Introduction: Localization studies are mandatory prior to revision surgery in patients with persistent hyperparathyroidism in order to improve surgical outcome and reduce the risk of lengthy... Show moreIntroduction: Localization studies are mandatory prior to revision surgery in patients with persistent hyperparathyroidism in order to improve surgical outcome and reduce the risk of lengthy explorations. However, in this case, noninvasive localization studies are reported to have a poor sensitivity. The aim of our study is to determine the accuracy of selective venous sampling (SVS) for parathyroid hormone (PTH) in localizing residual hyperactive parathyroid glands in patients with persistent or recurrent hyperparathyroidism. Patients and methods: We retrospectively evaluated the localizing accuracy of 20 PTH SVS performed prior to revision surgery in 18 patients with persistent or recurrent primary hyperparathyroidism (n=11) or autonomous (tertiary) hyperparathyroidism (n=7). Tc99m-methoxy-isobutyle-isonitrile (MIBI)-single photon emission computed tomography (SPECT) was also performed in all patients prior to revision surgery. Operative and pathological data were obtained from hospital records. Results: The SVS was able to accurately localize 15 of the 20 pathological glands removed at revision surgery, representing a sensitivity of 75%. This sensitivity is significantly higher than that of Tc99m-MIBI-SPECT, which was only 30% (P=0.012). Conclusion: Our findings demonstrate that SVS is a valuable localization study in patients with persistent or recurrent hyperparathyroidism, with a sensitivity significantly higher than that of Tc99m-MIBI-SPECT. Our data suggest that SVS represents a useful addition to the preoperative workup of these patients prior to revision surgery. Show less
Tejpar, S.; Bertagnolli, M.; Bosman, F.; Lenz, H.J.; Garraway, L.; Waldman, F.; ... ; Roth, A. 2010
The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups... Show moreThe number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era. The Oncologist 2010; 15: 390-404 Show less
Background: Accurate staging of colorectal cancer (CRC) with clinicopathological parameters is important for predicting prognosis and guiding treatment but provides no information about organ site... Show moreBackground: Accurate staging of colorectal cancer (CRC) with clinicopathological parameters is important for predicting prognosis and guiding treatment but provides no information about organ site of metastases. Patterns of genomic aberrations in primary colorectal tumors may reveal a chromosomal signature for organ specific metastases. Methods: Array Comparative Genomic Hybridization (aCGH) was employed to asses DNA copy number changes in primary colorectal tumors of three distinctive patient groups. This included formalin-fixed, paraffin-embedded tissue of patients who developed liver metastases (LM; n = 36), metastases (PM; n = 37) and a group that remained metastases-free (M0; n = 25). A novel statistical method for identifying recurrent copy number changes, KC-SMART, was used to find specific locations of genomic aberrations specific for various groups. We created a classifier for organ specific metastases based on the aCGH data using Prediction Analysis for Microarrays (PAM). Results: Specifically in the tumors of primary CRC patients who subsequently developed liver metastasis, KC-SMART analysis identified genomic aberrations on chromosome 20q. LM-PAM, a shrunken centroids classifier for liver metastases occurrence, was able to distinguish the LM group from the other groups (M0&PM) with 80% accuracy (78% sensitivity and 86% specificity). The classification is predominantly based on chromosome 20q aberrations. Conclusion: Liver specific CRC metastases may be predicted with a high accuracy based on specific genomic aberrations in the primary CRC tumor. The ability to predict the site of metastases is important for improvement of personalized patient management. Show less
Microsatellite instability (MSI) and genomic hypermethylation of methylated-in-tumor (MINT) loci are both strong prognostic indicators in a subgroup of patients with sporadic colorectal cancer (CRC... Show moreMicrosatellite instability (MSI) and genomic hypermethylation of methylated-in-tumor (MINT) loci are both strong prognostic indicators in a subgroup of patients with sporadic colorectal cancer (CRC). The present study was designed to determine whether the methylation of MINT loci during the progression of adenoma to CRC is related to MSI in CRC cases. Methylation index (MI) was measured by absolute quantitative assessment of methylated alleles at seven MINT loci in primary CRC with contiguous adenomatous and normal tissues of 79 patients. Results were then validated in primary CRC tissues from an independent group of 54 patients. Increased MI of both MINT loci 1 and 31 was significantly associated with MSI in CRC and was specific for adenoma. Total MI and the number of methylated loci were threefold (P = 0.02) and fivefold (P = 0.004) higher, respectively, in adenomas associated with microsatellitestable CRC versus microsatellite-unstable CRC. MINT MI was found to be correlated with mismatch repair protein expression, MSI, BRAF (V600E) mutation status, mut-L homologue 1 methylation status, and disease-specific survival in the second independent validation group of patients. MI of specific MINT loci may be prognostic indicators of colorectal adenomas that will develop into sporadic microsatellite-unstable CRCs. Increased MINT locus methylation appears to precede MSI and may have utility in defining clinical pathology in the absence of features of malignant invasive tumors. (Am J pathol 2010, 177:2347-2356; DOI: 10.2353/ajpath.2010.091103) Show less
Background MUTYH-associated polyposis is a recessively inherited disorder characterized by a lifetime risk of colorectal cancer that is up to 100%. Because specific histological and molecular... Show moreBackground MUTYH-associated polyposis is a recessively inherited disorder characterized by a lifetime risk of colorectal cancer that is up to 100%. Because specific histological and molecular genetic features of MUTYH-associated polyposis colorectal cancers might influence tumor behavior and patient survival, we compared survival between patients with MUTYH-associated polyposis colorectal cancer and matched control patients with colorectal cancer from the general population. Methods In this retrospective multicenter cohort study from Europe, 147 patients with MUTYH-associated polyposis colorectal cancer were compared with 272 population-based control patients with colorectal cancer who were matched for country, age at diagnosis, year of diagnosis, stage, and subsite of colorectal cancer. Kaplan-Meier survival and Cox regression analyses were used to compare survival between patients with MUTYH-associated polyposis colorectal cancer and control patients with colorectal cancer. All statistical tests were two-sided. Results Five-year survival for patients with MUTYH-associated polyposis colorectal cancer was 78% (95% confidence interval [CI] = 70% to 84%) and for control patients was 63% (95% CI = 56% to 69%) (log-rank test, P = .002). After adjustment for differences in age, stage, sex, subsite, country, and year of diagnosis, survival remained better for MUTYH-associated polyposis colorectal cancer patients than for control patients (hazard ratio of death = 0.48, 95% CI = 0.32 to 0.72). Conclusions In a European study cohort, we found statistically significantly better survival for patients with MUTYH-associated polyposis colorectal cancer than for matched control patients with colorectal cancer. Show less
Mesker, W.; Johnstone, E.; Huijbers, A.; Pelt, G. van; Midgley, R.; Morreau, H.; ... ; Tollenaar, R. 2010
Common genetic variation at human 8q23.3 is significantly associated with colorectal cancer (CRC) risk. To elucidate the basis of this association we compared the frequency of common variants at... Show moreCommon genetic variation at human 8q23.3 is significantly associated with colorectal cancer (CRC) risk. To elucidate the basis of this association we compared the frequency of common variants at 8q23.3 in 1,964 CRC cases and 2,081 healthy controls. Reporter gene studies showed that the single nucleotide polymorphism rs16888589 acts as an allele-specific transcriptional repressor. Chromosome conformation capture (3C) analysis demonstrated that the genomic region harboring rs16888589 interacts with the promoter of gene for eukaryotic translation initiation factor 3, subunit H (EIF3H). We show that increased expression of EIF3H gene increases CRC growth and invasiveness thereby providing a biological mechanism for the 8q23.3 association. These data provide evidence for a functional basis for the non-coding risk variant rs16888589 at 8q23.3 and provides novel insight into the etiological basis of CRC. Show less
Middeldorp, A.; Jagmohan-Changur, S.C.; Klift, H.M. van der; Puijenbroek, M. van; Houwing-Duistermaat, J.J.; Webb, E.; ... ; Wijnen, J. 2010
Approximately 40% of colorectal cancer (CRC) families with a diagnosis of hereditary nonpolyposis CRC on the basis of clinical criteria are not a consequence of mismatch repair (MMR) deficiency.... Show moreApproximately 40% of colorectal cancer (CRC) families with a diagnosis of hereditary nonpolyposis CRC on the basis of clinical criteria are not a consequence of mismatch repair (MMR) deficiency. Such families provide supporting evidence for the existence of a hitherto unidentified highly penetrant gene mutation. To gain further understanding of MMR-competent familial colorectal cancer (FCC), we studied seven large families with an unexplained predisposition for CRC to identify genetic regions that could harbor CRC risk factors. First, we conducted a genome-wide linkage scan using 10K single-nucleotide polymorphism (SNP) arrays to search for disease loci. Second, we studied the genomic profiles of the tumors of affected family members to identify commonly altered genomic regions likely to harbor tumor suppressor genes. Finally, we studied the possible role of recently identified low-risk variants in the familial aggregation of CRC in these families. Linkage analysis did not reveal clear regions of linkage to CRC. However, our results provide support linkage to 3q, a region that has previously been linked to CRC susceptibility. Tumor profiling did not reveal any genomic regions commonly targeted in the tumors studied here. Overall, the genomic profiles of the tumors show some resemblance to sporadic CRC, but additional aberrations were also present. Furthermore, the FCC families did not appear to have an enrichment of low-risk CRC susceptibility loci. These data suggest that factors other than a highly penetrant risk factor, such as low or moderate-penetrance risk factors, may explain the increased cancer risk in a subset of familial CRCs. (C) 2010 Wiley-Liss, Inc. Show less
Background: Germline mutations of the succinate dehydrogenase subunit B gene (SDHB) predispose carriers for paragangliomas, and current estimates of the chance of mutation carriers actually... Show moreBackground: Germline mutations of the succinate dehydrogenase subunit B gene (SDHB) predispose carriers for paragangliomas, and current estimates of the chance of mutation carriers actually developing tumors (penetrance) are high. We evaluate the phenotype and penetrance of a germline SDHB mutation in a large and clinically well-characterized paraganglioma family. Methods: Following identification of the mutation in a 31 year old index-patient, extensive clinical screening was performed in mutation carriers to evaluate the presence of head and neck, thoracic and abdominal paragangliomas. Presymptomatic DNA testing was performed in 19 family members. Results: DNA analysis detected 14 further SDHB mutation carriers. Three mutation carriers (median age 78 years) declined clinical surveillance, but had no clinical signs or symptoms associated with paragangliomas. The remaining 11 mutation carriers (mean age 53, range 37-76 years) consented to clinical screening. In only two, aged 43 and 48 years, were subclinical vagal paragangliomas identified. Conclusions: Only three of the fifteen mutation carriers in this family have developed paraganglioma, which results in a calculated penetrance of 26% at 48 years of age. This figure is lower than current estimates, and we conclude that the co-operation of this family allowed an almost complete attainment of mutation carriers, and the extensive clinical evaluation carried out allowed us to identify all affected individuals. Show less
Up to 30% of stage II patients with curatively resected colorectal cancer (CRC) will develop disease recurrence. We evaluated whether examination of lymph nodes by multilevel sectioning and... Show moreUp to 30% of stage II patients with curatively resected colorectal cancer (CRC) will develop disease recurrence. We evaluated whether examination of lymph nodes by multilevel sectioning and immunohistochemical staining can improve prognostication. Lymph nodes (n = 780) from 36 CRC patients who had developed disease recurrence (cases) and 72 patients who showed no recurrence of disease for at least 5 years (controls) were analyzed. Sections of 4 levels at 200-mu m interval were immunohistochemically stained for cytokeratin expression. The first level was analyzed by conventional and automated microscopy, and the 3 following levels were analyzed by automated microscopy for the presence of tumor cells. Overall, cases showed more micrometastases (3 patients) than controls (1 patient). Analysis of a second level led to the additional detection of 1 patient with micrometastases (case) and 1 patient with macrometastasis (case). Examining more levels only led to additional isolated tumor cells, which were equally divided between cases and controls. Likewise, automated microscopy resulted only in detection of additional isolated tumor cells when compared with conventional microscopy. In multivariate analysis, micrometastases [odds ratio (OR) 26.3, 95% confidence interval (CI) 1.9-364.8, p = 0.015], T4 stage (OR 4.8, 95% CI 1.4-16.7, p = 0.013) and number of lymph nodes (OR 0.9, 95% CI 0.8-1.0, p = 0.028) were independent predictors for disease recurrence. Lymph node analysis of 2 levels and immunohistochemical staining add to the detection of macrometastases and micrometastases in CRC. Micrometastases were found to be an independent predictor of disease recurrence. Isolated tumor cells were of no prognostic significance. Show less
Heterozygous mutations in PMS2 are involved in Lynch syndrome, whereas biallelic mutations are found in Constitutional mismatch repair-deficiency syndrome patients. Mutation detection is... Show moreHeterozygous mutations in PMS2 are involved in Lynch syndrome, whereas biallelic mutations are found in Constitutional mismatch repair-deficiency syndrome patients. Mutation detection is complicated by the occurrence of sequence exchange events between the duplicated regions of PMS2 and PMS2CL. We investigated the frequency of such events with a nonspecific polymerase chain reaction (PCR) strategy, coamplifying both PMS2 and PMS2CL sequences. This allowed us to score ratios between gene and pseudogene-specific nucleotides at 29 PSV sites from exon 11 to the end of the gene. We found sequence transfer at all investigated PSVs from intron 12 to the 3' end of the gene in 4 to 52% of DNA samples. Overall, sequence exchange between PMS2 and PMS2CL was observed in 69% (83/120) of individuals. We demonstrate that mutation scanning with PMS2-specific PCR primers and MLPA probes, designed on PSVs, in the 3' duplicated region is unreliable, and present an RNA-based mutation detection strategy to improve reliability. Using this strategy, we found 19 different putative pathogenic PMS2 mutations. Four of these (21%) are lying in the region with frequent sequence transfer and are missed or called incorrectly as homozygous with several PSV-based mutation detection methods. Hum Mutat 31:578-587, 2010. (C) 2010 Wiley-Liss, Inc. Show less
Purpose: Risk assessment for locoregional disease recurrence would be highly valuable in preoperative treatment planning for patients undergoing primary rectal tumor resection. Epigenetic... Show morePurpose: Risk assessment for locoregional disease recurrence would be highly valuable in preoperative treatment planning for patients undergoing primary rectal tumor resection. Epigenetic aberrations such as DNA methylation have been shown to be significant prognostic biomarkers of disease outcome. In this study, we evaluated the significance of a quantitative epigenetic multimarker panel analysis of primary tumors to predict local recurrence in rectal cancer patients from a retrospective multicenter clinical trial. Experimental Design: Primary tumors were studied from patients enrolled in the trial who underwent total mesorectal excision for rectal cancer (n = 325). Methylation levels of seven methylated-in-tumor (MINT) loci were assessed by absolute quantitative assessment of methylated alleles. Unsupervised random forest clustering of quantitative MINT methylation data was used to show subclassification into groups with matching methylation profiles. Results: Variable importance parameters [Gini-Index (GI)] of the clustering algorithm indicated MINT3 and MINT17 (GI, 20.2 and 20.7, respectively) to be informative for patient grouping compared with the other MINT loci (highest GI, 12.2). When using this two-biomarker panel, four different patient clusters were identified. One cluster containing 73% (184 of 251) of the patients was at significantly increased risk of local recurrence (hazard ratio, 10.23; 95% confidence interval, 1.38-75.91) in multivariate analysis, corrected for standard prognostic factors of rectal cancer. This group showed a significantly higher local recurrence probability than patients receiving preoperative radiation (P < 0.0001). Conclusion: Quantitative epigenetic subclassification of rectal cancers has clinical utility in distinguishing tumors with increased risk for local recurrence and may help tailor treatment regimens for locoregional control. Clin Cancer Res; 16(10); 2811-8. (C) 2010 AACR. Show less
Roon, E.H.J. van; Puijenbroek, M. van; Middeldorp, A.; Eijk, R. van; Meijer, E.J. de; Erasmus, D.; ... ; Morreau, H. 2010
Background: To investigate the etiology of MLH1 promoter methylation in mismatch repair (MMR) mutation-negative early onset MSI-H colon cancer. As this type of colon cancer is associated with high... Show moreBackground: To investigate the etiology of MLH1 promoter methylation in mismatch repair (MMR) mutation-negative early onset MSI-H colon cancer. As this type of colon cancer is associated with high ages, young patients bearing this type of malignancy are rare and could provide additional insight into the etiology of sporadic MSI-H colon cancer. Methods: We studied a set of 46 MSI-H colon tumors cases with MLH1 promoter methylation which was enriched for patients with an age of onset below 50 years (n = 13). Tumors were tested for CIMP marker methylation and mutations linked to methylation: BRAF, KRAS, GADD45A and the MLH1 -93G>A polymorphism. When available, normal colon and leukocyte DNA was tested for GADD45A mutations and germline MLH1 methylation. SNP array analysis was performed on a subset of tumors. Results: We identified two cases (33 and 60 years) with MLH1 germline promoter methylation. BRAF mutations were less frequent in colon cancer patients below 50 years relative to patients above 50 years (p-value: 0.044). CIMP-high was infrequent and related to BRAF mutations in patients below 50 years. In comparison with published controls the G>A polymorphism was associated with our cohort. Although similar distribution of the pathogenic A allele was observed in the patients with an age of onset above and below 50 years, the significance for the association was lost for the group under 50 years. GADD45A sequencing yielded an unclassified variant. Tumors from both age groups showed infrequent copy number changes and loss-of-heterozygosity. Conclusion: Somatic or germline GADD45A mutations did not explain sporadic MSI-H colon cancer. Although germline MLH1 methylation was found in two individuals, locus-specific somatic MLH1 hypermethylation explained the majority of sporadic early onset MSI-H colon cancer cases. Our data do not suggest an intrinsic tendency for CpG island hypermethylation in these early onset MSI-H tumors other than through somatic mutation of BRAF. Show less
Drost, M.; Zonneveld, J.B.M.; Dijk, L. van; Morreau, H.; Tops, C.M.; Vasen, H.F.A.; ... ; Wind, N. de 2010
The hereditary colon and endometrium cancer predisposition Lynch Syndrome (also called HNPCC) is caused by a germ-line mutation in one of the DNA mismatch repair (MMR) genes. A significant fraction... Show moreThe hereditary colon and endometrium cancer predisposition Lynch Syndrome (also called HNPCC) is caused by a germ-line mutation in one of the DNA mismatch repair (MMR) genes. A significant fraction of the gene alterations detected in suspected Lynch Syndrome patients is comprised of amino acid substitutions. The relevance for cancer risk of these variants is difficult to assess, as currently no time- and cost-effective, validated, and widely applicable functional assays for the measurement of MMR activity are available. Here we describe a rapid, cell-free, and easily quantifiable MMR activity assay for the diagnostic assessment of variants of the MLH1 MMR protein. This assay allows the parallel generation and functional analysis of a series of variants of the MLH1 protein in vitro using readily available, or preprepared, reagents. Using this assay we have tested 26 MLH1 variants and of these, 15 had lost activity. These results are in concordance with those obtained from first-generation assays and with in silico and pathology data. After its multifocal technical and clinical validation this assay could have great impact for the diagnosis and counseling of carriers of an MLH1 variant and their relatives. Show less
Objective: Cure rate for primary hyperparathyroidism (PHPT) is reported to be 94-100% 1 year after surgery, but recent data suggest recurrence in 4% of the patients 1-5 years post-operatively. The... Show moreObjective: Cure rate for primary hyperparathyroidism (PHPT) is reported to be 94-100% 1 year after surgery, but recent data suggest recurrence in 4% of the patients 1-5 years post-operatively. The aim of our study was to establish the cure rate and its maintenance in the long-term after parathyroidectomy (PTx) in patients with sporadic PHPT. Design: Evaluation of recurrence in patients with sporadic hyperparathyroidism who underwent PTx 1-24 years prior to the study. Patients and methods: We identified 111 patients who underwent initial PTx between 1984 and 2008, and had no MEN-1, MEN-2, or CaR mutation; parathyroid carcinoma; a history of lithium use; or renal failure. Thirty-eight patients were lost to follow-up or were unwilling or unable to participate in the study. Cure was defined as maintenance of normal serum calcium and parathyroid hormone concentrations 6 months after PTx. Results: Cure was achieved in 68 of 73 patients studied (93%) and was sustained in all for 6+/-5 years. Conclusion: The cure rate of sporadic PHPT after initial surgery is 93%. When cure is achieved, this is sustained in 100% of the patients for up to 24 years post-operatively. Our data suggest that closer early follow-up is advocated in all patients undergoing PTx to definitively establish cure and to provide a safety net for those with residual gland pathology. The data do not support the need for long-term follow-up when cure is established 6 months after PTx. Show less
Eijk, R. van; Puijenbroek, M. van; Chhatta, A.R.; Gupta, N.; Vossen, R.H.A.M.; Lips, E.H.; ... ; Wezel, T. van 2010
Kirsten RAS (KRAS) is a small GTPase that plays a key role in Ras/mitogen-activated protein kinase signaling; somatic mutations in KRAS are frequently found in many cancers. The most common KRAS... Show moreKirsten RAS (KRAS) is a small GTPase that plays a key role in Ras/mitogen-activated protein kinase signaling; somatic mutations in KRAS are frequently found in many cancers. The most common KRAS mutations result in a constitutively active protein. Accurate detection of KRAS mutations is pivotal to the molecular diagnosis of cancer and may guide proper treatment selection. Here, we describe a two-step KRAS mutation screening protocol that combines whole-genome amplification (WGA), high-resolution melting analysis (HRM) as a prescreen method for mutation carrying samples, and direct Sanger sequencing of DNA from formalin-fixed, paraffin-embedded (FFPE) tissue, from which limited amounts of DNA are available. We developed target-specific primers, thereby avoiding amplification of homologous KRAS sequences. The addition of herring sperm DNA facilitated WGA in DNA samples isolated from as few ass 100 cells. KRAS mutation screening using high-resolution melting analysis on wgaDNA from formalin-fixed, paraffin-embedded tissue is highly sensitive and specific; additionally, this method is feasible for screening of clinical specimens, as illustrated by our analysis of pancreatic cancers. Furthermore, PCR on wgaDNA does not introduce genotypic changes, as opposed to unamplified genomic DNA. This method can, after validation, be applied to virtually any potentially mutated region in the genome. (J Mol Diagn 2010, 12:27-34; DOI: 10.2353/jmoldx.2010.090028) Show less
Eijk, R. van; Eilers, P.H.C.; Natte, R.; Cleton-Jansen, A.M.; Morreau, H.; Wezel, T. van; Oosting, J. 2010
Background: Multiplex Ligation-Dependent Probe Amplification (MLPA) is an application that can be used for the detection of multiple chromosomal aberrations in a single experiment. In one reaction,... Show moreBackground: Multiplex Ligation-Dependent Probe Amplification (MLPA) is an application that can be used for the detection of multiple chromosomal aberrations in a single experiment. In one reaction, up to 50 different genomic sequences can be analysed. For a reliable work-flow, tools are needed for administrative support, data management, normalisation, visualisation, reporting and interpretation. Results: Here, we developed a data management system, MLPAInter for MLPA interpretation, that is windows executable and has a stand-alone database for monitoring and interpreting the MLPA data stream that is generated from the experimental setup to analysis, quality control and visualisation. A statistical approach is applied for the normalisation and analysis of large series of MLPA traces, making use of multiple control samples and internal controls. Conclusions: MLPAinter visualises MLPA data in plots with information about sample replicates, normalisation settings, and sample characteristics. This integrated approach helps in the automated handling of large series of MLPA data and guarantees a quick and streamlined dataflow from the beginning of an experiment to an authorised report. Show less
It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in... Show moreIt is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT. British Journal of Cancer (2010) 102, 447-454. doi:10.1038/sj.bjc.6605338 www.bjcancer.com Published online 17 November 2009 (C) 2010 Cancer Research UK Show less
