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Shuji Ogino

Publications and source records attributed to Shuji Ogino.

At least 19 recordsLinked to original sources
PubMed2026

MyGeneRisk Colon: A Web-Based Tool for Personalized Colorectal Cancer Risk Prediction Based on Genetics and Lifestyle.

Colorectal cancer (CRC) is a leading cause of cancer-related death, with incidence rising substantially among individuals under 50 years of age. Polygenic risk scores (PRS) hold promise for identifying high-risk individuals; when combined with lifestyle factors, they substantially improve prediction accuracy compared with models based on lifestyle factors alone. However, few clinical tools currently exist that facilitate this integrated, PRS-enhanced risk assessment. To bridge this gap, we developed MyGeneRisk Colo n, a publicly accessible web portal that delivers individualized CRC risk prediction by incorporating genetic, demographic, family history, and lifestyle factors. This paper details the development of the underlying risk prediction model, the portal's architecture and data security, our reporting framework, and engagement with a community advisory panel. Designed as a user-friendly platform, MyGeneRisk Colon aims to effectively communicate personalized CRC risk profiles and educate users and healthcare providers about prevention strategies.

Journal Article↗
PubMed2025

Genetic risk factors modulate the association between physical activity and colorectal cancer.

BACKGROUND: Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene-PA interaction analysis. METHODS: Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (&#x2265; 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity. RESULTS: PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81-0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6&#xd7;10- 8). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75-0.85), but no significant PA-CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5&#xd7;10- 8). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72-0.82). CONCLUSIONS: In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5, suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.

GWAS↗
PubMed2025

Tumor-immune partitioning and clustering algorithm for identifying tumor-immune cell spatial interaction signatures within the tumor microenvironment.

BACKGROUND: Growing evidence supports the importance of characterizing the organizational patterns of various cellular constituents in the tumor microenvironment in precision oncology. Most existing data on immune cell infiltrates in tumors, which are based on immune cell counts or nearest neighbor-type analyses, have failed to fully capture the cellular organization and heterogeneity. METHODS: We introduce a computational algorithm, termed Tumor-Immune Partitioning and Clustering (TIPC), that jointly measures immune cell partitioning between tumor epithelial and stromal areas and immune cell clustering versus dispersion. As proof-of-principle, we applied TIPC to a prospective cohort incident tumor biobank containing 931 colorectal carcinoma cases. TIPC identified tumor subtypes with unique spatial patterns between tumor cells and T lymphocytes linked to certain molecular pathologic and prognostic features. T lymphocyte identification and phenotyping were achieved using multiplexed (multispectral) immunofluorescence. In a separate hepatocellular carcinoma cohort, we replaced the stromal component with specific immune cell types-CXCR3+CD68+ or CD8+-to profile their spatial relationships with CXCL9+CD68+ cells. RESULTS: Six unsupervised TIPC subtypes based on T lymphocyte distribution patterns were identified, comprising two cold and four hot subtypes. Three of the four hot subtypes were associated with significantly longer colorectal cancer (CRC)-specific survival compared to a reference cold subtype. Our analysis showed that variations in T-cell densities among the TIPC subtypes did not strictly correlate with prognostic benefits, underscoring the prognostic significance of immune cell spatial patterns. Additionally, TIPC revealed two spatially distinct and cell density-specific subtypes among microsatellite instability-high colorectal cancers, indicating its potential to upgrade tumor subtyping. TIPC was also applied to additional immune cell types, eosinophils and neutrophils, identified using morphology and supervised machine learning; here two tumor subtypes with similarly low densities, namely 'cold, tumor-rich' and 'cold, stroma-rich', exhibited differential prognostic associations. Lastly, we validated our methods and results using The Cancer Genome Atlas colon and rectal adenocarcinoma data (n = 570). Moreover, applying TIPC to hepatocellular carcinoma cases (n = 27) highlighted critical cell interactions like CXCL9-CXCR3 and CXCL9-CD8. CONCLUSIONS: Unsupervised discoveries of microgeometric tissue organizational patterns and novel tumor subtypes using the TIPC algorithm can deepen our understanding of the tumor immune microenvironment and likely inform precision cancer immunotherapy.

Humans↗
PubMed2006

Loss of nuclear p27 (CDKN1B/KIP1) in colorectal cancer is correlated with microsatellite instability and CIMP.

Downregulation of p27 (cyclin-dependent kinase inhibitor-1B, CDKN1B or KIP1) is caused by increased ubiquitin-mediated proteasomal degradation in colorectal cancer, and has been associated with poor prognosis. CpG island methylator phenotype (CIMP) is a phenotype of colorectal cancer with extensive promoter methylation, and associated with high degree of microsatellite instability (MSI-H) and BRAF mutations. We have recently shown that both CIMP and MSI-H are inversely associated with downregulation of p21 (CDKN1A or CIP1), another cyclin-dependent kinase inhibitor. However, no study to date has examined relationship between p27 and CIMP status in colorectal cancer. Using MethyLight assays, we measured DNA methylation in five CIMP-specific gene promoters {CACNA1G, CDKN2A (p16), CRABP1, MLH1 and NEUROG1} in 706 colorectal cancer samples obtained from two large prospective cohorts. Among the 706 tumors, 112 (16%) were CIMP-high tumors with >or=4/5 methylated promoters. We assessed p27 and p53 expressions by immunohistochemistry. Loss of nuclear p27 expression {observed in 231 tumors (33%)} was significantly associated with CIMP-high, MSI-H and BRAF mutations, and these associations were much more pronounced among p53-negative tumors than p53-positive tumors. When CIMP-high and non-CIMP-high tumors were stratified by MSI status (or KRAS and BRAF status), CIMP-high and MSI-H (but not BRAF mutations) were still significantly associated with nuclear p27 loss. Nuclear p27 loss did not appear to be directly related to CDKN2A (p16) methylation. We conclude that downregulation of nuclear p27 is associated with CIMP-high and MSI-H in colorectal cancer. These associations are stronger among p53 wild-type tumors, implying important interplay of p27 and p53 functions (or dysfunctions) in the development of various molecular subtypes of colorectal cancer.

Cell Nucleus↗
PubMed2006

The isopeptidase USP2a protects human prostate cancer from apoptosis.

Deubiquitinating enzymes can prevent the destruction of protein substrates prior to proteasomal degradation. The ubiquitin-specific protease 2a (USP2a) deubiquitinates the antiapoptotic proteins Fatty Acid Synthase and Mdm2. Here, we show that when USP2a is overexpressed in nontransformed cells, it exhibits oncogenic behavior both in vitro and in vivo and prevents apoptosis induced by chemotherapeutic agents. Notably, USP2a silencing in several human cancer cell lines results in apoptosis. Gene set enrichment analysis, which focuses on groups of genes sharing biological function or regulatory pathways, was done on microarray expression data from human prostate cancers. The cell death-related gene set, as well as a selected cluster of validated p53 target genes, were significantly enriched in the low USP2a expression group of tumors. Conversely, genes implicated in fatty acid metabolism were significantly associated with tumors expressing high USP2a (44%). The expression profile analysis is consistent with the effects of USP2a on its known targets, i.e., Fatty Acid Synthase and Mdm2, defining a subset of prostate tumors resistant to apoptosis. USP2a thus represents a therapeutic target in prostate cancer.

Apoptosis↗
PubMed2006

Epigenetic profiling of synchronous colorectal neoplasias by quantitative DNA methylation analysis.

Transcriptional inactivation of tumor-suppressor genes by promoter CpG island methylation is thought to be an important mechanism in human carcinogenesis. The CpG island methylator phenotype (CIMP) with extensive promoter methylation appears to be a distinct epigenetic subtype of colorectal carcinoma. Most previous studies on CpG island methylation in colorectal carcinoma used methylation-specific PCR, which may detect low levels of DNA methylation with little or no biological significance. In contrast, quantitative DNA methylation assays have been shown to provide useful information beyond that which can be achieved with methylation-specific PCR. Synchronous neoplasias provide a unique model for investigators to examine molecular alterations in multistep tumorigenesis within one individual. However, no study to date has quantified DNA methylation of CIMP-specific promoters in synchronous colorectal neoplasias. Utilizing real-time PCR (MethyLight), we quantified DNA methylation in five CIMP-specific gene promoters [CACNA1G (calcium channel, voltage-dependent, T type alpha-1G subunit), CDKN2A (p16/INK4A), CRABP1 (cellular retinoic acid binding protein-1), MLH1 and NEUROG1 (neurogenin 1)] and MGMT in six synchronous carcinoma pairs (12 carcinomas) and eight synchronous carcinoma and adenoma pairs (16 tumors). We found that while some synchronous tumor pairs showed discordant promoter methylation patterns, other tumor pairs showed similar, but not exactly identical, patterns of promoter methylation. All but two pairs showed concordant patterns of CIMP status (CIMP positive vs CIMP negative) (P = 0.05 in cancer pairs). BRAF mutations were present in only CIMP-positive tumors. A high degree of microsatellite instability (MSI-H) was observed in both CIMP-positive and CIMP-negative tumors. KRAS mutations were not concordant in any synchronous neoplasia pair. In conclusion, epigenetic alterations at CIMP-specific promoter CpG islands in synchronous colorectal neoplasias likely have both random and nonrandom components.

Adenocarcinoma↗
PubMed2006

Distinct molecular features of colorectal carcinoma with signet ring cell component and colorectal carcinoma with mucinous component.

Signet ring cell carcinoma and mucinous carcinoma are distinct subtypes of colorectal adenocarcinoma. The morphologic and molecular spectra of colorectal carcinomas with various signet ring cell components and colorectal carcinomas with various mucinous components, compared to non-mucinous adenocarcinomas, have not been examined. The study groups consisted of 39 carcinomas with various signet ring cell components ('the signet group'), 167 carcinomas with various mucinous components ('the mucinous group'), and 457 nonmucinous adenocarcinoma. We visually estimated the amounts of signet ring cell and mucinous components in tumors, and subclassified the signet and mucinous groups according to the amount of each component (< or = 19, 20-49, and > or = 50%). We sequenced BRAF and KRAS, analyzed for microsatellite instability (MSI) and 18q loss of heterozygosity (LOH), and performed immunohistochemistry for TP53, cyclooxygenase-2 (COX2), MLH1, O-6-methylguanine DNA methyltransferase (MGMT), p16 (CDKN2A), and fatty acid synthase (FASN). Signet ring cell carcinoma (> or = 50% signet ring cell tumors) and < or = 49% signet ring cell tumors showed similar molecular features. Except for MSI and MGMT, > or = 50% mucinous tumors and < or = 49% mucinous tumors also showed similar molecular features. BRAF mutations, MSI, and MLH1 loss were more frequent in both the signet and mucinous groups than nonmucinous carcinoma. More frequent KRAS mutations and less frequent p16 loss and TP53 positivity were observed in the mucinous group than nonmucinous carcinoma. 18q LOH and COX2 overexpression were less common in the signet group than nonmucinous carcinoma. FASN levels were highest in the mucinous group, followed by nonmucinous carcinoma, and lowest in the signet group. In conclusion, a minor (< or = 49%) signet ring cell or mucinous component in colorectal carcinoma suggests molecular features similar to > or = 50% signet ring cell or mucinous carcinoma, respectively. Signet ring cell carcinoma and mucinous carcinoma are related subtypes of colorectal adenocarcinoma, but have molecular features distinct from each other.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Correlation of pathologic features with CpG island methylator phenotype (CIMP) by quantitative DNA methylation analysis in colorectal carcinoma.

Extensive gene promoter methylation in colorectal carcinoma has been termed the CpG island methylator phenotype (CIMP). Previous studies on CIMP used primarily methylation-specific polymerase chain reaction (PCR), which, unfortunately, may detect low levels of methylation that has little or no biological significance. Utilizing quantitative real-time PCR (MethyLight), we measured DNA methylation in a panel of 5 CIMP-specific gene promoters (CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1) in 459 colorectal carcinomas obtained from 2 large prospective cohort studies. CIMP was defined as tumors that showed methylation in >or=4/5 promoters. CIMP was significantly associated with the presence of mucinous or signet ring cell morphology, marked Crohn's-like lymphoid reaction, tumor infiltrating lymphocytes, marked peritumoral lymphocytic reaction, tumor necrosis, tumor cell sheeting, and poor differentiation. All these features have previously been associated with microsatellite instability (MSI). Therefore, we divided the 459 colorectal carcinomas into 6 subtypes, namely, MSI-high (MSI-H)/CIMP, MSI-H/non-CIMP, MSI-low (MSI-L)/CIMP, MSI-L/non-CIMP, microsatellite stable/CIMP, and micro satellite sstable/non-CIMP. Compared with MSI-H/non-CIMP, MSI-H/CIMP was associated with marked tumor infiltrating lymphocytes, tumor necrosis, sheeting, and poor differentiation (all P<or=0.05). Compared with MSI-L/non-CIMP, MSI-L/CIMP was associated with tumors that had <50% signet ring cell component, marked tumor infiltrating lymphocytes, and poor differentiation (all P<0.05). In conclusion, several pathologic features that have previously been shown to be associated with MSI are also significantly associated with CIMP. Both MSI and CIMP appear to play a role in the pathogenesis of specific morphologic patterns of colorectal carcinoma.

Cell Differentiation↗
PubMed2006

Combined analysis of COX-2 and p53 expressions reveals synergistic inverse correlations with microsatellite instability and CpG island methylator phenotype in colorectal cancer.

Cyclooxygenase-2 (COX-2) overexpression and mutations of p53 (a known COX-2 regulator) are inversely associated with microsatellite instability-high (MSI-H) and CpG island methylator phenotype (CIMP) characterized by extensive promoter methylation, is associated with MSI-H. However, no studies have comprehensively examined interrelations between COX-2, p53, MSI, and CIMP. Using MethyLight, we measured DNA methylation in five CIMP-specific gene promoters [CACNA1G, CDKN2A (p16/INK4A), CRABP1, MLH1, and NEUROG1] in relatively unbiased samples of 751 colorectal cancer cases obtained from two large prospective cohorts; 115 (15%) tumors were CIMP-high (> or = 4 of 5 methylated promoters), 251 (33%) were CIMP-low (1 to 3 methylated promoters), and the remaining 385 (51%) were CIMP-0 (no methylated promoters). CIMP-high tumors were much less frequent in COX-2+/p53+ tumors (4.6%) than in COX-2+/p53- tumors (19%; P < .0001), COX-2-/p53+ tumors (17%; P = .04), and COX-2-/p53- tumors (28%; P < .0001). In addition, COX-2+/p53+ tumors were significantly less common in MSI-H CIMP-high tumors (9.7%) than in non-MSI-H CIMP-low/CIMP-0 tumors (44-47%; P < .0001). In conclusion, COX-2 and p53 alterations were synergistically inversely correlated with both MSI-H and CIMP-high. Our data suggest that a combined analysis of COX-2 and p53 may be more useful for the molecular classification of colorectal cancer than either COX-2 or p53 analysis alone.

Cohort Studies↗
PubMed2006

Precision and performance characteristics of bisulfite conversion and real-time PCR (MethyLight) for quantitative DNA methylation analysis.

Assays to measure DNA methylation, which are important in epigenetic research and clinical diagnostics, typically rely on conversion of unmethylated cytosine to uracil by sodium bisulfite. However, no study has comprehensively evaluated the precision and performance characteristics of sodium bisulfite conversion and subsequent quantitative methylation assay. We developed quantitative real-time polymerase chain reaction (MethyLight) to measure percentage of methylated reference (PMR, ie, degree of methylation) for the MGMT, MLH1, and CDKN2A (p16) promoters. To measure the precision of bisulfite conversion, we bisulfite-treated seven different aliquots of DNA from each of four paraffin-embedded colon cancer samples. To assess run-to-run variation, we repeated MethyLight five times. Bisulfite-to-bisulfite coefficient of variation (CV) of PMR ranged from 0.10 to 0.38 (mean, 0.21), and run-to-run CV of PMR ranged from 0.046 to 0.60 (mean, 0.31). Interclass correlation coefficients were 0.74 to 0.84 for the three loci, indicating good reproducibility. DNA mixing study with methylated and unmethylated DNA showed good linearity of the assay. Of 272 colorectal cancers evaluated, most showed PMR either <1 or >10, and promoter methylation (PMR >4) was tightly associated with loss of respective protein expression (P < 10(-16)). In conclusion, sodium bisulfite conversion and quantitative MethyLight assays have good precision and linearity and can be effectively used for high-throughput DNA methylation analysis on paraffin-embedded tissue.

Adaptor Proteins, Signal Transducing↗
PubMed2006

CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations.

The CpG island methylator phenotype (CIMP or CIMP-high) with extensive promoter methylation seems to be a distinct epigenotype of colorectal cancer. However, no study has comprehensively examined features of colorectal cancer with less extensive promoter methylation (designated as "CIMP-low"). Using real-time polymerase chain reaction (MethyLight), we quantified DNA methylation in five CIMP-specific gene promoters [CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1] in 840 relatively unbiased, population-based colorectal cancer samples, obtained from two large prospective cohort studies. CIMP-low (defined as 1/5 to 3/5 methylated promoters) colorectal cancers were significantly more common among men (38 versus 30% in women, P = 0.01) and among KRAS-mutated tumors (44 versus 30% in KRAS/BRAF wild-type tumors, P = 0.0003; 19% in BRAF-mutated tumors, P < 0.0001). In addition, KRAS mutations were significantly more common in CIMP-low tumors (47%) than in CIMP-high tumors (with > or =4/5 methylated promoters, 12%, P < 0.0001) and CIMP-0 tumors (with 0/5 methylated promoters, 37%, P = 0.007). The associations of CIMP-low tumors with male sex and KRAS mutations still existed after tumors were stratified by microsatellite instability status. In conclusion, CIMP-low colorectal cancer is associated with male sex and KRAS mutations. The hypothesis that CIMP-low tumors are different from CIMP-high and CIMP-0 tumors needs to be tested further.

Colorectal Neoplasms↗
PubMed2006

Efficacy of cetuximab after treatment with oral epidermal growth factor receptor tyrosine kinase inhibitor-based chemotherapy in metastatic colorectal cancer.

PURPOSE: We studied the efficacy of cetuximab therapy in patients with metastatic colorectal cancer (mCRC) previously treated with an oral inhibitor of the tyrosine kinase domain of the epidermal growth factor receptor. PATIENTS AND METHODS: We reviewed the posttrial records of 73 patients with mCRC who participated in 1 of 3 clinical trials that examined a combination of gefitinib or erlotinib with standard cytotoxic chemotherapy. Medical and pharmacy records were used to identify patients who were subsequently treated with cetuximab-based therapy. Computed tomography scans during cetuximab-based therapy were reviewed, and the clinical activity of cetuximab was assessed by response rate using Response Evaluation Criteria in Solid Tumors and progression-free survival. RESULTS: Twenty-four patients with mCRC previously treated with gefitinib or erlotinib and combination cytotoxic chemotherapy who subsequently received cetuximab-based therapy were identified. While receiving cetuximab-based therapy, no patient experienced a partial or complete response; however, 3 patients (16% of patients with available scans for formal measurements) had a minor response, defined as a 15%-29.9% decrease in the sum of longest dimensions of target lesions, and 72% had stable disease. The progression-free survival was 5.1 months for all patients and 6 months for patients who had documented progression of disease while previously receiving gefitinib- or erlotinib-based therapy. CONCLUSION: Cetuximab appears to have clinical benefit in patients with mCRC previously treated with a chemotherapy regimen that included an oral tyrosine kinase inhibitor of epidermal growth factor receptor. Whether these results apply to other cancer types is unknown but worthy of further study.

Adult↗
PubMed2005

Molecular alterations in tumors and response to combination chemotherapy with gefitinib for advanced colorectal cancer.

PURPOSE: Recently, activating mutations of the epidermal growth factor receptor (EGFR) gene were discovered in non-small cell lung cancers sensitive to gefitinib (ZD1839, an EGFR tyrosine kinase inhibitor) but not in gefitinib-resistant cancers. Abnormalities of EGFR and related pathways may have an effect on responsiveness of advanced colorectal cancer to combination chemotherapy with gefitinib. EXPERIMENTAL DESIGN: We examined patients with previously untreated metastatic colorectal cancer, who were enrolled into two phase I/II trials of combination chemotherapy (irinotecan, leucovorin, and 5-fluorouracil) and daily oral gefitinib. We obtained paraffin tissue blocks of primary tumors from 31 patients, sequenced the EGFR, KRAS, and BRAF genes, and did immunohistochemistry for EGFR, phosphorylated AKT1, p53, p21, and p27. RESULTS: Twelve (39%) of the 31 patients experienced a partial objective response to the therapy. A novel EGFR mutation in exon 18 (c.2170G>A, p.Gly724Ser) was identified in only one patient who did not experience an objective tumor response. EGFR immunohistochemistry was not predictive of responsiveness. In contrast, loss of p21 was associated with a higher response rate to therapy (P = 0.05). Moreover, the response rate among patients whose tumors maintained p21 expression and possessed a mutation in p53 was only 9% (1 of 11, P = 0.005). Overexpression of phosphorylated AKT1 also seemed to predict a trend towards resistance to the therapy. CONCLUSIONS: p21 expression in colorectal cancer, especially in combination with p53 mutation, is a predictor of resistance to the combination chemotherapy with gefitinib. Activating EGFR mutations are rare in colorectal cancer and do not seem to confer sensitivity to gefitinib and chemotherapy.

Adult↗
PubMed2005

Sensitive sequencing method for KRAS mutation detection by Pyrosequencing.

Both benign and malignant tumors represent heterogenous tissue containing tumor cells and non-neoplastic mesenchymal and inflammatory cells. To detect a minority of mutant KRAS alleles among abundant wild-type alleles, we developed a sensitive DNA sequencing assay using Pyrosequencing, ie, nucleotide extension sequencing with an allele quantification capability. We designed our Pyrosequencing assay for use with whole-genome-amplified DNA from paraffin-embedded tissue. Assessing various mixtures of DNA from mutant KRAS cell lines and DNA from a wild-type KRAS cell line, we found that mutation detection rates for Pyrosequencing were superior to dideoxy sequencing. In addition, Pyrosequencing proved superior to dideoxy sequencing in the detection of KRAS mutations from DNA mixtures of paraffin-embedded colon cancer and normal tissue as well as from paraffin-embedded pancreatic cancers. Quantification of mutant alleles by Pyrosequencing was precise and useful for assay validation, monitoring, and quality assurance. Our Pyrosequencing method is simple, robust, and sensitive, with a detection limit of approximately 5% mutant alleles. It is particularly useful for tumors containing abundant non-neoplastic cells. In addition, the applicability of this assay for DNA amplified by whole-genome amplification technique provides an expanded source of DNA for large-scale studies.

Colonic Neoplasms↗
PubMed2004

Bayesian analysis and risk assessment in genetic counseling and testing.

Risk assessment is an essential component of genetic counseling and testing, and Bayesian analysis plays a central role in genetic risk assessment. Bayesian analysis allows calculation of the probability of a particular hypothesis, either disease or carrier status, based on family information and/or genetic test results. Genetic risk should be assessed as accurately as possible for family decision making. Additional information, from the pedigree and/or from genetic testing, can often dramatically improve the accuracy of genetic risk assessment. We illustrate herein the application of Bayes' theorem and describe important basic principles in genetic risk assessment.

Bayes Theorem↗
PubMed2004

New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations.

Most spinal muscular atrophy patients lack both copies of SMN1. Loss of SMN1 ('0-copy alleles') can occur by gene deletion or SMN1-to-SMN2 gene conversion. Despite worldwide efforts to map the segmental duplications within the SMN region, most assemblies do not correctly delineate these genes. A near pericentromeric location provides impetus for the strong evidence that SMN1 and SMN2 arose from a primate-specific paralogous gene duplication. Here we meta-analyzed our recent laboratory results together with available published data, in order to calculate new mutation rates and allele/haplotype frequencies in this recalcitrant and highly unstable region of the human genome. Based on our tested assumption of compliance with Hardy-Weinberg equilibrium, we conclude that the SMN1 allele frequencies are: '0-copy disease alleles,' 0.013; '1-copy normal alleles,' 0.95; '2-copy normal alleles (ie, two copies of SMN1 on one chromosome),' 0.038; and '1(D) disease alleles (SMN1 with a small intragenic mutation),' 0.00024. The SMN1 haplotype ['(SMN1 copy number)-(SMN2 copy number)'] frequencies are: '0-0,' 0.00048; '0-1,' 0.0086; '0-2,' 0.0042; '1-0,' 0.27; '1-1,' 0.66; '1-2,' 0.015; '2-0,' 0.027; and '2-1,' 0.012. Paternal and maternal de novo mutation rates are 2.1 x 10(-4) and 4.2 x 10(-5), respectively. Our data provide the basis for the most accurate genetic risk calculations, as well as new insights on the evolution of the SMN region, with evidence that nucleotide position 840 (where a transition 840C>T functionally distinguishes SMN2 from SMN1) constitutes a mutation hotspot. Our data also suggest selection of the 1-1 haplotype and the presence of rare chromosomes with three copies of SMN1.

Computer Simulation↗