to screen for genomic imbalances in nine hepatoblastomas. Additionally, we investigated the expression pattern of selected genes exhibiting copy number changes. RESULTS: Analysis showed mainly whole-chromosome or chromosome-arm aneuploidies, but some focal aberrations were also mapped. Expression analysis of 48 genes mapped at one 10 Mb amplification at 2q24 revealed upregulation of DAPL1, ERMN, GALNT5, SCN1A and SCN3A in the set of tumors compared with differentiated livers. CONCLUSION: These genes appear as candidates for hepatoblastoma tumorigenesis.
Asunto(s)
Cromosomas Humanos Par 2/genética , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Aneuploidia , Aberraciones Cromosómicas , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Estudios de Asociación Genética , Humanos , Oncogenes , Estudios Retrospectivos , Regulación hacia ArribaRESUMEN
Copy number variations (CNVs) have been previously associated with several different neurodevelopmental psychiatric disorders, such as autism, schizophrenia, and attention deficit hyperactivity disorder (ADHD). The present study consisted of a pilot genome-wide screen for CNVs in a cohort of 16 patients with early-onset obsessive-compulsive disorder (OCD) and 12 mentally healthy individuals, using array-based comparative genomic hybridization (aCGH) on 44K arrays. A small rare paternal inherited microdeletion (â¼64 kb) was identified in chromosome 15q13.3 of one male patient with very early onset OCD. The father did not have OCD. The deletion encompassed part of the FMN1 gene, which is involved with the glutamatergic system. This finding supports the hypothesis of a complex network of several genes expressed in the brain contributing for the genetic risk of OCD, and also supports the glutamatergic involvement in OCD, which has been previously reported in the literature.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 15 , Trastorno Obsesivo Compulsivo/genética , Adolescente , Edad de Inicio , Estudios de Casos y Controles , Niño , Preescolar , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Proteínas Fetales/genética , Forminas , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Proteínas de Microfilamentos/genética , Proteínas Nucleares/genéticaRESUMEN
Melanoma and pancreatic cancer are two low frequency types of cancer. In this study, three patients who developed both melanoma and intraepithelial neoplasia of the pancreas were tested for CDKN2A mutations and deletions, and investigated for rare germline copy number variations (CNVs). The three patients were negative for CDKN2A point mutations and intragenic deletions. One of these patients carried two large (>300 kb) germline CNVs, both genomic duplications affecting coding sequences that are not copy number variable in the population. A second patient exhibited loss of the entire Y chromosome, an event probably coincidental related to his advanced age (79 years-old). Our data pinpoint that rare germline CNVs harboring genes can contribute to the cancer predisposition of melanoma and intraepithelial neoplasia of the pancreas.