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Computed tomography (CT) scanners are equipped with automatic tube current modulation (ATCM) systems that adjust the current to compensate for variations in patient attenuation. CT dosimetry variables are not defined for ATCM situations and, thus, only the averaged values are displayed and analysed. The patient effective dose (E), which is derived from a weighted sum of organ equivalent doses, will be modified by the ATCM. Values for E for chest-abdomen-pelvis CT scans have been calculated using the ImPACT spreadsheet for patients on five CT scanners. Values for E resulting from the z-axis modulation under ATCM have been compared with results assessed using the same effective mAs values with constant tube currents. Mean values for E under ATCM were within ±10 % of those for fixed tube currents for all scanners. Cumulative dose distributions under ATCM have been simulated for two patient scans using single-slice dose profiles measured in elliptical and cylindrical phantoms on one scanner. Contributions to the effective dose from organs in the upper thorax under ATCM are 30-35 % lower for superficial tissues (e.g. breast) and 15-20 % lower for deeper organs (e.g. lungs). The effect on doses to organs in the abdomen depends on body shape, and they can be 10-22 % higher for larger patients. Results indicate that scan dosimetry parameters, dose-length product and effective mAs averaged over the whole scan can provide an assessment in terms of E that is sufficiently accurate to quantify relative risk for routine patient exposures under ATCM. [ABSTRACT FROM AUTHOR]

Objective: This article reports on a pilot study designed to collect dose data representative of current CT chest abdomen pelvis (CAP) practice in Scotland, make any immediately obvious interventions and to identify if the current UK diagnostic reference level (DRL) of 940 mGy cm is still appropriate. The aims are to identify if a Scotland-wide picture archiving and communication system (PACS)-based dose audit of a number of CT examinations is likely to have value in terms of optimization of patient doses and to comment on the significance of the results in terms of future optimization strategies. Methods: Dose audit of CT CAP examinations at 32 different scanner sites across Scotland using accepted data collection and analysis methods. The minimum sample size was 30. Results: Results indicate that CT CAP doses are lower than those previously reported (median, 800 mGy cm, 75th percentile 840 mGy cm) but follow a distribution that is not in keeping with the concept of DRLs as presently understood or implemented. Conclusion: There is value in a PACS-based dose audit project to provide serial snapshots of patient doses as optimization efforts take place and to revise current knowledge about CT doses. In our opinion, the results call into question whether DRLs or the concept of "achievable dose" are suitable for devising optimization strategies once a certain degree of optimization has taken place. Advances in knowledge: The results reported here suggest that it may be time to take a different approach to optimization, concentrating on tools that are more refined than the DRL, which may have become more of a compliance tool than an aid to optimization. [ABSTRACT FROM AUTHOR]

Modern CT scanners modulate tube current during scans according to patient size, shape and attenuation. However, the ATCM (automatic tube current modulation) systems for different CT manufacturers work on different principles. Although the systems are used for the majority of patients and examinations, there is no standard phantom for routine quality control of CT scanner ATCM operation. The ideal phantom for testing these systems should be capable of evaluating how tube current and image quality as well as dose vary according to changes in patient size and shape. For this study, a conical phantom designed by ImPACT has been compared with two phantoms made from elliptical sections with varying dimensions. The concept of the designs is to reflect the ATCM performance for the varying shapes and dimensions along the length of the human body. The first phantom comprises five elliptical sections with a wide range of different dimensions and the second has three sections that are more similar in size. The phantoms have been used to test ATCM systems for Philips, Siemens, GE and Toshiba scanners. Although the results of the tube current modulation patterns were similar for all CT scanners, the abrupt changes in attenuation for the first sectional phantom provoked an abnormal ATCM response for the GE and Toshiba scanners. The second sectional phantom was developed from the results of the first, and was more effective for ATCM system testing and could be used for dose and image quality assessment in standard positions. However, the ImPACT conical phantom provided the best overall assessment of performance in terms of tube current modulations and noise pattern. [ABSTRACT FROM AUTHOR]

Computed tomography (CT) performance assessments relating to patient dose to the body are made conventionally in 320 mm diameter cylindrical acrylic phantoms. The cross section of the human trunk is closer to an ellipse and automatic tube current modulation (ATCM) systems adjust the exposure level with orientation in the x-y plane, changing the dose distribution within the body. This study has investigated differences in the distributions of dose within a standard cylindrical body phantom and an elliptical dosimetry phantom for Toshiba, General Electric and Philips CT scanners, and recorded changes with the application of the ATCM. Single slice dose profiles have been recorded within the phantoms using Gafchromic film. CT dose indices along 100 mm lengths have been calculated and data sets combined to simulate helical scans, from which values for cumulative doses have been derived. The doses in the centre of the elliptical phantom are 70-100% larger than for the cylindrical one and in the anterior are around 20-40% larger, while the doses in the lateral positions are similar for the two phantom shapes. The differences between the anterior and lateral doses were larger for the Toshiba scanner and this is thought to be linked to the narrower profile of the beam produced by the bow-tie filter. When the ATCM mode for the Toshiba scanner is implemented, the doses in the anterior and posterior positions are reduced preferentially, bringing them closer to the doses in the lateral positions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We have recently described the N-terminal RAS association domain family of genes, RASSF7-10. Previously, we cloned the N-terminal RASSF10 gene and demonstrated frequent methylation of the associated 5′-CpG island in acute lymphoblastic leukemia. To characterize RASSF10 gene expression, we demonstrate that in developing Xenopus embryos, RASSF10 shows a very striking pattern in the rhombencephalon (hind brain). It is also expressed in other parts of the brain and other organs. Due to the well-defined expression pattern in the brain of Xenopus embryos, we analyzed the methylation status of the RASSF10-associated 5′-CpG island in astrocytic gliomas. RASSF10 was frequently methylated in WHO grade II-III astrocytomas and WHO grade IV primary glioblastomas (67.5%), but was unmethylated in grade I astrocytomas and in DNA from age matched control brain samples. RASSF10 gene expression both at the mRNA and protein levels could be switched back on in methylated glioma cell lines after treatment with 5-aza-2′-deoxycytidine. In secondary glioblastomas (sGBM), RASSF10 methylation was an independent prognostic factor associated with worst progression-free survival and overall survival and occurred at an early stage in their development. In cell culture experiments, overexpression of RASSF10 mediated a reduction in the colony forming ability of two RASSF10-methylated glioma cell lines. Conversely, RNAi-mediated knockdown of RASSF10-stimulated anchorage-independent growth of U87 glioma cells, increased their viability and caused an increase in the cells' proliferative ability. We generated and characterized a RASSF10-specific antibody and demonstrated for the first time that RASSF10 subcellular localization is cell-cycle dependent with RASSF10 colocalizing to centrosomes and associated microtubules during mitosis. This is the first report demonstrating that RASSF10 can act as a tumor suppressor gene and is frequently methylated in gliomas and can potentially be developed into a prognostic marker for sGBM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Promoter region hypermethylation and transcriptional silencing is a frequent cause of tumour suppressor gene (TSG) inactivation in many human cancers. Previously, to identify candidate epigenetically inactivated TSGs in renal cell carcinoma (RCC), we monitored changes in gene expression in four RCC cell lines after treatment with the demethylating agent 5-azacytidine. This enabled us to identify HAI-2/SPINT2 as a novel epigenetically inactivated candidate RCC TSG. To identify further candidate TSGs, we undertook bioinformatic and molecular genetic evaluation of a further 60 genes differentially expressed after demethylation. In addition to HAI-2/SPINT2, four genes (PLAU, CDH1, IGFB3 and MT1G) had previously been shown to undergo promoter methylation in RCC. After bioinformatic prioritisation, expression and/or methylation analysis of RCC cell lines+/-primary tumours was performed for 34 genes. KRT19 and CXCL16 were methylated in RCC cell lines and primary RCC; however, 22 genes were differentially expressed after demethylation but did not show primary tumour-specific methylation (methylated in normal tissue (n=1); methylated only in RCC cell lines (n=9) and not methylated in RCC cell lines (n=12)). Re-expression of CXCL16 reduced growth of an RCC cell line in vitro. In a summary, a functional epigenomic analysis of four RCC cell lines using microarrays representing 11 000 human genes yielded both known and novel candidate TSGs epigenetically inactivated in RCC, suggesting that this is valid strategy for the identification of novel TSGs and biomarkers. [ABSTRACT FROM AUTHOR]

A range of techniques has been developed in conventional radiography for the chest, because of technical difficulties in imaging the wide variation of tissue densities. These techniques can differ significantly in tube potential selection, for scatter reduction and in application of manual or automatic exposure control. In this study a geometric chest phantom designed to simulate a chest image, has been used to study image quality on an indirect digital radiography (DR) system. Relative values for the signal-to-noise ratio (SNR), have been derived from analysis of contrast detail objects within the lung, heart and subdiaphragm regions of the phantom. Results showing the variation in SNR and detail perception with tube potential are presented for three radiographic techniques: using a grid, an air gap and no scatter reduction. SNR measurements provided a useful objective measure for assessment of image quality for optimising DR systems. [ABSTRACT FROM AUTHOR]

Automatic exposure controls (AECs) used with computed radiography (CR) equipment need to be set for a constant signal level in the resultant images. The response varies with the energy of the X-ray beam in a different way from conventional film screen combinations. Dose to the imaging receptor has been employed in adjustment of the AECs for varying exposure conditions for CR systems installed in hospitals in the west of Scotland. However, other parameters could potentially be applied. In this study, three quantifies have been investigated for use in setting the AEC function: the exposure indicator defined by the CR manufacturer, dose to the image receptor and image noise. Experiences gained in setting up the systems are described and results of a patient dose survey are reported. [ABSTRACT FROM AUTHOR]

Epigenetic alterations in the 11p15.5 imprinted gene cluster are frequent in human cancers and are associated with disordered imprinting of insulin-like growth factor (IGF)2 and H19. Recently, an imprinted gene cluster at 14q32 has been defined and includes two closely linked but reciprocally imprinted genes, DLK1 and GTL2, that have similarities to IGF2 and H19, respectively. Both GTL2 and H19 are maternally expressed RNAs with no protein product and display paternal allele promoter region methylation, and DLK1 and IGF2 are both paternally expressed. To determine whether methylation alterations within the 14q32 imprinted domain occur in human tumorigenesis, we investigated the status of the GTL2 promoter differentially methylated region (DMR) in 20 neuroblastoma tumours, 20 phaeochromocytomas and, 40 Wilms'tumours. Hypermethylation of the GTL2 promoter DMR was detected in 25%of neuroblastomas, 10%of phaeochromocytoma and 2.5%of Wilms'tumours. Tumours with GTL2 promoter DMR hypermethylation also demonstrated hypermethylation at an upstream intergenic DMR thought to represent a germline imprinting control element. Analysis of neuroblastoma cell lines revealed that GTL2 DMR hypermethylation was associated with transcriptional repression of GTL2. These epigenetic findings are similar to those reported in Wilms'tumours in which H19 repression and DMR hypermethylation is associated with loss of imprinting (LOI, biallelic expression) of IGF2. However, a neuroblastoma cell line with hypermethylation of the GTL2 promoter and intergenic DMR did not show LOI of DLK1 and although treatment with a demethylating agent restored GTL2 expression and reduced DLK1 expression. As described for IGF2/H19, epigenetic changes at DLK1/GTL2 occur in human cancers. However, these changes are not associated with DLK1 LOI highlighting differences in the imprinting control mechanisms operating in the IGF2-H19 and DLK1-GTL2 domains. GTL2 promoter and intergenic DMR hypermethylation is associated with the loss of GTL2 expression and this may contribute to tumorigenesis in a subset of human cancers.British Journal of Cancer (2005) 92, 1574-1580. doi:10.1038/sj.bjc.6602478 www.bjcancer.com Published online 29 March 2005 [ABSTRACT FROM AUTHOR]

Germline mutations in the succinate dehydrogenase (SDH) (mitochondrial respiratory chain complex II) subunit B gene, SDHB, cause susceptibility to head and neck paraganglioma and phaeochromocytoma. Previously, we did not identify somatic SDHB mutations in sporadic phaeochromocytoma, but SDHB maps to 1p36, a region of frequent loss of heterozygosity (LOH) in neuroblastoma as well. Hence, to evaluate SDHB as a candidate neuroblastoma tumour suppressor gene (TSG) we performed mutation analysis in 46 primary neuroblastomas by direct sequencing, but did not identify germline or somatic SDHB mutations. As TSGs such as RASSF1A are frequently inactivated by promoter region hypermethylation, we designed a methylation-sensitive PCR-based assay to detect SDHB promoter region methylation. In 21% of primary neuroblastomas and 32% of phaeochromocytomas (32%) methylated (and unmethylated) alleles were detected. Although promoter region methylation was also detected in two neuroblastoma cell lines, this was not associated with silencing of SDHB expression, and treatment with a demethylating agent (5-azacytidine) did not increase SDH activity. These findings suggest that although germline SDHB mutations are an important cause of phaeochromocytoma susceptibility, somatic inactivation of SDHB does not have a major role in sporadic neural crest tumours and SDHB is not the target of 1p36 allele loss in neuroblastoma and phaeochromocytoma. [ABSTRACT FROM AUTHOR]

Background: Overexpression of the hypoxia inducible factor 1 (HIF-1) and HIF-2 transcription factors and the consequent upregulation of hypoxia inducible mRNAs is a feature of many human cancers and may be unrelated to tissue hypoxia. Thus, the YHI (von Hippel-Lindau) tumour suppressor gene (TSG) regulates HIF-1 and HIF-2 expression in normoxia by targeting the cc subunits for ubiquitination and proteolysis. Inactivation of the VHL TSG in VHL tumours and in sporadic clear cell renal cell carcinoma (RCC) results in overexpression of HIF-1 ond HIF-2. However, RCC without YHI inactivation may demonstrate HIF upregulation, suggesting that VHL independent pathways far HIF activation also exist. In RCC, three candidate HF activating genes exist-FIH-1 (factor inhibiting HIF), SDL-IB, and FH-which may be dependent or independent of VHL inactivation. Aims: To investigate FIH-1, SDHB, and FH for somatic mutations in sporadic RCC. Methods: Gene mutation was analysed in primary RCCs (clear cell RCCs, papillary RCCs, and oncocytomas) and RCC cell lines. SDHB mutation analysis was performed by denaturing high performance liquid chromatography followed by direct sequencing of aberrant PCR products. FH and FIH- 1 mutation analysis were performed by single stranded conformational polymorphism and direct sequencing of PCR products. Results: No mutations were identified in the three genes investigated. Conclusions: There was no evidence to suggest that somatic mutations occur in the FH, FIH-1, or SDHB TSGs in sporadic RCCs. [ABSTRACT FROM AUTHOR]

The 3p21.3 RASSF1A tumour suppressor gene (TSG) provides a paradigm for TSGs inactivated by promoter methylation rather than somatic mutations. Recently, we identified frequent promoter methylation without somatic mutations of SLIT2 in lung and breast cancers, suggesting similarities between SLIT2 and RASSF1A TSGs. Epigenetic inactivation of RASSF1A was first described in lung and breast cancers and subsequently in a wide range of human cancers including neuroblastoma, Wilms' tumour and renal cell carcinoma (RCC). These findings prompted us to investigate SLIT2 methylation in these three human cancers. We analysed 49 neuroblastomas (NBs), 37 Wilms' tumours and 48 RCC, and detected SLIT2 promoter methylation in 29% of NB, 38% of Wilms' tumours and 25% of RCC. Previously, we had demonstrated frequent RASSF1A methylation in the same tumour series and frequent CASP8 methylation in the NB and Wilms' tumour samples. However, there was no significant association between SLIT2 promoter methylation and RASSF1A or CASP8 methylation in NB and RCC. In Wilms' tumour, there was a trend for a negative association between RASSF1A and SLIT2 methylation, although this did not reach statistical significance. No associations were detected between SLIT2 promoter methylation and specific clinicopathological features in the tumours analysed. These findings implicate SLIT2 promoter methylation in the pathogenesis of both paediatric and adult cancers and suggest that further investigations of SLIT2 in other tumour types should be pursued. However, epigenetic inactivation of SLIT2 is less frequent than RASSF1A in the tumour types analysed.British Journal of Cancer (2004) 90, 515-521. doi:10.1038/sj.bjc.6601447 www.bjcancer.com [ABSTRACT FROM AUTHOR]

Germline mutations in the BHD gene cause the dominantly inherited cancer susceptibility disorder, Birt-Hogg-Dubé (BHD) syndrome. Individuals with BHD are reported to have an increased risk of renal cell carcinoma (RCC) and of colorectql polyps and cancer. The BHD gene maps to 17p11.2, and to investigate whether somatic inactivation of the BHD gene region is implicated in the pathogenesis of sporadic RCC and colorectal caner (CRC), we performed mutation analysis in 30 RCC primary tumours and cell lines, and 35 CRCs and cell lines. A somatic missense mutation (Ala444Ser) with loss of the wild type allele (consistent with a two hit mechanism of tumorigenesis) was detected in a primary clear cell RCC, and a further missense mutation (Ala238Val) was identified in a clear cell RCC cell line for which matched normal DNA was not available. A somatic missense substitution (Arg392Gly) was identified in a primary CRC, and the same change was detected in three RCCs (all oncocytomas) for which matched normal DNA was not available. A somatic missense substitution (Arg392Gly) was identified in a primary CRC, and the same change was detected in three RCCs (all oncocytomas) for which matched normal DNA was not available. A germline Arg320Gln missense variant detected in a primary CRC was not detected in 40 control individuals or in a further 159 familial and sporadic CRC cases. However, AA homozygotes for an intronic single nucleotide polymorphism (c. 1517+6 G →A) were under-represented in familial cases compared with controls (p=0.03). For some tumour suppressor genes, epigenetic silencing is a more common mechanism of inactivation tan somatic mutations. However, we did not detect evidence of epigenetic silencing of BHD in 19 CRC and RCC cell lines, and BHD promoter region hypermethylation was not detected in 20 primary RCCs. These findings suggest that BHD inactivation occurs in a subset of clear cell RCC and CRC. [ABSTRACT FROM AUTHOR]

We report on the development of a trapped-ion, microwave frequency standard based on the 12.6 GHz hyperfine transition in laser-cooled ytterbium-171 ions. The entire system fits into a 6U 19-in. rack unit (51 × 49 × 28 cm) and comprises laser, electronics, and physics package subsystems. As a first step towards a full evaluation of the system capability, we have measured the frequency instability of our system which is 3.6 × 10 - 12 / √ τ for averaging times between 30 and 1500 s . [ABSTRACT FROM AUTHOR]

Automatic tube current modulation (ATCM) systems are now used for the majority of CT scans. The principles of ATCM operation are different in CT scanners from different manufacturers. Toshiba and GE scanners base the current modulation on a target noise setting, while Philips and Siemens scanners use reference image and reference mAs concepts respectively. Knowledge of the relationships between patient size, dose and image noise are important for CT patient dose optimisation. In this study, the CT patient doses were surveyed for 14 CT scanners from four different CT scanner manufacturers. The patient cross sectional area, the tube current modulation and the image noise from the CT images were analysed using in-house software. The Toshiba and GE scanner results showed that noise levels are relatively constant but tube currents are dependent on patient size. As a result of this there is a wide range in tube current values across different patient sizes, and doses for large patients are significantly higher in these scanners. In contrast, in the Philips and Siemens scanners, tube currents are less dependent on patient size, the range in tube current is narrower, and the doses for larger patients are not as high. Image noise is more dependent on the patient size. [ABSTRACT FROM AUTHOR]

Presents the abstract "Functional Epigenomics Identifies Hepatocyte Growth Factor Activator Inhibitor Type 2/SPINT2 as a Frequently Inactivated Tumour Suppressor in Papillary and Clear Cell Renal Cell Carcinoma," by Mark Morris, D. Gentle, M. Abdulrahman, E. N. Maina, K. Gupta, R. E. Banks, M. S. Wiesener, T. Kishida, Y. Masahiro, B. Teh, F. Latif, and E. R. Maher.

Presents an abstract of the article "Mapping of an Renal Cell Carcinoma (RCC) Associated (3;6) Translocation and Identification of RCC Candidate Genes," by Mahera Adulrahman, R. E. Foster, M. R. Morris, E. Prigmore, S. Gribble, D. Gentle, C. Chu, P. M. T. Weston, V. Davison, N. Carter, F. Latif., and E. R. Maher.

Epigenetic inactivation of TSGs by promoter methylation has emerged as a major mechanism of TSG inactivation in human cancers. To date we have demonstrated that RASSF1A, DAPK and CASP 8 are methylated in >20% of primary renal cell carcinoma. In order to identify novel candidate TSGs epigenetically inactivated in RCC we have performed microarray expression analysis on 4 RCC cell lines before and after treatment with the demethylating agent 5-azacytidine. A total of 11,000 genes were analysed. >500 genes demonstrated a >two-fold change in expression in at least 1 RCC cell line. Candidate TSGs were prioritised according to: 1. Significant upregulation after demethylation, 2. Presence of 5' CpG islands, 3. Reports of epigenetic inactivation in non-RCC human cancers and 4. Function (if known). Results of microarray expression analysis were confirmed by RTPCR. 40 candidate TSGs were selected for further investigation by expression and promoter methylation analysis in further RCC cell lines and in primary RCC. 25 of the genes have been evaluated for expression in a larger set of RCC cell lines and 15 demonstrate downregulation in >20% of cell lines. To date, two genes have been analysed for methylation in cell lines and these demonstrated methylation in 22% and 33% respectively. These investigations will enable us to evaluate this strategy to identify novel RCC TSGs. [ABSTRACT FROM AUTHOR]

Germline mutations in the BHD gene cause the dominantly inherited cancer susceptibility disorder, Birt-Hogg-DubÚ (BHD) syndrome. Individuals with BHD are reported to have an increased risk of renal cell carcinoma and colorectal polyps and cancer. The BHD gene maps to 17p11.2 and to investigate whether somatic inactivation of the BHD gene region is implicated in the pathogenesis of sporadic RCC and colorectal cancer, we performed mutation analysis in 30 RCC primary tumours and cell lines and 35 colorectal cancers and cell lines. A somatic missense mutation (A444S) with loss of the wild type allele (consistent with Knudson's two-hit hypothesis) was detected in a primary clear cell RCC and a further missense mutation (A238V) was identified in clear cell RCC cell line for which matched normal DNA was not available. A somatic missense substitution (R392G) was identified in a primary colorectal cancer and the same change was detected in 3/6 oncocytomas tested for which matched normal DNA was not available. A germline R320Q missense variant detected in a primary colorectal cancer was not detected in 40 control individuals. For some TSGs, epigenetic silencing is a more common mechanism of inactivation. No evidence of epigenetic silencing of BHD was detected in 19 colorectal cancer and RCC cell lines, and BHD promoter region hypermethylation was not detected in 20 primary RCC. These findings suggest that BHD inactivation occurs in a subset of clear cell RCC and colorectal cancer. [ABSTRACT FROM AUTHOR]