Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 97
Filter
1.
J Math Biol ; 72(1-2): 47-86, 2016 Jan.
Article in English | MEDLINE | ID: mdl-25833184

ABSTRACT

Breakage-fusion-bridge cycles in cancer arise when a broken segment of DNA is duplicated and an end from each copy joined together. This structure then 'unfolds' into a new piece of palindromic DNA. This is one mechanism responsible for the localised amplicons observed in cancer genome data. Here we study the evolution space of breakage-fusion-bridge structures in detail. We firstly consider discrete representations of this space with 2-d trees to demonstrate that there are [Formula: see text] qualitatively distinct evolutions involving [Formula: see text] breakage-fusion-bridge cycles. Secondly we consider the stochastic nature of the process to show these evolutions are not equally likely, and also describe how amplicons become localized. Finally we highlight these methods by inferring the evolution of breakage-fusion-bridge cycles with data from primary tissue cancer samples.


Subject(s)
DNA Breaks , Evolution, Molecular , Models, Genetic , Cell Cycle/genetics , DNA Replication , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , DNA, Neoplasm/metabolism , Humans , Mathematical Concepts , Models, Molecular , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Nucleic Acid Conformation , Stochastic Processes
2.
Oncogene ; 34(46): 5699-708, 2015 Nov 12.
Article in English | MEDLINE | ID: mdl-25728682

ABSTRACT

Defining mechanisms that generate intratumour heterogeneity and branched evolution may inspire novel therapeutic approaches to limit tumour diversity and adaptation. SETD2 (Su(var), Enhancer of zeste, Trithorax-domain containing 2) trimethylates histone-3 lysine-36 (H3K36me3) at sites of active transcription and is mutated in diverse tumour types, including clear cell renal carcinomas (ccRCCs). Distinct SETD2 mutations have been identified in spatially separated regions in ccRCC, indicative of intratumour heterogeneity. In this study, we have addressed the consequences of SETD2 loss-of-function through an integrated bioinformatics and functional genomics approach. We find that bi-allelic SETD2 aberrations are not associated with microsatellite instability in ccRCC. SETD2 depletion in ccRCC cells revealed aberrant and reduced nucleosome compaction and chromatin association of the key replication proteins minichromosome maintenance complex component (MCM7) and DNA polymerase δ hindering replication fork progression, and failure to load lens epithelium-derived growth factor and the Rad51 homologous recombination repair factor at DNA breaks. Consistent with these data, we observe chromosomal breakpoint locations are biased away from H3K36me3 sites in SETD2 wild-type ccRCCs relative to tumours with bi-allelic SETD2 aberrations and that H3K36me3-negative ccRCCs display elevated DNA damage in vivo. These data suggest a role for SETD2 in maintaining genome integrity through nucleosome stabilization, suppression of replication stress and the coordination of DNA repair.


Subject(s)
Carcinoma, Renal Cell/genetics , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Kidney Neoplasms/genetics , Mutation , Carcinoma, Renal Cell/metabolism , Cell Line, Tumor , DNA Repair , DNA Replication , Genetic Heterogeneity , Histones/metabolism , Humans , Kidney Neoplasms/metabolism , Microsatellite Instability , Nucleosomes/pathology
3.
N Engl J Med ; 365(15): 1384-95, 2011 Oct 13.
Article in English | MEDLINE | ID: mdl-21995386

ABSTRACT

BACKGROUND: Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. METHODS: We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. RESULTS: We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. CONCLUSIONS: Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.).


Subject(s)
Myelodysplastic Syndromes/genetics , Phosphoproteins/genetics , Point Mutation , Ribonucleoprotein, U2 Small Nuclear/genetics , Erythrocytes/pathology , Gene Expression Profiling , High-Throughput Nucleotide Sequencing , Humans , Phenotype , RNA Splicing Factors
4.
J Med Genet ; 47(5): 342-7, 2010 May.
Article in English | MEDLINE | ID: mdl-19948536

ABSTRACT

BACKGROUND: Localisation of the breakpoints of chromosomal translocations has aided the discovery of several disease genes but has traditionally required laborious investigation of chromosomes by fluorescent in situ hybridisation approaches. Here, a strategy that utilises genome-wide paired-end massively parallel DNA sequencing to rapidly map translocation breakpoints is reported. This method was used to fine map a de novo t(5;6)(q21;q21) translocation in a child with bilateral, young-onset Wilms tumour. METHODS AND RESULTS: Genome-wide paired-end sequencing was performed for approximately 6 million randomly generated approximately 3 kb fragments from constitutional DNA containing the translocation, and six fragments in which one end mapped to chromosome 5 and the other to chromosome 6 were identified. This mapped the translocation breakpoints to within 1.7 kb. Then, PCR assays that amplified across the rearrangement junction were designed to characterise the breakpoints at sequence-level resolution. The 6q21 breakpoint transects and truncates HACE1, an E3 ubiquitin-protein ligase that has been implicated as a somatically inactivated target in Wilms tumourigenesis. To evaluate the contribution of HACE1 to Wilms tumour predisposition, the gene was mutationally screened in 450 individuals with Wilms tumour. One child with unilateral Wilms tumour and a truncating HACE1 mutation was identified. CONCLUSIONS: These data indicate that constitutional disruption of HACE1 likely predisposes to Wilms tumour. However, HACE1 mutations are rare and therefore can only make a small contribution to Wilms tumour incidence. More broadly, this study demonstrates the utility of genome-wide paired-end sequencing in the delineation of apparently balanced chromosomal translocations, for which it is likely to become the method of choice.


Subject(s)
Chromosome Breakpoints , Kidney Neoplasms/genetics , Translocation, Genetic , Ubiquitin-Protein Ligases/genetics , Wilms Tumor/genetics , Adolescent , Base Sequence , Chromosome Mapping , Chromosomes, Human, Pair 5/genetics , Chromosomes, Human, Pair 6/genetics , Codon, Nonsense , DNA Primers/genetics , DNA, Neoplasm/genetics , Genes, Wilms Tumor , Genetic Predisposition to Disease , Humans , Male , Molecular Sequence Data
5.
Br J Cancer ; 100(2): 370-5, 2009 Jan 27.
Article in English | MEDLINE | ID: mdl-19165201

ABSTRACT

LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the Peutz-Jeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/genetics , Mitogen-Activated Protein Kinase Kinases/metabolism , Mutation/genetics , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/genetics , ras Proteins/genetics , AMP-Activated Protein Kinase Kinases , Antibiotics, Antineoplastic/pharmacology , Benzamides/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Proliferation/drug effects , Immunoblotting , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 1/metabolism , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/metabolism , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins p21(ras) , Signal Transduction/drug effects , Sirolimus/pharmacology , TOR Serine-Threonine Kinases , Tumor Cells, Cultured , ras Proteins/metabolism
6.
Curr Protoc Hum Genet ; Chapter 10: Unit 10.11, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18428421

ABSTRACT

COSMIC is currently the most comprehensive global resource for information on somatic mutations in human cancer, combining curation of the scientific literature with tumor resequencing data from the Cancer Genome Project at the Sanger Institute, U.K. Almost 4800 genes and 250000 tumors have been examined, resulting in over 50000 mutations available for investigation. This information can be accessed in a number of ways, the most convenient being the Web-based system which allows detailed data mining, presenting the results in easily interpretable formats. This unit describes the graphical system in detail, elaborating an example walkthrough and the many ways that the resulting information can be thoroughly investigated by combining data, respecializing the query, or viewing the results in different ways. Alternate protocols overview the available precompiled data files available for download.


Subject(s)
Databases, Genetic , Mutation , Catalogs as Topic , Computer Graphics , Genetics, Medical , Humans , Internet , Neoplasms/classification , Neoplasms/genetics , Oncogenes , Phenotype
7.
Br J Cancer ; 97(12): 1701-6, 2007 Dec 17.
Article in English | MEDLINE | ID: mdl-17971766

ABSTRACT

Testicular microlithiasis (TM) is characterised by small intratesticular calcifications, which can be visualised by ultrasound. Men with testicular germ cell tumour (TGCT) have a higher frequency of TM than men without TGCT. To clarify the association between TGCT and TM and to investigate the relationship between TGCT susceptibility and TM, we recruited TGCT patients with and without family history of TGCT, unaffected male relatives and healthy male controls from the UK. Testicular ultrasound data were analysed from 328 men. Testicular microlithiasis was more frequent in TGCT cases than controls (36.7 vs 17.8%, age adjusted P<0.0001) and in unaffected male relatives than controls (34.5 vs 17.8%, age adjusted P=0.02). Testicular germ cell tumour case and matched relative pairs showed greater concordance for TM than would be expected by chance (P=0.05). We show that TM is present at a higher frequency in relatives of TGCT cases than expected by chance indicating that TM is a familial risk factor for TGCT. Although the familiality of TM could be due to shared exposures, it is likely that there exists a genetic susceptibility to TM that also predisposes to TGCT. We suggest that TM is an alternative manifestation of a TGCT susceptibility allele.


Subject(s)
Genetic Predisposition to Disease , Lithiasis/genetics , Neoplasms, Germ Cell and Embryonal/genetics , Testicular Neoplasms/genetics , Case-Control Studies , Humans , Male , Risk Factors
8.
Oncogene ; 26(50): 7158-62, 2007 Nov 01.
Article in English | MEDLINE | ID: mdl-17525745

ABSTRACT

Endometrial carcinoma is the most common gynecological malignancy in the United States. Although most women present with early disease confined to the uterus, the majority of persistent or recurrent tumors are refractory to current chemotherapies. We have identified a total of 11 different FGFR2 mutations in 3/10 (30%) of endometrial cell lines and 19/187 (10%) of primary uterine tumors. Mutations were seen primarily in tumors of the endometrioid histologic subtype (18/115 cases investigated, 16%). The majority of the somatic mutations identified were identical to germline activating mutations in FGFR2 and FGFR3 that cause Apert Syndrome, Beare-Stevenson Syndrome, hypochondroplasia, achondroplasia and SADDAN syndrome. The two most common somatic mutations identified were S252W (in eight tumors) and N550K (in five samples). Four novel mutations were identified, three of which are also likely to result in receptor gain-of-function. Extensive functional analyses have already been performed on many of these mutations, demonstrating they result in receptor activation through a variety of mechanisms. The discovery of activating FGFR2 mutations in endometrial carcinoma raises the possibility of employing anti-FGFR molecularly targeted therapies in patients with advanced or recurrent endometrial carcinoma.


Subject(s)
Bone Diseases, Developmental/genetics , Carcinoma, Endometrioid/genetics , Carcinosarcoma/genetics , Craniosynostoses/genetics , Endometrial Neoplasms/genetics , Germ-Line Mutation , Receptor, Fibroblast Growth Factor, Type 2/genetics , Aged , Amino Acid Substitution/genetics , Cell Line, Tumor , Female , Humans
9.
Bioinformatics ; 23(13): 1689-91, 2007 Jul 01.
Article in English | MEDLINE | ID: mdl-17485433

ABSTRACT

UNLABELLED: The undertaking of large-scale DNA sequencing screens for somatic variants in human cancers requires accurate and rapid processing of traces for variants. Due to their often aneuploid nature and admixed normal tissue, heterozygous variants found in primary cancers are often subtle and difficult to detect. To address these issues, we have developed a mutation detection algorithm, AutoCSA, specifically optimized for the high throughput screening of cancer samples. AVAILABILITY: http://www.sanger.ac.uk/genetics/CGP/Software/AutoCSA.


Subject(s)
Algorithms , Chromosome Mapping/methods , DNA Mutational Analysis/methods , DNA, Neoplasm/genetics , Genetic Testing/methods , Neoplasms/diagnosis , Neoplasms/genetics , Base Sequence , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Humans , Molecular Sequence Data , Software
10.
Br J Cancer ; 96(2): 357-61, 2007 Jan 29.
Article in English | MEDLINE | ID: mdl-17211466

ABSTRACT

Testicular germ cell tumour (TGCT) is the most common malignancy in men aged 15-45 years. A small deletion on the Y chromosome known as 'gr/gr' was shown to be associated with a two-fold increased risk of TGCT, increasing to three-fold in cases with a family history of TGCT. Additional deletions of the Y chromosome, known as AZFa, AZFb and AZFc, are described in patients with infertility; however, complete deletions of these regions have not been identified in TGCT patients. We screened the Y chromosome in a series of TGCT cases to evaluate if additional deletions of Y were implicated in TGCT susceptibility. Single copy Y chromosome STS markers with an average inter-marker spacing of 128 kb were examined in constitutional DNA of 271 index TGCT patients. Three markers showed evidence of deletions, sY1291, indicative of 'gr/gr' (eight out of 271; 2.9%), Y-DAZ3 contained within 'gr/gr' (21 out of 271; 7.7%) and a single deletion of the marker G66152 was identified in one TGCT case. No other markers demonstrated deletions. While several regions of the Y chromosome are known to be deleted and associated with infertility, our study provides no evidence to suggest regions of Y deletion, other than 'gr/gr', are associated with susceptibility to TGCT in UK patients.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Y , Neoplasms, Germ Cell and Embryonal/genetics , Testicular Neoplasms/genetics , Genetic Markers , Humans , Male , Physical Chromosome Mapping
11.
Clin Genet ; 70(6): 509-15, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17100996

ABSTRACT

We describe three families with X-linked mental retardation, two with a deletion of a single amino acid and one with a missense mutation in the proximal domain of the RSK2(RPS6KA3) (ribosomal protein S6 kinase, 90 kDa, polypeptide 3) protein similar to mutations found in Coffin-Lowry syndrome (CLS). In two families, the clinical diagnosis had been nonsyndromic X-linked mental retardation. In the third family, although CLS had been suspected, the clinical features were atypical and the degree of intellectual disability much less than expected. These families show that strict reliance on classical clinical criteria for mutation testing may result in a missed diagnosis. A less targeted screening approach to mutation testing is advocated.


Subject(s)
Coffin-Lowry Syndrome/genetics , Mental Retardation, X-Linked/genetics , Mutation/genetics , Phenotype , Ribosomal Protein S6 Kinases, 90-kDa/genetics , Amino Acid Sequence , Base Sequence , Female , Genetic Testing/methods , Humans , Male , Molecular Sequence Data , Pedigree , Sequence Analysis, DNA
12.
Br J Cancer ; 94(2): 318-22, 2006 Jan 30.
Article in English | MEDLINE | ID: mdl-16421597

ABSTRACT

The Catalogue Of Somatic Mutations In Cancer (COSMIC) database and web site was developed to preserve somatic mutation data and share it with the community. Over the past 25 years, approximately 350 cancer genes have been identified, of which 311 are somatically mutated. COSMIC has been expanded and now holds data previously reported in the scientific literature for 28 known cancer genes. In addition, there is data from the systematic sequencing of 518 protein kinase genes. The total gene count in COSMIC stands at 538; 25 have a mutation frequency above 5% in one or more tumour type, no mutations were found in 333 genes and 180 are rarely mutated with frequencies <5% in any tumour set. The COSMIC web site has been expanded to give more views and summaries of the data and provide faster query routes and downloads. In addition, there is a new section describing mutations found through a screen of known cancer genes in 728 cancer cell lines including the NCI-60 set of cancer cell lines.


Subject(s)
Databases, Genetic , Internet , Mutation , Neoplasms/genetics , Humans
14.
Article in English | MEDLINE | ID: mdl-16869737

ABSTRACT

All cancers arise due to the accumulation of mutations in critical target genes that, when altered, give rise to selective advantage in the cell and its progeny that harbor them. Knowledge of these mutations is key in understanding the biology of cancer initiation and progression, as well as the development of more targeted therapeutic strategies. We have undertaken a systematic screen of all annotated protein kinases in the human genome for mutations in a series of cancers including breast, non-small-cell lung, and testicular cancer. Our results show a wide diversity in mutation prevalence within and between tumor types. We have identified a mutator phenotype in human breast previously undescribed. The results presented from sequencing the same 1.3 million base pairs through several tumor types suggest that most of the observed mutations are likely to be passenger events rather than causally implicated in oncogenesis. However, this work does provide evidence for the likely existence of multiple, infrequently mutated kinases.


Subject(s)
Mutation , Neoplasms/enzymology , Neoplasms/genetics , Protein Kinases/genetics , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/genetics , Female , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Male , Testicular Neoplasms/enzymology , Testicular Neoplasms/genetics
15.
Br J Cancer ; 91(2): 355-8, 2004 Jul 19.
Article in English | MEDLINE | ID: mdl-15188009

ABSTRACT

The discovery of mutations in cancer genes has advanced our understanding of cancer. These results are dispersed across the scientific literature and with the availability of the human genome sequence will continue to accrue. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website have been developed to store somatic mutation data in a single location and display the data and other information related to human cancer. To populate this resource, data has currently been extracted from reports in the scientific literature for somatic mutations in four genes, BRAF, HRAS, KRAS2 and NRAS. At present, the database holds information on 66 634 samples and reports a total of 10 647 mutations. Through the web pages, these data can be queried, displayed as figures or tables and exported in a number of formats. COSMIC is an ongoing project that will continue to curate somatic mutation data and release it through the website.


Subject(s)
Databases, Factual , Internet , Mutation , Neoplasms/genetics , Genes, ras , Humans , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins B-raf , Proto-Oncogene Proteins c-raf/genetics , Proto-Oncogene Proteins p21(ras) , ras Proteins
16.
Br J Cancer ; 90(12): 2397-401, 2004 Jun 14.
Article in English | MEDLINE | ID: mdl-15150569

ABSTRACT

Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases (P=0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes.


Subject(s)
Germ-Line Mutation , Neoplasms, Germ Cell and Embryonal/genetics , Proto-Oncogene Proteins c-kit/genetics , Testicular Neoplasms/genetics , DNA Mutational Analysis , Exons , Humans , Male , Neoplasms, Germ Cell and Embryonal/pathology , Pedigree , Testicular Neoplasms/pathology
17.
Ann Oncol ; 13(12): 1899-907, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12453858

ABSTRACT

BACKGROUND: The Sardinian population is genetically homogeneous and could be useful in understanding better the genetics of a complex disease like breast cancer (BC). PATIENTS AND METHODS: Using a screening assay based on a combination of single-strand conformation polymorphism, denaturing high-performance liquid chromatography and sequence analysis, 47 Sardinian families with three or more BC cases were screened for germline mutations in BRCA1 and BRCA2 genes. RESULTS: Three BRCA1/2 germline sequence variants were identified. While BRCA2-Ile3412Val is a missense variant with unknown functional significance, BRCA2-8765delAG and BRCA1-Lys505ter are two deleterious mutations (due to their predicted effects on protein truncation), which were found in seven families (15%). BRCA2-8765delAG was found in six of eight (75%) BRCA1/2-positive families and seven of 501 (1.4%) unselected and consecutively collected BC patients. Prevalence of BRCA1/2 mutations in BC families was significantly correlated with the total number of female BCs (P <0.01) and increased by the presence of (i) at least one case of ovarian or male BC, or (ii) three generations affected, or (iii) bilateral BC. CONCLUSIONS: Identification of such features should address BC patients and their families to genetic counseling and BRCA1/2 mutational analysis. In addition, this is the first report of a detailed BRCA1/2 mutation screening in Sardinia, having immediate implications for the clinical management of BC families.


Subject(s)
Breast Neoplasms/epidemiology , Breast Neoplasms/genetics , Genes, BRCA1 , Genes, BRCA2 , Genetic Counseling/standards , Genetic Predisposition to Disease , Germ-Line Mutation , Adult , Aged , Biomarkers, Tumor/analysis , Breast Neoplasms, Male/epidemiology , Breast Neoplasms, Male/genetics , DNA Mutational Analysis , Female , Genetic Counseling/trends , Genetic Testing , Humans , Incidence , Italy/epidemiology , Male , Middle Aged , Pedigree , Polymerase Chain Reaction/methods , Polymorphism, Single-Stranded Conformational , Population Surveillance , Risk Factors , Survival Analysis
18.
Br J Cancer ; 87(8): 905-8, 2002 Oct 07.
Article in English | MEDLINE | ID: mdl-12373607

ABSTRACT

The candidate prostate cancer susceptibility gene HPC2/ELAC2 has two common coding polymorphisms: (Ser-->Leu 217) and (Ala-->Thr 541). The Thr541 variant in the HPC2/ELAC2 gene has previously been reported to be at an increased frequency in prostate cancer cases. To evaluate this hypothesis we genotyped 432 prostate cancer patients (including 262 patients diagnosed 55 years (OR=1.27, 95% CI 0.59-2.74). We conclude that any association between the Thr541 variant and prostate cancer is likely to be weak.


Subject(s)
Genetic Predisposition to Disease/genetics , Mutation/genetics , Neoplasm Proteins/genetics , Polymorphism, Genetic , Prostatic Neoplasms/genetics , Adult , Age of Onset , Aged , Aged, 80 and over , Case-Control Studies , DNA/blood , DNA/genetics , DNA, Neoplasm/metabolism , Female , Genetic Variation/genetics , Genotype , Humans , Male , Middle Aged , Odds Ratio , Prostatic Neoplasms/pathology , Risk Factors
19.
Br J Cancer ; 86(1): 76-83, 2002 Jan 07.
Article in English | MEDLINE | ID: mdl-11857015

ABSTRACT

In computing the probability that a woman is a BRCA1 or BRCA2 carrier for genetic counselling purposes, it is important to allow for the fact that other breast cancer susceptibility genes may exist. We used data from both a population based series of breast cancer cases and high risk families in the UK, with information on BRCA1 and BRCA2 mutation status, to investigate the genetic models that can best explain familial breast cancer outside BRCA1 and BRCA2 families. We also evaluated the evidence for risk modifiers in BRCA1 and BRCA2 carriers. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene 'BRCA3', and a polygenic effect using segregation analysis. The hypergeometric polygenic model was used to approximate polygenic inheritance and the effect of risk modifiers. BRCA1 and BRCA2 could not explain all the observed familial clustering. The best fitting model for the residual familial breast cancer was the polygenic, although a model with a single recessive allele produced a similar fit. There was also significant evidence for a modifying effect of other genes on the risks of breast cancer in BRCA1 and BRCA2 mutation carriers. Under this model, the frequency of BRCA1 was estimated to be 0.051% (95% CI: 0.021-0.125%) and of BRCA2 0.068% (95% CI: 0.033-0.141%). The breast cancer risk by age 70 years, based on the average incidence over all modifiers was estimated to be 35.3% for BRCA1 and 50.3% for BRCA2. The corresponding ovarian cancer risks were 25.9% for BRCA1 and 9.1% for BRCA2. The findings suggest that several common, low penetrance genes with multiplicative effects on risk may account for the residual non-BRCA1/2 familial aggregation of breast cancer. The modifying effect may explain the previously reported differences between population based estimates for BRCA1/2 penetrance and estimates based on high-risk families.


Subject(s)
Breast Neoplasms/genetics , Models, Genetic , Adult , Aged , Female , Genes, BRCA1 , Genes, BRCA2 , Humans , Middle Aged , Mutation
20.
Am J Med Genet ; 104(3): 246-9, 2001 Dec 01.
Article in English | MEDLINE | ID: mdl-11754052

ABSTRACT

A 14-month-old boy presenting with Wilms tumor (WT) was found to have a small de novo deletion of the long arm of chromosome 12 (12q11-12q13.11). Microsatellite analysis of this region from constitutional DNA showed that the paternal allele was absent between the markers D12S331 and D12S1713 (inclusive). In the WT there was no evidence of loss of the maternal chromosome. Constitutional chromosome abnormalities can often point to the presence of genes that are important in disease, and the deletion of chromosome 12 in this patient may indicate a gene involved in WT. To determine whether a WT predisposition locus exists at 12q we examined the region in two familial Wilms tumor (FWT) pedigrees unlinked to the known FWT genes on chromosomes 17q (FWT1), 19q (FWT2), and 11p (WT1). In both families WT did not segregate with chromosome 12q markers located within the deletion boundaries.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 12/genetics , Wilms Tumor/genetics , DNA/genetics , Family Health , Female , Genotype , Humans , Infant , Lod Score , Male , Microsatellite Repeats , Wilms Tumor/pathology
SELECTION OF CITATIONS
SEARCH DETAIL
...