Background & Aims Colorectal cancers (CRCs) diagnosed within a few years after an index colonoscopy can arise from missed lesions or the development of a new tumor. We investigated the proportion, ...characteristics, and factors that predict interval CRCs that develop within 6-60 months of colonoscopy. Methods We performed a population-based cohort study of Utah residents who underwent colonoscopy examinations from 1995 through 2009 at Intermountain Healthcare or the University of Utah Health System, which provide care to more than 85% of state residents. Colonoscopy results were linked with cancer histories from the Utah Population Database to identify patients who underwent colonoscopy 6-60 months before a diagnosis of CRC (interval cancer). Logistic regression was performed to identify risk factors associated with interval cancers. Results Of 126,851 patients who underwent colonoscopies, 2659 were diagnosed with CRC; 6% of these CRCs (159 of 2659) developed within 6 to 60 months of a colonoscopy. Sex and age were not associated with interval CRCs. A higher percentage of patients with interval CRC were found to have adenomas at their index colonoscopy (57.2%), compared with patients found to have CRC detected at colonoscopy (36%) or patients who did not develop cancer (26%) ( P < .001). Interval CRCs tended to be earlier-stage tumors than those detected at index colonoscopy, and to be proximally located (odds ratio, 2.24; P < .001). Patients with interval CRC were more likely to have a family history of CRC (odds ratio, 2.27; P = .008) and had a lower risk of death than patients found to have CRC at their index colonoscopy (hazard ratio, 0.63; P < .001). Conclusions In a population-based study in Utah, 6% of all patients with CRC had interval cancers (cancer that developed within 6 to 60 months of a colonoscopy). Interval CRCs were associated with the proximal colon, earlier-stage cancer, lower risk of death, higher rate of adenoma, and family history of CRC. These findings indicate that interval colorectal tumors may arise as the result of distinct biologic features and/or suboptimal management of polyps at colonoscopy.
Hereditary and Familial Colon Cancer Jasperson, Kory W; Tuohy, Thérèse M; Neklason, Deborah W ...
Gastroenterology,
06/2010, Volume:
138, Issue:
6
Journal Article
Peer reviewed
Open access
Between 2% to 5% of all colon cancers arise in the setting of well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and certain ...hamartomatous polyposis conditions. Each is associated with a high risk of colon cancer. In addition to the syndromes, up to one-third of colon cancers exhibit increased familial risk, likely related to inheritance. A number of less penetrant, but possibly more frequent susceptibility genes have been identified for this level of inheritance. Clarification of predisposing genes allows for accurate risk assessment and more precise screening approaches. This review examines the colon cancer syndromes, their genetics and management, and also the common familial colon cancers with current genetic advances and screening guidelines.
Accurate estimation of recent shared ancestry is important for genetics, evolution, medicine, conservation biology, and forensics. Established methods estimate kinship accurately for first-degree ...through third-degree relatives. We demonstrate that chromosomal segments shared by two individuals due to identity by descent (IBD) provide much additional information about shared ancestry. We developed a maximum-likelihood method for the estimation of recent shared ancestry (ERSA) from the number and lengths of IBD segments derived from high-density SNP or whole-genome sequence data. We used ERSA to estimate relationships from SNP genotypes in 169 individuals from three large, well-defined human pedigrees. ERSA is accurate to within one degree of relationship for 97% of first-degree through fifth-degree relatives and 80% of sixth-degree and seventh-degree relatives. We demonstrate that ERSA's statistical power approaches the maximum theoretical limit imposed by the fact that distant relatives frequently share no DNA through a common ancestor. ERSA greatly expands the range of relationships that can be estimated from genetic data and is implemented in a freely available software package.
Background & Aims Colorectal cancer (CRC) frequently develops in multiple members of the same families, but more data are needed to prepare effective screening guidelines. We quantified the risk of ...CRC and adenomas in first-degree relatives (FDRs) and second-degree relatives and first cousins of individuals with CRC, and stratified risk based on age at cancer diagnosis. Methods We performed a case-control study of Utah residents, 50–80 years old, who underwent colonoscopy from 1995 through 2009. Index cases (exposed to colonoscopy) were colonoscopy patients with a CRC diagnosis. Age- and sex-matched individuals, unexposed to colonoscopy (controls) were selected to form the comparison groups for determining risk in relatives. Colonoscopy results were linked to cancer and pedigree information from the Utah Population Database to investigate familial aggregation of colorectal neoplasia using Cox regression analysis. Results Of 126,936 patients who underwent a colonoscopy, 3804 were diagnosed with CRC and defined the index cases. FDRs had an increased risk of CRC (hazard rate ratio HRR, 1.79; 95% confidence interval CI,1.59–2.03), as did second-degree relatives (HRR, 1.32; 95% CI, 1.19–1.47) and first cousins (HRR, 1.15; 95% CI, 1.07–1.25), compared with relatives of controls. This risk was greater for FDRs when index patients developed CRC at younger than age 60 years (HRR, 2.11; 95% CI, 1.70–2.63), compared with older than age 60 years (HRR, 1.77; 95% CI, 1.58–1.99). The risk of adenomas (HRR, 1.82; 95% CI, 1.66–2.00) and adenomas with villous histology (HRR, 2.43; 95% CI, 1.96–3.01) also were increased in FDRs. Three percent of CRCs in FDRs would have been missed if the current guidelines, which stratify screening recommendations by the age of the proband, were strictly followed. Conclusions FDRs, second-degree relatives, and first cousins of patients who undergo colonoscopy and are found to have CRC have a significant increase in the risk of colorectal neoplasia. These data should be considered when establishing CRC screening guidelines for individuals and families.
Patients diagnosed with colorectal cancer (CRC) are at risk for synchronous and metachronous lesions at the time of diagnosis or during follow-up evaluation. We performed a population-based study to ...evaluate the rate, predictors, and familial risk for synchronous and metachronous CRC in Utah.
All newly diagnosed cases of CRC between 1980 and 2010 were obtained from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database.
Of the 18,782 patients diagnosed with CRC, 134 were diagnosed with synchronous CRC (0.71%) and 300 were diagnosed with metachronous CRC (1.60%). The risk for synchronous CRC was significantly higher in men (odds ratio OR, 1.45; 95% confidence interval CI, 1.02-2.06) and in patients aged 65 years or older (OR, 1.50; 95% CI, 1.02-2.21). Synchronous CRCs were located more often in the proximal colon (OR, 1.70; 95% CI, 1.20-2.41). First-degree relatives of cases with synchronous (OR, 1.86; 95% CI, 1.37-2.53), metachronous (OR, 2.34; 95% CI, 1.62-3.36), or solitary CRC (OR, 1.75; 95% CI, 1.63-1.88) were at increased risk for developing CRC, compared with relatives of CRC-free individuals. Four percent of first-degree relatives of patients with synchronous or metachronous cancer developed CRC at younger ages than the age recommended for initiating CRC screening (based on familial risk), and therefore would not have been screened.
Of patients diagnosed with CRC, 2.3% are found to have synchronous lesions or develop metachronous CRC during follow-up evaluation. Relatives of these patients have a greater risk of CRC than those without a family history of CRC. These results highlight the importance of obtaining a thorough family history and adhering strictly to surveillance guidelines during management of high-risk patients.
Objective
The degenerative muscle diseases Duchenne (DMD) and Becker muscular dystrophy result from mutations in the DMD gene, which encodes the dystrophin protein. Recent improvements in mutational ...analysis techniques have resulted in the increasing identification of deep intronic point mutations, which alter splicing such that intronic sequences are included in the messenger RNA as “pseudoexons.” We sought to test the hypothesis that the clinical phenotype correlates with splicing efficiency of these mutations, and to test the feasibility of antisense oligonucleotide (AON)–mediated pseudoexon skipping.
Methods
We identified three pseudoexon insertion mutations in dystrophinopathy patients, two of whom had tissue available for further analysis. For these two out‐of‐frame pseudoexon mutations (one associated with Becker muscular dystrophy and one with DMD), mutation‐induced splicing was tested by quantitative reverse transcription polymerase chain reaction; pseudoexon skipping was tested using AONs composed of 2′‐O‐methyl–modified bases on a phosphorothioate backbone to treat cultured primary myoblasts.
Results
Variable amounts of pseudoexon inclusion correlates with the severity of the dystrophinopathy phenotype in these two patients. AON treatment directed at the pseudoexon results in the expression of full‐length dystrophin in a DMD myoblast line.
Interpretation
Both DMD and Becker muscular dystrophy can result from out‐of‐frame pseudoexons, with the difference in phenotype being due to variable efficiency of the newly generated splicing signal. AON‐mediated pseudoexon skipping therapy is a viable approach to these patients and would be predicted to result in increased expression of wild‐type dystrophin protein. Ann Neurol 2007
Familial adenomatous polyposis FAP (OMIM 175100) is an autosomal dominant colorectal cancer predisposition syndrome characterized by hundreds to thousands of colonic polyps and, if untreated by a ...combination of screening and/or surgical intervention, a ~99% lifetime risk of colorectal cancer. A subset of FAP patients develop an attenuated form of the condition characterized by lower numbers of colonic polyps (highly variable, but generally less than 100) and a lower lifetime risk of colorectal cancer, on the order of 70%. We report the diagnosis of three attenuated FAP families due to a 1.4-kb deletion within intron 14 of APC, originally reported clinically as a variant of unknown significance (VUS). Sequence analysis suggests that this arose through an Alu-mediated recombination event with a locus on chromosome 6q22.1. This mutation is inherited by family members who presented with an attenuated FAP phenotype, with variable age of onset and severity. Sequence analysis of mRNA revealed an increase in the level of aberrant splicing of exon 14, resulting in the generation of an exon 13-exon 15 splice-form that is predicted to lead to a frameshift and protein truncation at codon 673. The relatively mild phenotypic presentation and the intra-familial variation are consistent with the leaky nature of exon 14 splicing in normal APC. The inferred founder of these three families may account for as yet undetected affected branches of this kindred. This and similar types of intronic mutations may account for a significant proportion of FAP cases where APC clinical analysis fails because of the current limitations of testing options.
Demyelination is the hallmark of numerous neurodegenerative conditions, including multiple sclerosis. Oligodendrocyte progenitors (OPCs), which normally mature into myelin-forming oligodendrocytes, ...are typically present around demyelinated lesions but do not remyelinate affected axons. Here, we find that the glycosaminoglycan hyaluronan accumulates in demyelinated lesions from individuals with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. A high molecular weight (HMW) form of hyaluronan synthesized by astrocytes accumulates in chronic demyelinated lesions. This form of hyaluronan inhibits remyelination after lysolecithin-induced white matter demyelination. OPCs accrue and do not mature into myelin-forming cells in demyelinating lesions where HMW hyaluronan is present. Furthermore, the addition of HMW hyaluronan to OPC cultures reversibly inhibits progenitor-cell maturation, whereas degrading hyaluronan in astrocyte-OPC cocultures promotes oligodendrocyte maturation. HMW hyaluronan may therefore contribute substantially to remyelination failure by preventing the maturation of OPCs that are recruited to demyelinating lesions.
Summary
Shared genomic segment (SGS) analysis uses dense single nucleotide polymorphism genotyping in high‐risk (HR) pedigrees to identify regions of sharing between cases. Here, we illustrate the ...power of SGS to identify dominant rare risk variants. Using simulated pedigrees, we consider 12 disease models based on disease prevalence, minor allele frequency and penetrance to represent disease loci that explain 0.2–99.8% of total disease risk. Pedigrees were required to contain ≥15 meioses between all cases and to be HR based on significant excess of disease (P < 0.001 or P < 0.00001). Across these scenarios, the power for a single pedigree ranged widely. Nonetheless, fewer than 10 pedigrees were sufficient for excellent power in the majority of models. Power increased with the risk attributable to the disease locus, penetrance and the excess of disease in the pedigree. Sharing allowing for one sporadic case was uniformly more powerful than sharing using all cases. Furthermore, an SGS analysis using a large attenuated familial adenomatous polyposis pedigree identified a 1.96 Mb region containing the known causal APC gene with genome‐wide significance. SGS is a powerful method for detecting rare variants and a valuable complement to genome‐wide association studies and linkage analysis.
Some truncating mutations of the APC tumor suppressor gene are associated with an attenuated phenotype of familial adenomatous polyposis coli (AAPC). This work demonstrates that APC alleles with 5′ ...mutations produce APC protein that down-regulates β-catenin, inhibits β-catenin/T cell factor-mediated transactivation, and induces cell-cycle arrest. Transfection studies demonstrate that cap-independent translation is initiated internally at an AUG at codon 184 of APC. Furthermore, APC coding sequence between AAPC mutations and AUG 184 permits internal ribosome entry in a bicistronic vector. These data suggest that AAPC alleles in vivo may produce functional APC by internal initiation and establish a functional correlation between 5′ APC mutations and their associated clinical phenotype.
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