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Dive into the research topics where Christopher J. Ricketts is active.

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Featured researches published by Christopher J. Ricketts.


Journal of the National Cancer Institute | 2008

Germline SDHB mutations and familial renal cell carcinoma.

Christopher J. Ricketts; Emma R. Woodward; Pip Killick; Mark R. Morris; Dewi Astuti; Farida Latif; Eamonn R. Maher

Familial renal cell carcinoma (RCC) is a heterogeneous disorder that is most commonly caused by germline mutations in the VHL, MET, and FLCN genes or by constitutional chromosome 3 translocations. However, for many patients with familial RCC, the genetic basis of the disease is undefined. We investigated whether germline mutations in fumarate hydratase (FH) or succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD) were associated with RCC susceptibility in 68 patients with no clinical evidence of an RCC susceptibility syndrome. No mutations in FH, SDHC, or SDHD were identified in probands, but 3 of the 68 (4.4%) probands had a germline SDHB mutation. Patients with a germline SDHB mutation presented with familial RCC (n = 1) or bilateral RCC (n = 2) and no personal or family history of pheochromocytoma or head and neck paraganglioma. Age at diagnosis of RCC in SDHB mutation carriers ranged from 24 to 73 years. These findings 1) demonstrate that patients with suspected inherited RCC should be examined for germline SDHB mutations, 2) suggest that all identified SDHB mutation carriers should be offered surveillance for RCC, and 3) provide a further link between familial RCC and activation of hypoxic-gene response pathways.


Human Mutation | 2010

Tumor Risks and Genotype-Phenotype-Proteotype Analysis in 358 Patients With Germline Mutations in SDHB and SDHD

Christopher J. Ricketts; Julia R. Forman; Eleanor Rattenberry; Nicola Bradshaw; Fiona Lalloo; Louise Izatt; Trevor Cole; Ruth Armstrong; V.K. Ajith Kumar; Patrick J. Morrison; A. Brew Atkinson; Fiona Douglas; Steve Ball; Jackie Cook; Umasuthan Srirangalingam; Pip Killick; Gail Kirby; Simon Aylwin; Emma R. Woodward; D. Gareth Evans; Shirley Hodgson; Vicky Murday; Shern L. Chew; John M. C. Connell; Tom L. Blundell; Fiona Macdonald; Eamonn R. Maher

Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and extraadrenal pheochromocytomas, head and neck paragangliomas (HNPGL), and other tumor types. We report tumor risks in 358 patients with SDHB (n=295) and SDHD (n=63) mutations. Risks of HNPGL and pheochromocytoma in SDHB mutation carriers were 29% and 52%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) were higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) were identified. No clear genotype–phenotype correlations were detected for SDHB mutations. However, SDHD mutations predicted to result in loss of expression or a truncated or unstable protein were associated with a significantly increased risk of pheochromocytoma compared to missense mutations that were not predicted to impair protein stability (most such cases had the common p.Pro81Leu mutation). Analysis of the largest cohort of SDHB/D mutation carriers has enhanced estimates of penetrance and tumor risk and supports in silicon protein structure prediction analysis for functional assessment of mutations. The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma risks suggests differing mechanisms of tumorigenesis in SDH‐associated HNPGL and pheochromocytoma. Hum Mutat 31:41–51, 2010.


JAMA | 2010

Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas.

Li Yao; Francesca Schiavi; Alberto Cascón; Yuejuan Qin; Lucía Inglada-Pérez; Elizabeth E. King; Rodrigo A. Toledo; Tonino Ercolino; Elena Rapizzi; Christopher J. Ricketts; Luigi Mori; Mara Giacchè; Antonella Mendola; Elisa Taschin; Francesca Boaretto; Paola Loli; Maurizio Iacobone; Gian Paolo Rossi; Bernadette Biondi; José Viana Lima-Junior; Claudio E. Kater; Marie Bex; Miikka Vikkula; Ashley B. Grossman; Stephen B. Gruber; Marta Barontini; Alexandre Persu; Maurizio Castellano; Sergio P. A. Toledo; Eamonn R. Maher

CONTEXT Pheochromocytomas and paragangliomas are genetically heterogeneous neural crest-derived neoplasms. We recently identified germline mutations of the novel transmembrane-encoding gene FP/TMEM127 in familial and sporadic pheochromocytomas consistent with a tumor suppressor effect. OBJECTIVES To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro. DESIGN, SETTING, AND PARTICIPANTS We sequenced the FP/TMEM127 gene in 990 individuals with pheochromocytomas and/or paragangliomas, including 898 previously unreported cases without mutations in other susceptibility genes from 8 independent worldwide referral centers between January 2009 and June 2010. A multiplex polymerase chain reaction-based method was developed to screen for large gene deletions in 545 of these samples. Confocal microscopy of 5 transfected mutant proteins was used to determine their subcellular localization. MAIN OUTCOME MEASURES The frequency and type of FP/TMEM127 mutation or deletion was assessed and correlated with clinical variables; the subcellular localization of 5 overexpressed mutants was compared with wild-type FP/TMEM127 protein. RESULTS We identified 19 potentially pathogenic FP/TMEM127 germline mutations in 20 independent families, but no large deletions were detected. All mutation carriers had adrenal tumors, including 7 bilateral (P = 2.7 × 10(-4)) and/or with familial disease (5 of 20 samples; P = .005). The median age at disease onset in the FP/TMEM127 mutation group was similar to that of patients without a mutation (41.5 vs 45 years, respectively; P = .54). The most common presentation was that of a single benign adrenal tumor in patients older than 40 years. Malignancy was seen in 1 mutation carrier (5%). Expression of 5 novel FP/TMEM127 mutations in cell lines revealed diffuse localization of the mutant proteins in contrast with the discrete multiorganelle distribution of wild-type TMEM127. CONCLUSIONS Germline mutations of FP/TMEM127 were associated with pheochromocytoma but not paraganglioma and occurred in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular distribution of the FP/TMEM127 protein.


Nature Genetics | 2012

Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility.

Dewi Astuti; Mark R. Morris; Wendy N. Cooper; Raymond H.J. Staals; Naomi C. Wake; Graham Fews; Harmeet Gill; Dean Gentle; Salwati Shuib; Christopher J. Ricketts; Trevor Cole; Anthonie J. van Essen; Richard A. van Lingen; Giovanni Neri; John M. Opitz; Patrick Rump; Irene Stolte-Dijkstra; Ferenc Müller; Ger J. M. Pruijn; Farida Latif; Eamonn R. Maher

Perlman syndrome is a congenital overgrowth syndrome inherited in an autosomal recessive manner that is associated with Wilms tumor susceptibility. We mapped a previously unknown susceptibility locus to 2q37.1 and identified germline mutations in DIS3L2, a homolog of the Schizosaccharomyces pombe dis3 gene, in individuals with Perlman syndrome. Yeast dis3 mutant strains have mitotic abnormalities. Yeast Dis3 and its human homologs, DIS3 and DIS3L1, have exoribonuclease activity and bind to the core RNA exosome complex. DIS3L2 has a different intracellular localization and lacks the PIN domain found in DIS3 and DIS3L1; nevertheless, we show that DIS3L2 has exonuclease activity. DIS3L2 inactivation was associated with mitotic abnormalities and altered expression of mitotic checkpoint proteins. DIS3L2 overexpression suppressed the growth of human cancer cell lines, and knockdown enhanced the growth of these cells. We also detected evidence of DIS3L2 mutations in sporadic Wilms tumor. These observations suggest that DIS3L2 has a critical role in RNA metabolism and is essential for the regulation of cell growth and division.


Oncogene | 2011

Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma

Mark R. Morris; Christopher J. Ricketts; Dean Gentle; Fiona E. McRonald; N Carli; H Khalili; Michael D Brown; Takeshi Kishida; Masahiro Yao; Rosamonde E. Banks; Noel W. Clarke; Farida Latif; Eamonn R. Maher

The detection of promoter region hypermethylation and transcriptional silencing has facilitated the identification of candidate renal cell carcinoma (RCC) tumour suppressor genes (TSGs). We have used a genome-wide strategy (methylated DNA immunoprecipitation (MeDIP) and whole-genome array analysis in combination with high-density expression array analysis) to identify genes that are frequently methylated and silenced in RCC. MeDIP analysis on 9 RCC tumours and 3 non-malignant normal kidney tissue samples was performed, and an initial shortlist of 56 candidate genes that were methylated by array analysis was further investigated; 9 genes were confirmed to show frequent promoter region methylation in primary RCC tumour samples (KLHL35 (39%), QPCT (19%), SCUBE3 (19%), ZSCAN18 (32%), CCDC8 (35%), FBN2 (34%), ATP5G2 (36%), PCDH8 (58%) and CORO6 (22%)). RNAi knockdown for KLHL35, QPCT, SCUBE3, ZSCAN18, CCDC8 and FBN2 resulted in an anchorage-independent growth advantage. Tumour methylation of SCUBE3 was associated with a significantly increased risk of cancer death or relapse (P=0.0046). The identification of candidate epigenetically inactivated RCC TSGs provides new insights into renal tumourigenesis.


The Journal of Urology | 2012

Succinate Dehydrogenase Kidney Cancer: An Aggressive Example of the Warburg Effect in Cancer

Christopher J. Ricketts; Brian Shuch; Cathy D. Vocke; Adam R. Metwalli; Gennady Bratslavsky; Lindsay A. Middelton; Youfeng Yang; Ming-Hui Wei; Stephen E. Pautler; James Peterson; Catherine A. Stolle; Berton Zbar; Maria J. Merino; Laura S. Schmidt; Peter A. Pinto; Ramaprasad Srinivasan; Karel Pacak; W. Marston Linehan

PURPOSE Recently, a new renal cell cancer syndrome has been linked to germline mutation of multiple subunits (SDHB/C/D) of the Krebs cycle enzyme, succinate dehydrogenase. We report our experience with the diagnosis, evaluation and treatment of this novel form of hereditary kidney cancer. MATERIALS AND METHODS Patients with suspected hereditary kidney cancer were enrolled on a National Cancer Institute institutional review board approved protocol to study inherited forms of kidney cancer. Individuals from families with germline SDHB, SDHC and SDHD mutations, and kidney cancer underwent comprehensive clinical and genetic evaluation. RESULTS A total of 14 patients from 12 SDHB mutation families were evaluated. Patients presented with renal cell cancer at an early age (33 years, range 15 to 62), metastatic kidney cancer developed in 4 and some families had no manifestation other than kidney tumors. An additional family with 6 individuals found to have clear cell renal cell cancer that presented at a young average age (47 years, range 40 to 53) was identified with a germline SDHC mutation (R133X) Metastatic disease developed in 2 of these family members. A patient with a history of carotid body paragangliomas and an aggressive form of kidney cancer was evaluated from a family with a germline SDHD mutation. CONCLUSIONS SDH mutation associated renal cell carcinoma can be an aggressive type of kidney cancer, especially in younger individuals. Although detection and management of early tumors is most often associated with a good outcome, based on our initial experience with these patients and our long-term experience with hereditary leiomyomatosis and renal cell carcinoma, we recommend careful surveillance of patients at risk for SDH mutation associated renal cell carcinoma and wide surgical excision of renal tumors.


Oncogene | 2010

Identification of candidate tumour suppressor genes frequently methylated in renal cell carcinoma

Mark R. Morris; Christopher J. Ricketts; Dean Gentle; Mahera Abdulrahman; Noel W. Clarke; Michael L. Brown; Takeshi Kishida; Masahiro Yao; Farida Latif; Eamonn R. Maher

Promoter region hyermethylation and transcriptional silencing is a frequent cause of tumour suppressor gene (TSG) inactivation in many types of human cancers. Functional epigenetic studies, in which gene expression is induced by treatment with demethylating agents, may identify novel genes with tumour-specific methylation. We used high-density gene expression microarrays in a functional epigenetic study of 11 renal cell carcinoma (RCC) cell lines. Twenty-eight genes were then selected for analysis of promoter methylation status in cell lines and primary RCC. Eight genes (BNC1, PDLIM4, RPRM, CST6, SFRP1, GREM1, COL14A1 and COL15A1) showed frequent (>30% of RCC tested) tumour-specific promoter region methylation. Hypermethylation was associated with transcriptional silencing. Re-expression of BNC1, CST6, RPRM and SFRP1 suppressed the growth of RCC cell lines and RNA interference knock-down of BNC1, SFRP1 and COL14A1 increased the growth of RCC cell lines. Methylation of BNC1 or COL14A1 was associated with a poorer prognosis independent of tumour size, stage or grade. The identification of these epigenetically inactivated candidate RCC TSGs can provide insights into renal tumourigenesis and a basis for developing novel therapies and biomarkers for prognosis and detection.


Cancer Research | 2011

Genome-Wide DNA Methylation Profiling of CpG Islands in Breast Cancer Identifies Novel Genes Associated with Tumorigenicity

Victoria Hill; Christopher J. Ricketts; Ivan Bièche; Sophie Vacher; Dean Gentle; Cheryl M. Lewis; Eamonn R. Maher; Farida Latif

Epigenetic profiling of tumor DNAs may reveal important new theranostic targets to improve prognosis and treatment of advanced cancer patients. In this study, we performed a genome-wide profile of DNA methylation patterns in sporadic breast tumors by using the HumanMethylation27 BeadChips to assess relationships between DNA methylation changes and patient tumor characteristics. The arrays identified 264 hypermethylated loci/genes present in genomic CpG islands. Hierarchical clustering based on methylation levels divided the specimens into three distinct groups, within which certain clinical features also clustered. Statistically significant differences were determined between overall methylation levels of these clusters and estrogen receptor and progesterone receptor (ER/PR) status (P = 0.001), tumor relapse (P = 0.035), and lymph node metastasis (P = 0.042). We identified several individual methylated genes associated with clinical features, including six genes (RECK, SFRP2, UAP1L1, ACADL, ITR, and UGT3A1) that showed statistical significance between methylation and relapse-free survival. Notably, the RECK gene in this group has been associated in other cancers with poorest prognosis. Among the leading relapse-associated genes and the genes associated with ER/PR status, we sequenced an independent set of paired normal/tumor breast DNA samples to confirm tumor specificity of methylation. Further, we carried out quantitative real-time reverse transcriptase PCR to confirm reduced expression in methylated tumors. Our findings suggest the utility for the DNA methylation patterns in these genes as clinically useful surrogate markers in breast cancer, as well as new molecular pathways for further investigation as therapeutic targets.


Molecular Cancer Research | 2013

A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma

Megan N. Farley; Laura S. Schmidt; Jessica Mester; Samuel Peña-Llopis; Andrea Pavia-Jimenez; Alana Christie; Cathy D. Vocke; Christopher J. Ricketts; James Peterson; Lindsay A. Middelton; Lisa N. Kinch; Nick V. Grishin; Maria J. Merino; Adam R. Metwalli; Chao Xing; Xian Jin Xie; Patricia L M Dahia; Charis Eng; W. Marston Linehan; James Brugarolas

Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including the von Hippel-Lindau (VHL) tumor suppressor, which is also mutated in sporadic RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BRCA1-associated protein-1 (BAP1) gene is mutated in sporadic RCC. The BAP1 gene encodes a nuclear deubiquitinase and appears to be a classic two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade, clear-cell RCC (ccRCC) and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, the BAP1 gene was sequenced in 83 unrelated probands with unexplained familial RCC. Interestingly, a novel variant (c.41T>A; p.L14H) was uncovered that cosegregated with the RCC phenotype. The p.L14H variant targets a highly conserved residue in the catalytic domain, which is frequently targeted by missense mutations. The family with the novel BAP1 variant was characterized by early-onset ccRCC, occasionally of high Fuhrman grade, and lacked other features that typify VHL syndrome. These findings suggest that BAP1 is an early-onset familial RCC predisposing gene. Implications: BAP1 mutations may drive tumor development in a subset of patients with inherited renal cell cancer. Mol Cancer Res; 11(9); 1061–71. ©2013 AACR.


Clinical Cancer Research | 2008

Familial Non-VHL Clear Cell (Conventional) Renal Cell Carcinoma: Clinical Features, Segregation Analysis, and Mutation Analysis of FLCN

Emma R. Woodward; Christopher J. Ricketts; Pip Killick; Sophie Gad; Mark R. Morris; Fred Kavalier; Shirley Hodgson; Sophie Giraud; Brigitte Bressac-de Paillerets; Cyril Chapman; Bernard Escudier; Farida Latif; Stéphane Richard; Eamonn R. Maher

Purpose: Familial renal cell carcinoma (RCC) is genetically heterogeneous. The most common histopathologic subtype of sporadic and familial RCC is clear cell (cRCC) and von Hippel-Lindau (VHL) disease is the most common cause of inherited cRCC. Familial cRCC may also be associated with chromosome 3 translocations and has recently been described in patients with Birt-Hogg-Dube (BHD) syndrome, caused by germline FLCN mutation. Fewer than 20 kindreds with familial cRCC without VHL disease or a constitutional translocation have been described. The purpose of this investigation was to define the clinical and genetic features of familial non-VHL cRCC (FcRCC) and to evaluate whether unrecognized BHD syndrome might be present in patients with apparent nonsyndromic RCC susceptibility. Experimental Design: We analyzed the clinical features of, and undertook segregation analysis in, 60 kindreds containing two or more cases of RCC (at least one confirmed case of cRCC) and no evidence of an RCC susceptibility syndrome. We also undertook FLCN analysis to evaluate whether unrecognized BHD syndrome might be present in 69 patients with apparent nonsyndromic RCC susceptibility. Results: FcRCC was characterized by an earlier age at onset than sporadic cases and more frequent occurrence of bilateral or multicentric tumors. Segregation analysis showed autosomal dominant inheritance with sex- and age-dependent penetrance. A germline FLCN mutation was detected in 3 of 69 (4.3%) patients with apparent nonsyndromic RCC susceptibility. Conclusions: We describe the clinical and genetic features of the largest series of FcRCC and recommend these patients be offered FLCN analysis, in addition to constitutional cytogenetic and VHL analysis.

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W. Marston Linehan

National Institutes of Health

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Cathy D. Vocke

National Institutes of Health

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Youfeng Yang

National Institutes of Health

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Maria J. Merino

National Institutes of Health

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Carole Sourbier

National Institutes of Health

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Farida Latif

University of Birmingham

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Mark R. Morris

University of Wolverhampton

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Darmood Wei

University of North Carolina at Chapel Hill

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