Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0094170
Title: Systematic study on genetic and epimutational profile of a cohort of amsterdam criteria-defined lynch syndrome in Singapore
Authors: Liu Y.
Chew M.H. 
Goh X.W.
Tan S.Y. 
Loi C.T.T.
Tan Y.M.
Law H.Y. 
Koh P.K.
Tang C.L. 
Keywords: adult
aged
article
controlled study
DNA sequence
epigenetics
ethnicity
female
gene
gene deletion
gene duplication
gene expression profiling
gene identification
gene mutation
genetic analysis
genetic screening
genotype phenotype correlation
germ line
hereditary nonpolyposis colorectal cancer
human
human tissue
immunohistochemistry
major clinical study
male
methylation
microsatellite instability
mismatch repair
MLH1 gene
molecular diagnosis
MSH2 gene
MSH6 gene
multiplex ligation dependent probe amplification
mutational analysis
PMS2 gene
Singapore
very elderly
young adult
cohort analysis
genetics
genotype
hereditary nonpolyposis colorectal cancer
middle aged
mutation
phenotype
systems biology
Adult
Aged
Aged, 80 and over
Cohort Studies
Colorectal Neoplasms, Hereditary Nonpolyposis
DNA Mismatch Repair
Epigenomics
Female
Genotype
Humans
Male
Middle Aged
Mutation
Phenotype
Singapore
Systems Biology
Young Adult
Issue Date: 2014
Citation: Liu Y., Chew M.H., Goh X.W., Tan S.Y., Loi C.T.T., Tan Y.M., Law H.Y., Koh P.K., Tang C.L. (2014). Systematic study on genetic and epimutational profile of a cohort of amsterdam criteria-defined lynch syndrome in Singapore. PLoS ONE 9 (4) : e94170. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0094170
Abstract: Background: Germline defects of mismatch repair (MMR) genes underlie Lynch Syndrome (LS). We aimed to gain comprehensive genetic and epigenetic profiles of LS families in Singapore, which will facilitate efficient molecular diagnosis of LS in Singapore and the region. Methods: Fifty nine unrelated families were studied. Mutations in exons, splice-site junctions and promoters of five MMR genes were scanned by high resolution melting assay followed by DNA sequencing, large fragment deletions/duplications and promoter methylation in MLH1 , MSH2, MSH6 and PMS2 were evaluated by multiplex ligation-dependent probe amplification. Tumor microsatellite instability (MSI) was assessed with five mononucleotide markers and immunohistochemical staining (IHC) was also performed. Results: Pathogenic defects, all confined to MLH1 and MSH2, were identified in 17 out of 59 (28.8%) families. The mutational spectrum was highly heterogeneous and 28 novel variants were identified. One recurrent mutation in MLH1 (c.793C>T) was also observed. 92.9% sensitivity for indication of germline mutations conferred by IHC surpassed 64.3% sensitivity by MSI. Furthermore, 15.6% patients with MSS tumors harbored pathogenic mutations. Conclusions: Among major ethnic groups in Singapore, all pathogenic germline defects were confined to MLH1 and MSH2. Caution should be applied when the Amsterdam criteria and consensus microsatellite marker panel recommended in the revised Bethesda guidelines are applied to the local context. We recommend a screening strategy for the local LS by starting with tumor IHC and the hotspot mutation testing at MLH1 c.793C>T followed by comprehensive mutation scanning in MLH1 and MSH2 prior to proceeding to other MMR genes. © 2014 Liu et al.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/161419
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0094170
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