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PURPOSE: To define the spectrum of germline pathogenic variants (PVs) and copy number variant (CNV) in cancer susceptibility genes to the burden of breast and ovarian cancer (BC, OvC) in high-risk Brazilians in Minas Gerais with health insurance, southeast Brazil, undergoing multigene panel testing (MGPT). METHODS: Genotyping eligible individuals with health insurance in the Brazilian healthcare system for Hereditary Breast and Ovarian Cancer Syndrome to undergo molecular testing for 44 or 141-gene panels, a decision that was insurance driven. RESULTS: Overall, 701 individuals clinically defined as high BC/OvC risk, underwent MGPT from 1/2021 to 10/2022, with ~ 50% genotyped with a 44-gene panel and the rest with a 141-gene panel. Overall, 16.4% and 22.6% of genotyped individuals harbored PVs using 44-gene and the 141 gene panel, respectively. The most frequently mutated genes were: BRCA2 (3.7%); BRCA1 (3.6%) and monoallelic MUTYH (3.1%). CONCLUSION: The rate of PVs detected in high-risk individuals in this study was twice the 10% threshold used in Brazilian health guidelines. MGPT doubled the detection rate of PVs in cancer susceptibility genes in high-risk individuals compared with BRCA1/BRCA2 genotyping alone. The spectrum of PVs in Southern Brazil is diverse, with few recurring variants such as TP53 (0.6%), suggesting regional founder effects. The use of MGPT in hereditary cancer in Minas Gerais significantly increased the detection rate of P/LPVs compared to existing guidelines and should be considered as the primary genotyping modality in assessing hereditary cancer risk in Brazil.
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Predisposição Genética para Doença , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Feminino , Brasil/epidemiologia , Pessoa de Meia-Idade , Adulto , Testes Genéticos/métodos , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Variações do Número de Cópias de DNA , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Idoso , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Genótipo , Proteína BRCA1/genética , DNA GlicosilasesRESUMO
BACKGROUND: In Colombia and worldwide, breast cancer (BC) is the most frequently diagnosed neoplasia and the leading cause of death from cancer among women. Studies predominantly involve hereditary and familial cases, demonstrating a gap in the literature regarding the identification of germline mutations in unselected patients from Latin-America. Identification of pathogenic/likely pathogenic (P/LP) variants is important for shaping national genetic analysis policies, genetic counseling, and early detection strategies. The present study included 400 women with unselected breast cancer (BC), in whom we analyzed ten genes, using Whole Exome Sequencing (WES), know to confer risk for BC, with the aim of determining the genomic profile of previously unreported P/LP variants in the affected population. Additionally, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to identify Large Genomic Rearrangements (LGRs) in the BRCA1/2 genes. To ascertain the functional impact of a recurrent intronic variant (ATM c.5496 + 2_5496 + 5delTAAG), a minigene assay was conducted. RESULTS: We ascertained the frequency of P/LP germline variants in BRCA2 (2.5%), ATM (1.25%), BRCA1 (0.75%), PALB2 (0.50%), CHEK2 (0.50%), BARD1 (0.25%), and RAD51D (0.25%) genes in the population of study. P/LP variants account for 6% of the total population analyzed. No LGRs were detected in our study. We identified 1.75% of recurrent variants in BRCA2 and ATM genes. One of them corresponds to the ATM c.5496 + 2_5496 + 5delTAAG. Functional validation of this variant demonstrated a splicing alteration probably modifying the Pincer domain and subsequent protein structure. CONCLUSION: This study described for the first time the genomic profile of ten risk genes in Colombian women with unselected BC. Our findings underscore the significance of population-based research, advocating the consideration of molecular testing in all women with cancer.
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Proteína BRCA2 , Neoplasias da Mama , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Feminino , Mutação em Linhagem Germinativa/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/epidemiologia , Colômbia/epidemiologia , Pessoa de Meia-Idade , Adulto , Proteína BRCA2/genética , Proteína BRCA1/genética , Sequenciamento do Exoma , Idoso , Testes Genéticos/métodos , Proteínas Mutadas de Ataxia Telangiectasia/genéticaRESUMO
Hypertriglyceridemia (HTG) is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. It is well stablished that the severe cases of disease often present with an underlying genetic cause. In this study, we determined the frequency and variation spectrum of genes involved in the triglyceride metabolism in a series of Brazilian patients with severe HTG. A total of 212 patients with very high HTG, defined with fasting triglycerides (TG) ≥ 880 mg/ dL, that underwent a multi-gene panel testing were included in this research. Germline deleterious variants (i.e. Pathogenic/Likely Pathogenic (P/LP) variants) were identified in 28 out of 212 patients, reflecting an overall diagnostic yield of 13% in our cohort. Variants of unknown significance (VUS) were identified in 87 patients, and represent 80% of detected variants in this dataset. We confirm the LPL as the most frequently mutated gene in patients with severe HTG, and we had only one suspected case of familial chylomicronemia syndrome, caused by a homozygous variant in LMF1, in our cohort. Notably, we report 16 distinct and novel variants (P/LP and VUS), each of them representing a single case, not previously reported in any public databases or other studies. Our data expand our knowledge of genetic variation spectrum in patients with severe HTG in the Brazilian population, often underrepresented in public genomic databases, being also a valuable clinical resource for genetic counseling and healthcare programs in the country.
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PURPOSE: We evaluated the prevalence of homologous recombination deficiencies (HRD) to determine the efficacy of different techniques and clinical characteristics of patients. METHODS: This retrospective study included patients with metastatic prostate cancer who underwent molecular testing at our hospital between 2016 and 2022. We used tumor tissue, ctDNA, and lymphocytes for somatic or germline testing. We analyzed the clinical characteristics and survival outcomes. RESULTS: 144 patients were tested (113 somatic, 21 germline, and 10 both). Technical issues prevented the analysis of 23 prostatic samples (18.7%). 12 (8.3%) patients had HRD. BRCA2 was the most frequent mutation (66.7%). Patients with HRD were younger (57.5 years). Patients with BRCA mutations had poorer survival (31.9 vs 56.3 months, p = 0.048). CONCLUSION: In our institution, 8.3% of the patients had HRD. Tumor tissue analysis failed in 18.7% of tests. ctDNA analysis is an alternative detection method. BRCA mutations are correlated with poor prognosis.
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Proteína BRCA2 , Recombinação Homóloga , Neoplasias da Próstata , Humanos , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/mortalidade , Idoso , Proteína BRCA2/genética , Mutação , Prognóstico , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Idoso de 80 Anos ou mais , Mutação em Linhagem Germinativa , Proteína BRCA1/genética , AdultoRESUMO
TP53 gene disruption, including 17p13 deletion [del(17p)] and/or TP53 mutations, is a negative prognostic biomarker in chronic lymphocytic leukemia (CLL) associated with disease progression, treatment failure and shorter survival. Germline variants in p53 signaling pathway genes could also lead to p53 dysfunction, but their involvement in CLL has not been thoroughly evaluated. The aim of this study was to determine the association of TP53, MDM2 and NQO1 gene variability with clinical and genetic data of CLL patients. Individual genotype and haplotype data of CLL patients were compared with clinical prognostic factors, cytogenetic and molecular cytogenetic findings as well as IGHV and TP53 mutational status. The study included 116 CLL patients and 161 healthy blood donors. TP53 (rs1042522, rs59758982, rs1625895), NQO1 (rs1800566) and MDM2 (rs2279744, rs150550023) variants were genotyped using different PCR approaches. Analysis of genotype frequencies revealed no association with the risk of CLL. TP53 rs1042522, rs1625895 and MDM2 rs2279744 variants were significantly associated with abnormal karyotype and the presence of del(17p). Similarly, these two TP53 variants were associated with TP53 disruption. Moreover, TP53 C-A-nondel and G-A-del haplotypes (rs1042522-rs1625895-rs59758982) were associated with an increased likelihood of carrying del(17p) and TP53 disruptions. MDM2 T-nondel haplotype (rs2279744-rs150550023) was found to be a low risk factor for del(17p) (OR = 0.32; CI: 0.12-0.82; p = 0.02) and TP53 disruptions (OR = 0.41; CI: 0.18-0.95; p = 0.04). Our findings suggest that TP53 and MDM2 variants may modulate the risk to have chromosome alterations and TP53 disruptions, particularly del(17p). To our knowledge this is the first study of several germline variants in p53 pathway genes in Argentine patients with CLL.
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Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of TP53 with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes BAX and TP53I3 failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had lower CD8+ T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC was marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.
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BACKGROUND: Germline mutations in BRCA1 and BRCA2 genes are among the main causes of hereditary ovarian cancer. Identifying these mutations may reduce cancer risk, facilitate early detection, and enable personalized treatment. However, genetic testing is limited in the Brazilian Public Health System, and data regarding germline mutations in many regions are scarce. Therefore, the study aimed to investigate the prevalence of germline mutations in BRCA1 and BRCA2 in women with ovarian cancer treated in the Public Health System in Pernambuco, Brazil. METHODS: A cross-sectional study was conducted in the Hereditary Cancer Program from two reference oncological centers in Pernambuco. Women (n = 45) with high-grade serous ovarian cancer underwent genetic counseling and DNA sequencing for BRCA1 and BRCA2 genes. RESULTS: The prevalence of deleterious mutations in the BRCA1 and BRCA2 genes was 33%. Of the 15 germline mutations found, 13 were in BRCA1 and 2 in BRCA2; two mutations of unknown clinical significance were also found in BRCA2. Mutations c.5266dupC and c.2215 A > T were the most frequent; each was mutation observed in three patients. Additionally, the mutations c.7645dupT and c.921dupT were reported for the first time. CONCLUSION: One in three women showed a pathogenic mutation, demonstrating a significant prevalence of germline mutations in this sample. Additionally, the small sample revealed an interesting number of mutations, indicating the need to explore more regions of the country.
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Genes BRCA2 , Neoplasias Ovarianas , Humanos , Feminino , Brasil/epidemiologia , Mutação em Linhagem Germinativa , Estudos Transversais , Saúde Pública , Predisposição Genética para Doença , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Proteína BRCA2/genética , Proteína BRCA1/genéticaRESUMO
B-cell acute lymphoblastic leukemia (B-ALL) is one of the most common childhood cancers worldwide. Although most cases are sporadic, some familial forms, inherited as autosomal dominant traits with incomplete penetrance, have been described over the last few years. Germline pathogenic variants in transcription factors such as PAX5, IKZF1, and ETV6 have been identified as causal in familial forms. The proband was a 7-year-old Mexican girl diagnosed with high-risk B-ALL at five years and 11 months of age. Family history showed that the proband's mother had high-risk B-ALL at 16 months of age. She received chemotherapy and was discharged at nine years of age without any evidence of recurrence of leukemia. The proband's father was outside the family nucleus, but no history of leukemia or cancer was present up to the last contact with the mother. We performed exome sequencing on the proband and the proband's mother and identified the PAX5 variant NM_016734.3:c.963del: p.(Ala322LeufsTer11), located in the transactivation domain of the PAX5 protein. The variant was classified as probably pathogenic according to the ACMG criteria. To the best of our knowledge, this is the first Mexican family with an inherited increased risk of childhood B-ALL caused by a novel germline pathogenic variant of PAX5. Identifying individuals with a hereditary predisposition to cancer is essential for modern oncological practice. Individuals at high risk of leukemia would benefit from hematopoietic stem cell transplantation, but family members carrying the pathogenic variant should be excluded as hematopoietic stem cell donors.
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Purpose: The aim was to assess the diagnostic yield of next generation sequencing (NGS) multi-gene panels for breast and ovarian cancer in a high-complexity cancer centre in Chile. Additionally, our goal was to broaden the genotypic spectrum of BRCA variants already identified in Chilean families. Methods: Retrospective analysis was conducted on the genetic test results of 722 individuals from Fundación Arturo López Pérez's genetic counselling unit between 2016 and 2021. A comprehensive literature review encompassing articles analysing the frequency of germinal pathogenic variants in BRCA1/2 within the Chilean population was undertaken. Results: 23.5% of the panels had positive results, with 60% due to pathogenic variants in the BRCA1/2 genes. Seven previously unreported variants in BRCA1 from Chilean studies were identified.One or more variants of uncertain significance were detected in 31% of the results, and 11.5% of the families in this cohort presented copy number variants (CNVs) in BRCA1/2.8 studies analysed the frequency of pathogenic variants in BRCA1/2 in the Chilean population between 2006 and 2023, with a frequency between 7.1% and 17.1%.51 BRCA1 variants in 149 families have been reported in Chile and 38 BRCA2 variants in 132 families. Nine founder pathogenic variants identified by one study were present in 51.9% of the total Chilean families reported. Conclusion: Our findings advocate for the integration of NGS multi-gene panel testing as a primary strategy within our population. This approach allows for the comprehensive assessment of single nucleotide variants and CNVs in BRCA1/2, alongside other high and moderately penetrant genes associated with breast and ovarian cancer.
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Structural variants (SVs) pose a challenge to detect and interpret, but their study provides novel biological insights and molecular diagnosis underlying rare diseases. The aim of this study was to resolve a 9p24 rearrangement segregating in a family through five generations with a congenital heart defect (congenital pulmonary and aortic valvular stenosis and pulmonary artery stenosis), by applying a combined genomic analysis. The analysis involved multiple techniques, including karyotype, chromosomal microarray analysis (CMA), FISH, genome sequencing (GS), RNA-seq, and optical genome mapping (OGM). A complex 9p24 SV was hinted at by CMA results, showing three interspersed duplicated segments. Combined GS and OGM analyses revealed that the 9p24 duplications constitute a complex SV, on which a set of breakpoints matches the boundaries of the CMA duplicated sequences. The proposed structure for this complex rearrangement implies three duplications associated with an inversion of ~ 2 Mb region on chromosome 9 and a SINE element insertion at the more distal breakpoint. Interestingly, this genomic structure of rearrangement forms a chimeric transcript of the KANK1/DMRT1 loci, which was confirmed by both RNA-seq and Sanger sequencing on blood samples from 9p24 rearrangement carriers. Altogether with breakpoint amplification and FISH analysis, this combined approach allowed a deep characterization of this complex rearrangement. Although the genotype-phenotype correlation remains elusive from the molecular mechanism point of view, this study identified a large genomic rearrangement at 9p24 segregating with a familial congenital heart defect, revealing a genetic biomarker that was successfully applied for embryo selection, changing the reproductive perspective of affected individuals.
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Cromossomos , Variações do Número de Cópias de DNA , Humanos , Inversão Cromossômica , Sequência de Bases , Células Germinativas , Proteínas do Citoesqueleto/genética , Proteínas Adaptadoras de Transdução de Sinal/genéticaRESUMO
BACKGROUND: The median age for Prostate Cancer (PCa) diagnosis is 66 years, but 10% are diagnosed before 55 years. Studies on early-onset PCa remain both limited and controversial. This investigation sought to identify and characterize germline variants within Brazilian PCa patients classified as either early or later onset disease. METHODS: Peripheral blood DNA from 71 PCa patients: 18 younger (≤ 55 years) and 53 older (≥ 60 years) was used for Targeted DNA sequencing of 20 genes linked to DNA damage response, transcriptional regulation, cell cycle, and epigenetic control. Subsequent genetic variant identification was performed and variant functional impacts were analyzed with in silico prediction. RESULTS: A higher frequency of variants in the BRCA2 and KMT2C genes across both age groups. KMT2C has been linked to the epigenetic dysregulation observed during disease progression in PCa. We present the first instance of KMT2C mutation within the blood of Brazilian PCa patients. Furthermore, out of the recognized variants within the KMT2C gene, 7 were designated as deleterious. Thirteen deleterious variants were exclusively detected in the younger group, while the older group exhibited 37 variants. Within these findings, 4 novel variants emerged, including 1 designated as pathogenic. CONCLUSIONS: Our findings contribute to a deeper understanding of the genetic factors associated with PCa susceptibility in different age groups, especially among the Brazilian population. This is the first investigation to explore germline variants specifically in younger Brazilian PCa patients, with high relevance given the genetic diversity of the population in Brazil. Additionally, our work presents evidence of functionally deleterious germline variants within the KMT2C gene among Brazilian PCa patients. The identification of novel and functionally significant variants in the KMT2C gene emphasizes its potential role in PCa development and warrants further investigation.
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Neoplasias da Próstata , Masculino , Humanos , Idoso , Brasil , Neoplasias da Próstata/patologia , Mutação em Linhagem Germinativa , Mutação , Células Germinativas/patologia , Predisposição Genética para DoençaRESUMO
Malignant mixed müllerian tumor (MMMT) is a rare neoplasm, consisting of carcinomatous (epithelial) and sarcomatous (mesenchymal) components that most commonly arise in the endometrium and more infrequently in the ovaries, fallopian tube, cervix, and vagina. Primary peritoneal carcinosarcoma (PPCS) is an extremely rare extragenital presentation of MMMT. Although the occurrence of breast cancer and epithelial ovarian carcinoma in association with BRCA pathogenic variants is firmly established, the etiologic role of these genes in the development of other tumor types is less well known. Here, we present a rare case of PPCS in a 42-year-old Brazilian woman with a BRCA2 pathogenic variant, c.2808_2811del (NM_000059.3). The patient developed metastatic breast cancer at the age of 37 and underwent a risk-reducing bilateral salpingo-oophorectomy 2 years later. She was then diagnosed with PPCS 3 years after the risk-reducing surgery. She underwent treatment with surgery, chemotherapy, and targeted therapy but passed away almost 5 years after the second primary tumor diagnosis. To our knowledge, this is the first case of peritoneal carcinosarcoma described in a BRCA2 pathogenic variant carrier, and its report leads to a better understanding of the disease's molecular features and possible therapeutic approaches.
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BACKGROUND: Childhood cancer is one of the primary causes of disease-related death in 5- to 14-year-old children and currently no prevention strategies exist to reduce the incidence of this disease. Childhood cancer has a larger hereditary component compared with cancer in adults. Few genetic studies have been conducted on children with cancer. Additionally, Latin American populations are underrepresented in genomic studies compared with other populations. Therefore, the aim of this study is to analyze germline mutations in a group of mixed-ancestry Mexican pediatric patients with solid and hematological cancers. METHODS: We analyzed genetic variants from 40 Mexican childhood cancer patients and their relatives. DNA from saliva or blood samples was used for whole-exome sequencing. All variants were identified following GATK best practices. RESULTS: We found that six patients (15%) were carriers of germline mutations in CDKN2A, CHEK2, DICER1, FANCA, MSH6, MUTYH, NF1, and SBDS cancer predisposition genes, and additional new variants predicted to be deleterious by in silico algorithms. A population genetics analysis detected five components consistent with the demographic models assumed for modern mixed-ancestry Mexicans. CONCLUSIONS: This report identifies potential genetic risk factors and provides a better understanding of the underlying mechanisms of childhood cancer in this population.
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Mutação em Linhagem Germinativa , Neoplasias , População Norte-Americana , Adulto , Humanos , Criança , Pré-Escolar , Adolescente , Predisposição Genética para Doença , Neoplasias/genética , Sequenciamento do Exoma , Ribonuclease III , RNA Helicases DEAD-boxRESUMO
Mexico has the in-house technical and regulatory capacity to undertake human genome editing (HGE) governance. However, its regulatory framework must be reformed to be more targeted and govern the application of any emerging HGE technologies, leaving no room for unethical or unsafe practices for reproductive purposes.
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Edição de Genes , Genoma Humano , Humanos , México , Edição de Genes/legislação & jurisprudência , Edição de Genes/ética , Edição de Genes/métodos , Genoma Humano/genéticaRESUMO
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.
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Melanoma , Neoplasias Cutâneas , Humanos , Brasil/epidemiologia , Predisposição Genética para Doença , Melanoma/epidemiologia , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Testes Genéticos , Mutação em Linhagem Germinativa , Inibidor p16 de Quinase Dependente de Ciclina/genética , Receptor Tipo 1 de Melanocortina/genéticaRESUMO
Background: There is an increasing amount of data from Latin America on the characterization of BRCA variants; however, there is limited information from Peru. We conducted a retrospective study to describe germline pathogenic/likely pathogenic(P/LP) variants and variants of uncertain/unknown significance (VUS) in the BRCA1 and BRCA2 genes in Peru, in patients with breast and ovarian cancer, candidates for treatment with poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors. Methods: The patients were evaluated during the period 2019-2021. Genomic DNA was isolated from peripheral blood samples and targeted sequencing was performed using the Ampliseq BRCA panel. Genetic variant interpretation was carried out in accordance with the recommendations of the American College of Medical Genetics and ClinVar. During this period, 525 patients (143 with breast cancer and 382 with ovarian cancer) were studied. Results: We found that 14.7% (21/143) of breast cancer patients and 20.7% (79/382) of ovarian cancer patients were carriers of P/LP variants in BRCA1/2. The most frequent pathogenic variants detected in BRCA1 were c.2105dupT (BIC: 2224insT, n=12, 18.75%), c.68_69delAG (BIC: 185delAG, n=6, 9.38%), c.140G>T and c.815_824dupAGCCATGTGG (n=5, 7.81%), while in BRCA2 were c.8023A>G (n=6, 16.67%), c.6024dupG (BIC: 6252insG, n=4, 11.11%), and c.9235delG (BIC: 9463delG, n=3, 8.33%). Regarding VUS, we found that 6.99% (10/143) of breast cancer patients and 7.33% (28/382) of ovarian cancer patients were carriers of a VUS in BRCA1/2. For BRCA1, the most frequent VUS was c.93C>G (n=2), and for BRCA2, c.5465A>T (n=4), c.3101T>C (n=3), c.205C>A and c.437T>C (n=2). Conclusion: We found a frequency of 14.7% germline mutations in breast cancer patients and 20.7% in ovarian cancer patients. The most recurrent mutations were BRCA1 c.2105dupT and BRCA2 c.8023A>G. We found that BRCA2 c.8023A>G, c.6024dupG, and c.9235delG were not previously reported in Peruvian patients. BRCA1 c.2344dupA is a novel mutation that has not been previously reported in any database. The frequency of VUS in our cohort was 7.2%.
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The sea louse Caligus rogercresseyi is a major ectoparasitic copepod that causes significant economic losses in the salmon farming industry. Despite recent advancements, the mechanisms underlying germline and embryo development in this species remain poorly understood. The Vasa gene encodes a highly conserved DEAD box helicase that is required for germ cell formation and function in many species. In this study, the Vasa gene was characterized in C. rogercresseyi, and its expression and function were analyzed. Phylogenetic analysis showed that the Cr-Vasa gene product formed clusters in clades with Vasa proteins from closely related species of crustaceans. Cr-Vasa gene expression patterns were assessed by qPCR, and the results showed a significantly higher relative expression level in adult females compared to copepodid, chalimus, and adult male stages. Tissue-specific localization of Cr-Vasa mRNA in C. rogercresseyi was determined using chromogenic in situ hybridization, and strong positive signal was observed in male testes, but also in the intestine and cuticle, while in females, it was observed in the ovaries, oocytes, cuticle, intestine, and egg strings. RNAi-mediated gene silencing of Cr-Vasa impacted embryonic development and reproductive output in adult female lice. Females from the dsVasa-treated group displayed unusual phenotypes, including shorter egg strings with numerous extra-embryonic inclusions, irregularly shaped abnormal embryos, and aborted egg strings. This study provides insights into the role of the Vasa gene in C. rogercresseyi embryonic development and reproductive output, which may have implications for the control of this parasitic copepod in the salmon farming industry.
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Copépodes , Doenças dos Peixes , Ftirápteros , Animais , Feminino , Masculino , Interferência de RNA , Copépodes/genética , Filogenia , Salmão , Doenças dos Peixes/genéticaRESUMO
BACKGROUND: Early identification of germline mutation carriers may be relevant for the optimal management of prostate cancer and to inform cancer risk in relatives. However, population minorities have limited access to genetic testing. The aim of this study was to describe the frequency of DNA repair gene pathogenic variants (PVs) among Mexican men with prostate cancer referred for Genomic Cancer Risk Assessment and testing. METHODS: Patients diagnosed with prostate cancer who meet criteria for genetic testing and enrolled in the Clinical Cancer Genomics Community Research Network at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City were included. Descriptive statistics were performed using frequency and proportions for categorical variables and median and range for quantitative variables. X2 and t test were used for group comparisons. RESULTS: A total of 199 men were enrolled, median age at diagnosis was 66 (range 44-88) years; 45% were de novo metastatic and 44% were high- very high and 10% were intermediate risk group. Four (2%) had a pathogenic germline variant; one each of the following genes: ATM, CHEK2, BRIP1, and MUTYH (all monoallelic). Younger men at diagnosis were more likely to carry a PV than older age at diagnosis (56.7 vs. 66.4 years, P = .01). CONCLUSION: Our results showed a low prevalence of known prostate cancer associated PVs and no BRCA PVs in Mexican men with prostate cancer. This suggests that the genetic and/or epidemiologic risk factors for prostate cancer are not well characterized in this specific population.
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Mutação em Linhagem Germinativa , Neoplasias da Próstata , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , México/epidemiologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Reparo do DNA/genética , Células Germinativas/patologia , Predisposição Genética para DoençaRESUMO
Gamete production is a fundamental process for reproduction; however, exposure to stress, such as increased environmental temperature, can decrease or even interrupt this process, affecting fertility. Thus, the survival of spermatogonial stem cells (SSCs) is crucial for the recovery of spermatogenesis upon stressful situations. Here, we show that the Notch pathway is implicated in such survival, by protecting the SSCs against thermal stress. First, we corroborated the impairment of spermatogenesis under heat stress in medaka, observing an arrest in metaphase I at 10 days of heat treatment, an increase in the number of spermatocytes, and downregulation of ndrg1b and sycp3. In addition, at 30 days of treatment, an interruption of spermatogenesis was observed with a strong loss of spermatocytes and spermatids. Then, the exposure of adult males to thermal stress condition induced apoptosis mainly in spermatogenic and supporting somatic cells, with the exception of the germinal region, where SSCs are located. Concomitantly, the Notch pathway-related genes were upregulated, including the ligands (dll4, jag1-2) and receptors (notch1a-3). Moreover, during thermal stress presenilin enhancer-2 (pen-2), the catalytic subunit of γ-secretase complex of the Notch pathway was restricted to the germinal region of the medaka testis, observed in somatic cells surrounding type A spermatogonia (SGa). The importance of Notch pathway was further supported by an ex vivo approach, in which the inhibition of this pathway activity induced a loss of SSCs. Overall, this study supports the importance of Notch pathways for the protection of SSCs under chronic thermal stress.