RESUMEN
Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (MQLS) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10-4) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. A PARP2 (rs200603922, p = 0.028) variant in the Australian dataset and a MUTYH (rs36053993, p = 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.
RESUMEN
Recurrent tumor copy number variations (CNVs) in prostate cancer (PrCa) have predominantly been discovered in sporadic tumor cohorts. Here, we examined familial prostate tumors for novel CNVs as prior studies suggest these harbor distinct CNVs. Array comparative genomic hybridization of 12 tumors from an Australian PrCa family, PcTas9, highlighted multiple recurrent CNVs, including amplification of EEF2 (19p13.3) in 100% of tumors. The EEF2 CNV was examined in a further 26 familial and seven sporadic tumors from the Australian cohort and in 494 tumors unselected for family history from The Cancer Genome Atlas (TCGA). EEF2 overexpression was observed in seven PcTas9 tumors, in addition to seven other predominantly familial tumors (ntotal = 34%). EEF2 amplification was only observed in 1.4% of TCGA tumors, however 7.5% harbored an EEF2 deletion. Analysis of genes co-expressed with EEF2 revealed significant upregulation of two genes, ZNF74 and ADSL, and downregulation of PLSCR1 in both EEF2 amplified familial tumors and EEF2 deleted TCGA tumors. Furthermore, in TCGA tumors, EEF2 amplification and deletion were significantly associated with a higher Gleason score. In summary, we identified a novel PrCa CNV that was predominantly amplified in familial tumors and deleted in unselected tumors. Our results provide further evidence that familial tumors harbor distinct CNVs, potentially due to an inherited predisposition, but also suggest that regardless of how EEF2 is dysregulated, a similar set of genes involved in key cancer pathways are impacted. Given the current lack of gene-based biomarkers and clinical targets in PrCa, further investigation of EEF2 is warranted.
Asunto(s)
Síndromes Neoplásicos Hereditarios , Neoplasias de la Próstata , Humanos , Masculino , Australia , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Amplificación de Genes , Recurrencia Local de Neoplasia/genética , Síndromes Neoplásicos Hereditarios/genética , Neoplasias de la Próstata/genética , Factores de Elongación de Péptidos/genéticaRESUMEN
There is strong interest in the characterisation of gene fusions and their use to enhance clinical practices in prostate cancer (PrCa). Significantly, ~50% of prostate tumours harbour a gene fusion. Inherited factors are thought to predispose to these events but, to date, only one study has investigated gene fusions in a familial context. Here, we examined the prevalence and diversity of gene fusions in 14 tumours from a single large PrCa family, PcTas9, using the TruSight® RNA Fusion Panel and Sanger sequencing validation. These fusions were then explored in The Cancer Genome Atlas (TCGA) PrCa data set (n = 494). Overall, 64.3% of PcTas9 tumours harboured a gene fusion, including known erythroblast transformation-specific (ETS) fusions involving ERG and ETV1, and two novel gene fusions, C19orf48:ETV4 and RYBP:FOXP1. Although 3' ETS genes were overexpressed in PcTas9 and TCGA tumour samples, 3' fusion of FOXP1 did not appear to alter its expression. In addition, PcTas9 fusion carriers were more likely to have lower-grade disease than noncarriers (p = 0.02). Likewise, TCGA tumours with high-grade disease were less likely to harbour fusions (p = 0.03). Our study further implicates an inherited predisposition to PrCa gene fusion events, which are associated with less aggressive tumours. This knowledge could lead to clinical strategies to predict men at risk for fusion-positive PrCa and, thus, identify patients who are more or less at risk of aggressive disease and/or responsive to particular therapies.
Asunto(s)
Proteínas de Unión al ADN , Neoplasias de la Próstata , Proteínas de Unión al ADN/genética , Factores de Transcripción Forkhead/genética , Fusión Génica , Predisposición Genética a la Enfermedad , Humanos , Masculino , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas Represoras/genética , Factores de Transcripción/genéticaAsunto(s)
Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias de la Próstata/genética , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Mutación/genética , Linaje , Análisis de Secuencia de ADNRESUMEN
Prostate cancer (PrCa) is highly heritable, and although rare variants contribute significantly to PrCa risk, few have been identified to date. Herein, whole-genome sequencing was performed in a large PrCa family featuring multiple affected relatives spanning several generations. A rare, predicted splice site EZH2 variant, rs78589034 (G > A), was identified as segregating with disease in all but two individuals in the family, one of whom was affected with lymphoma and bowel cancer and a female relative. This variant was significantly associated with disease risk in combined familial and sporadic PrCa datasets (n = 1551; odds ratio [OR] = 3.55, P = 1.20 × 10-5 ). Transcriptome analysis was performed on prostate tumour needle biopsies available for two rare variant carriers and two wild-type cases. Although no allele-dependent differences were detected in EZH2 transcripts, a distinct differential gene expression signature was observed when comparing prostate tissue from the rare variant carriers with the wild-type samples. The gene expression signature comprised known downstream targets of EZH2 and included the top-ranked genes, DUSP1, FOS, JUNB and EGR1, which were subsequently validated by qPCR. These data provide evidence that rs78589034 is associated with increased PrCa risk in Tasmanian men and further, that this variant may be associated with perturbed EZH2 function in prostate tissue. Disrupted EZH2 function is a driver of tumourigenesis in several cancers, including prostate, and is of significant interest as a therapeutic target.
Asunto(s)
Biomarcadores de Tumor/genética , Proteína Potenciadora del Homólogo Zeste 2/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/epidemiología , Transcriptoma , Anciano , Anciano de 80 o más Años , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Factores de Riesgo , Tasmania/epidemiología , Células Tumorales Cultivadas , Estados Unidos/epidemiologíaRESUMEN
The HOXB13 G84E variant is associated with risk of prostate cancer (PCa), however the role this variant plays in PCa development is unknown. This study examined 751 cases, 450 relatives and 355 controls to determine the contribution of this variant to PCa risk in Tasmania and investigated HOXB13 gene and protein expression in tumours from nine G84E heterozygote variant and 13 wild-type carriers. Quantitative PCR and immunohistochemistry showed that HOXB13 gene and protein expression did not differ between tumour samples from variant and wild-type carriers. Allele-specific transcription revealed that two of seven G84E carriers transcribed both the variant and wild-type allele, while five carriers transcribed the wild-type allele. Methylation of surrounding CpG sites was lower in the variant compared to the wild-type allele, however overall methylation across the region was very low. Notably, tumour characteristics were less aggressive in the two variant carriers that transcribed the variant allele compared to the five that did not. This study has shown that HOXB13 expression does not differ between tumour tissue of G84E variant carriers and non-carriers. Intriguingly, the G84E variant allele was rarely transcribed in carriers, suggesting that HOXB13 expression may be driven by the wild-type allele in the majority of carriers.
Asunto(s)
Expresión Génica/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Proteínas de Homeodominio/genética , Neoplasias de la Próstata/genética , Alelos , Estudios de Casos y Controles , Estudios de Cohortes , Metilación de ADN/genética , Formaldehído/farmacología , Genotipo , Heterocigoto , Humanos , Masculino , Adhesión en Parafina/métodos , Factores de Riesgo , Tasmania , Transcripción Genética/genéticaAsunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Antígeno-1 Asociado a Función de Linfocito/genética , Polimorfismo de Nucleótido Simple , Estudios de Cohortes , Predisposición Genética a la Enfermedad , Neoplasias Hematológicas/epidemiología , Neoplasias Hematológicas/genética , Humanos , Leucemia Linfocítica Crónica de Células B/epidemiología , Síndromes Neoplásicos Hereditarios/epidemiología , Síndromes Neoplásicos Hereditarios/genética , Análisis de Secuencia de ADN , Tasmania/epidemiologíaRESUMEN
We describe a collection of 11 families with ≥ 2 generations of family members whose condition has been diagnosed as a hematologic malignancy. In 9 of these families there was a significant decrease in age at diagnosis in each subsequent generation (anticipation). The mean age at diagnosis in the first generation was 67.8 years, 57.1 years in the second, and 41.8 years in the third (P < .0002). This was confirmed in both direct parent-offspring pairs with a mean reduction of 19 years in the age at diagnosis (P = .0087) and when the analysis was repeated only including cases of mature B-cell neoplasm (P = .0007). We believe that these families provide further insight into the nature of the underlying genetic mechanism of predisposition in these families.
Asunto(s)
Anticipación Genética/fisiología , Familia , Neoplasias Hematológicas/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
A family history of a haematological malignancy (HM) is known to be a risk factor for HMs. However, collections of large families with multiple cases of varied disease types are relatively rare. We describe a collection of 12 families with dense aggregations of multiple HM subtypes. Cases were ascertained from a population based study conducted between 1972 and 1980 in Tasmania, Australia. Diagnoses were confirmed through review and re-examination of stored tissue, pathology reports, Tasmanian Cancer Registry and flow cytometry records. Family trees were generated and kinship coefficients were calculated for all pairs of affected individuals. 120 cases were found in these families. Cases diagnosed with chronic lymphocytic leukaemia (CLL) demonstrated the most significantly increased aggregation (P < 0.0001). There was also significant evidence that those individuals diagnosed at an older age (>53 years), did not aggregate together in families with disease that presented at an earlier age (<20 years) (P = 0.009).
Asunto(s)
Neoplasias Hematológicas/genética , Síndromes Neoplásicos Hereditarios/genética , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Neoplasias Hematológicas/epidemiología , Humanos , Lactante , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/genética , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/epidemiología , Linaje , Sistema de Registros , Tasmania/epidemiología , Adulto JovenRESUMEN
Cell wall biogenesis and integrity are crucial for fungal growth, pathogenesis and survival, and are attractive targets for antifungal therapy. In this study, we identify, delete and analyse mutant strains for 10 genes involved in the PKC1 signal transduction pathway and its regulation in Cryptococcus neoformans. The kinases Bck1 and Mkk2 are critical for maintaining integrity, and deletion of each of these causes severe phenotypes different from each other. In stark contrast to results seen in Saccharomyces cerevisiae, a deletion in LRG1 has severe repercussions for the cell, and one in ROM2 has little effect. Also surprisingly, the phosphatase Ppg1 is crucial for cell integrity. These data indicate that the mechanisms of maintaining cell integrity differ between the two fungi. Deletions in SSD1 and PUF4, potential alternative regulators of cell integrity, also exhibit phenotypes. This is the first comprehensive analysis examining genes involved the maintenance of cell integrity in C. neoformans and sets the foundation for future biochemical and virulence studies.
Asunto(s)
Pared Celular/metabolismo , Cryptococcus neoformans/citología , Cryptococcus neoformans/metabolismo , Proteína Quinasa C/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Transducción de Señal/fisiología , Animales , Antifúngicos/farmacología , Bencenosulfonatos/metabolismo , Caspofungina , Pared Celular/efectos de los fármacos , Colorantes/metabolismo , Cryptococcus neoformans/efectos de los fármacos , Cryptococcus neoformans/genética , Equinocandinas , Colorantes Fluorescentes/metabolismo , Marcación de Gen , Humanos , Lipopéptidos , Melaninas/metabolismo , Péptidos Cíclicos/farmacología , Proteína Quinasa C/genética , Proteínas de Saccharomyces cerevisiae/genética , Transducción de Señal/genética , Temperatura , Azul de Tripano/metabolismoRESUMEN
We have developed a likelihood method to identify moderately distant genealogical relationships from genomewide scan data. The aim is to compare the genotypes of many pairs of people and identify those pairs most likely to be related to one another. We have tested the algorithm using the genotypes of 170 Tasmanians with multiple sclerosis recruited into a haplotype association study. It is estimated from genealogical records that approximately 65% of Tasmania's current population of 470,000 are direct descendants of the 13,000 female founders living in this island state of Australia in the mid-nineteenth century. All cases and four to five relatives of each case have been genotyped with microsatellite markers at a genomewide average density of 4 cM. Previous genealogical research has identified 51 pairwise relationships linking 56 of the 170 cases. Testing the likelihood calculation on these known relative pairs, we have good power to identify relationships up to degree eight (e.g. third cousins once removed). Applying the algorithm to all other pairs of cases, we have identified a further 61 putative relative pairs, with an estimated false discovery rate of 10%. The power to identify genealogical links should increase when the new, denser sets of SNP markers are used. Except in populations where there is a searchable electronic database containing virtually all genealogical links in the past six generations, the algorithm should be a useful aid for genealogists working on gene-mapping projects, both linkage studies and association studies.