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It is important to understand how knowledge of genomics can be translated from research into clinical practice and health policies. This review examines existing evidence on three key factors in the adoption of personalized medicine: utilization, preferences, and economic value, using two cancer examples: HER2/neu antigen testing and trastuzumab (Herceptin) treatment and genetic testing for Lynch syndrome. Our findings highlight areas in which additional research is required to build an evidence base addressing utilization of, preferences for, and the potential costs and benefits of personalized medicine. Major challenges include a lack of linked data, the need for relevant research frameworks and methodologies, and the clinical complexities of genomic-based diagnostics and treatment.
Curr Opin Mol Ther 2008 Jun
PMID:Challenges to the translation of genomic information into clinical practice and health policy: Utilization, preferences and economic value. 1853 33

Deletions of one or more exons in the mismatch repair genes MLH1 and MSH2 have been implicated in a significant fraction of hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Multiplex ligation-dependent probe amplification (MLPA) detection of deletions of multiple sequential exons is widely accepted; however, there is concern over the reliability of MLPA results showing single exon deletions. Given the clinical implications of a diagnosis of Lynch syndrome, it is important to use an alternative technique to confirm single exon deletions. To verify single exon deletions, we developed a SYBR Green-based quantitative polymerase chain reaction (PCR) assay. Clinical DNA samples containing deletions in 33 of the 35 exons in MLH1 and MSH2, previously screened by MLPA, were evaluated by quantitative PCR. Gene dosage ratios were determined by both the relative standard curve method and by the 2(-DeltaDeltaC(T)) method. Deleted exons had gene dosage ratios of 0.4 to 0.6, while nondeleted exons exhibited ratios of 0.8-1.3. We found 100% concordance between the quantitative PCR and MLPA results, including confirmation of all single exon deletions. The 2(-DeltaDeltaC(T)) method was as accurate as using standard curves for the calculation of ratios. Single exon deletions in MLH1 and MSH2 can be verified using quantitative PCR. Assays using this method are simple to design and easy to perform, making them ideal for confirmatory testing.
J Mol Diagn 2008 Jul
PMID:Confirmation of single exon deletions in MLH1 and MSH2 using quantitative polymerase chain reaction. 1855 72

Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes. Both microsatellite instability (MSI) testing and immunohistochemical analyses (IHC) of colon cancers are valuable diagnostic strategies for Lynch syndrome. We sought to determine whether these markers of MMR deficiency were also detectable in pre-cancerous colorectal adenomas. Fifteen subjects with a germline MMR gene mutation who had 44 adenomas removed during surveillance colonoscopy were identified. MSI testing and IHC for MLH1, MSH2, and MSH6 were performed. MSI was detected in 23 adenomas. There was a significant association between MSI and high-grade dysplasia (P = 0.006) and distal location (P = 0.0008). Loss of MMR protein by IHC was detected in 31 adenomas. A significant association was observed between loss of staining by IHC and high-grade dysplasia (P = 0.04). Among the 40 adenomas in which both MSI tests and IHC were performed, the presence of a germline mutation correlated with an abnormal MSI result in 58% of cases, an abnormal IHC result in 70% of cases, and either an abnormal MSI or IHC result in 73% of cases. The combination of MSI and IHC testing in colorectal adenomas is a sensitive screen for the detection of Lynch syndrome and may be particularly useful when Lynch syndrome is suspected and adenomatous polyps are the only tissues available for analysis.
J Mol Diagn 2009 May
PMID:Deficient DNA mismatch repair is common in Lynch syndrome-associated colorectal adenomas. 1932 97

Hereditary ovarian cancer accounts for at least 5% of the estimated 22,000 new cases of this disease during 2009. During this same time, over 15,000 will die from malignancy ascribed to ovarian origin. The bulk of these hereditary cases fits the hereditary breast-ovarian cancer syndrome, while virtually all of the remainder will be consonant with the Lynch syndrome, disorders which are autosomal dominantly inherited. Advances in molecular genetics have led to the identification of BRCA1 and BRCA2 gene mutations which predispose to the hereditary breast-ovarian cancer syndrome, and mutations in mismatch repair genes, the most common of which are MSH2 and MLH1, which predispose to Lynch syndrome. These discoveries enable relatively certain diagnosis, limited only by their variable penetrance, so that identification of mutation carriers through a comprehensive cancer family history might be possible. This paper reviews the subject of hereditary ovarian cancer, with particular attention to its molecular genetic basis, its pathology, and its phenotypic/genotypic heterogeneity.
Mol Oncol 2009 Apr
PMID:Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management. 1938 74

Anticipation, i.e. a decreasing age-at-onset in subsequent generations has been observed in a number of genetically triggered diseases. The impact of anticipation is generally studied in affected parent-child pairs. These analyses are restricted to pairs in which both individuals have been affected and are sensitive to right truncation of the data. We propose a normal random effects model that allows for right-censored observations and includes covariates, and draw statistical inference based on the likelihood function. We applied the model to the hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome family cohort from the national Danish HNPCC register. Age-at-onset was analyzed in 824 individuals from 2-4 generations in 125 families with proved disease-predisposing mutations. A significant effect from anticipation was identified with a mean of 3 years earlier age-at-onset per generation. The suggested model corrects for incomplete observations and considers families rather than affected pairs and thereby allows for studies of large sample sets, facilitates subgroup analyses and provides generation effect estimates.
Stat Appl Genet Mol Biol 2009
PMID:A parametric model for analyzing anticipation in genetically predisposed families. 1949 84

Lynch syndrome (LS) is caused by mutations in mismatch repair genes and is characterized by a high cumulative risk for the development of mainly colorectal carcinoma and endometrial carcinoma. Early detection of LS is important since surveillance can reduce morbidity and mortality. However, the diagnosis of LS is complicated by the absence of a pre-morbid phenotype and germline mutation analysis is expensive and time consuming. Therefore it is standard practice to precede germline mutation analysis by a molecular diagnostic work-up of tumours, guided by clinical and pathological criteria, to select patients for germline mutation analysis. In this review we address these molecular analyses, the central role for the pathologist in the selection of patients for germline diagnostics of LS, as well as the molecular basis of LS.
J Cell Mol Med 2010 Jan
PMID:A review on the molecular diagnostics of Lynch syndrome: a central role for the pathology laboratory. 1992 44

MicroRNAs (miRNA), small noncoding RNAs, are potential diagnostic and prognostic markers, as well as therapeutic targets. miRNA profiles of colorectal carcinomas have not been studied extensively in the context of microsatellite instability (MSI) status. We therefore evaluated 55 paired colorectal adenocarcinomas (CRC) and non-neoplastic mucosa samples using a panel of 24 miRNAs selected by literature review and prior studies in our laboratory. Stem-loop reverse transcriptase quantitative (real-time) polymerase chain reaction assays were done on RNA extracted from formalin-fixed, paraffin-embedded tissue of resection specimens. When miRNA expression was compared with clinicopathologic features and MSI status, eleven miRNAs (miR-183, -31, -20, -25, -92, -93, -17, -135a, -203, -133b, and -223) were over-expressed in CRC relative to mucosa, and nine (miR-192, -215, -26b, -143, -145, -191, -196a, -16, and let-7a) were under-expressed in CRC. Relative expression of miR-92, -223, -155, -196a, -31, and -26b were significantly different among MSI subgroups, and miR-31 and miR-223 were overexpressed in CRC of patients with hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome). Our findings indicate that miRNA expression in CRC is associated with MSI subgroups, including low MSI and HNPCC-associated cancers, and that miRNAs may have posttranscriptional gene regulatory roles in these MSI subgroups and possible effects on the clinicopathologic and biomarker characteristics.
J Mol Diagn 2010 Jul
PMID:Association of microRNA expression with microsatellite instability status in colorectal adenocarcinoma. 2041 77

Inactivation of MLH1 due to promoter hypermethylation strongly suggests a sporadic origin, providing exclusion criteria for Lynch syndrome. The aim of this study is to compare the utility of methylation analysis of MLH1 and BRAF V600E mutations for the selection of patients with MLH1 negative colorectal cancer for genetic testing. MLH1 methylation status was evaluated by MethyLight and methylation-specific MLPA (MS-MLPA) in tumor DNA from 73 colorectal cancer patients with loss of MLH1 protein expression. These tumors were analyzed for BRAF V600E mutations, and genetic testing for germline MLH1 mutations was performed in all corresponding patients. Ten patients had germline mutations in MLH1 and none of their tumors showed significant MLH1 methylation or BRAF V600E mutation. MLH1 genetic testing excluded patients by MethyLight in 47 patients (64%), by MS-MLPA in 49 (67%), and BRAF V600E mutation in only 25 patients (34%) (chi(2) P = 0.00001). Specificity was 75% for MethyLight, 78% for MS-MLPA and 40% for BRAF V600E mutation. The use of MethyLight or MS-MLPA instead of BRAF mutation resulted in a cost reduction of 41% and 45%, respectively, per every MLH1 mutation detected. Taken together, methylation analysis of MLH1 shows better performance characteristics than BRAF V600E mutation in the selection of patients for genetic testing of MLH1, especially when using MS-MLPA.
J Mol Diagn 2010 Jul
PMID:Methylation analysis of MLH1 improves the selection of patients for genetic testing in Lynch syndrome. 2048 14

Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is the most common hereditary colorectal cancer (CRC) syndrome, accounting for approximately 2-5% of all newly diagnosed cases of CRC. Patients with LS have an increased lifetime risk of colorectal (52.2% in women and 68.7% in men) and endometrial cancer (15-70%), as well as certain extra-colonic cancers. Germline mutations in one of several DNA mismatch repair genes underlie LS. Molecular testing has emerged as an indispensable strategy for the diagnosis of LS. The diagnostic work-up of at-risk individuals includes a careful family history evaluation, microsatellite instability, immunohistochemistry and germline DNA analysis. A positive test result can guide clinicians in formulating the appropriate screening, surveillance and management strategies. However, because of the absence of an overt phenotype, such as a diffuse polyposis, it is not always straightforward to recognize LS clinically.
Expert Rev Mol Diagn 2010 Jul
PMID:Application of molecular diagnostics for the detection of Lynch syndrome. 2062 13

The standard genetic test for Lynch syndrome (LS) frequently reveals an absence of pathogenic mutations in DNA mismatch repair genes known to be associated with LS. It was recently shown that germ line deletions in the last exons of EPCAM are involved in the etiology of LS. The aim of this study was to evaluate the prevalence of EPCAM deletions in a Spanish population and the clinical implications of deletion. Probands from 501 families suspected of having LS were enrolled in the study. Twenty-five cases with MSH2 loss were identified: 10 had mutations of MSH2, five had mutations of MSH6, and 10 did not show MSH2/MSH6 mutations. These 25 cases were analyzed for EPCAM deletions using multiplex ligation-dependent probe amplification, and deletions were mapped using long-range PCR analysis. One subject with no MSH2/MSH6 mutations had a large deletion in the EPCAM locus that extended for 8.7 kb and included exons 8 and 9. The tumor exhibited MSH2 promoter hypermethylation. EPCAM deletion analysis followed by MSH2 methylation testing of the tumor is a fast low-cost procedure that can be used to identify mutations that cause LS. We propose that this procedure be incorporated into clinical genetic analysis strategies and present a decision-support flow diagram for the diagnosis of LS.
J Mol Diagn 2010 Nov
PMID:EPCAM germ line deletions as causes of Lynch syndrome in Spanish patients. 2086 35


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