scholarly journals MLH1 and MSH2 Gene Mutations and Polymorphisms in Six Malay Families with Hereditary Nonpolyposis Colorectal Cancer

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Wan Khairunnisa Wan Juhari ◽  
Khairul Bariah Ahmad Amin Noordin ◽  
Wan Faiziah Wan Abdul Rahman ◽  
Andee Dzulkarnaen Zakaria ◽  
Ahmad Shanwani Mohd Sidek ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Nucleotide Polymorphisms ◽  
Msh2 Gene ◽  
Hereditary Nonpolyposis ◽  
The Impact

Background: Hereditary nonpolyposis colorectal cancer (HNPCC) also known as Lynch syndrome is commonly caused by genetic alterations in any of the four mismatch repair (MMR) genes; MLH1, MSH2, MSH6 and PMS2. This is the first study aimed to investigate genetic variants in Malay HNPCC families. Methods: Six Malay HNPCC families who fulfilled any of the Bethesda criteria were recruited into this study. A total of 3 ml of blood was withdrawn from each patient in the families. The samples were further analyzed using polymerase chain reaction and direct sequencing of the selected exons of MLH1 and MSH2 genes. Results: Two missense mutations and four single nucleotide polymorphisms (SNPs) were identified in six patients. These variants in the MLH1 and MSH2 genes were identified in four families who met the revised Bethesda guidelines. In two families, no mutation and polymorphism was identified in both the exon and intron of the respective genes. Of the mutations and polymorphisms identified, five have never been reported in Malay HNPCC families before. A missense mutation was detected in exon 5 of the MLH1 gene, c.394G>C (p.Asp132His) and four mutations and polymorphisms were detected in the MSH2 gene; heterozygous c.211+98T>C and c.211+9C>G and homozygous c.211+98T>C and c.211+9C>G, c.367-86A>C and c.382C>G. Conclusion: The results represented a new spectrum of mutations and polymorphisms in the Malay HNPCC families. However, a larger study involving additional families and analysis is required to determine the impact and nature of the identified mutations and polymorphisms.

BRCA1, BRCA2, and Hereditary Nonpolyposis Colorectal Cancer Gene Mutations in an Unselected Ovarian Cancer Population

1998 ◽  
Vol 53 (8) ◽  
pp. 477-478
Author(s):  
Stephen C. Rubin ◽  
M. Anne Blackwood ◽  
Christina Bandera ◽  
Kian Behbakht ◽  
Ivor Benjamin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Ovarian Cancer ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Gene Mutations ◽  
Cancer Gene ◽  
Hereditary Nonpolyposis ◽  
Brca1 Brca2

Genetic profiles of hereditary nonpolyposis colorectal cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 469-469
Author(s):  
C. Therklidsen ◽  
G. Jonsson ◽  
I. Bernstein ◽  
M. Nilbert
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Gene Mutations ◽  
Comparative Genomic ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
Hereditary Nonpolyposis ◽  
Gains And Losses ◽  
Mismatch Repair Gene Mutations

469 Background: With the aim to identify genetic markers of hereditary nonpolyposis colorectal cancer (HNPCC), we applied tiling BAC array-based comparative genomic hybridization (aCGH) to 46 HNPCC-associated colorectal cancer. Methods: 32 k iling BAC arrays were used to generate high-density genomic profiles. Tumors were selected through a case-control design with half of the tumors derived from individuals with disease-predisposing mismatch repair gene mutations and the reminder from phenotypic HNPCC families without identified mutations. In addition, an equal number of sporadic tumors were used for comparison. Results: Tumors with disease-predisposing germline mutations showed frequent gains of chromosomes 1p (39%), 17 (43%), 19 (57%) and 22q (30%). HNPCC associated tumors without mutations did as a group have more complex alterations with the most frequent changes being gains of 20q (70%), 19 (35%), 17 (26%) and loss of 18 (39%). Gains of 1p and 20q and loss of chromosome 18 were identified as significant discriminators between HNPCC tumors with/without germline MMR gene mutations. Conclusions: The aCGH profiles of HNPCC-associated colorectal cancer suggest that specific gains and losses may be used to distinguish between tumors with/without germline mismatch repair gene mutations. No significant financial relationships to disclose.

scholarly journals Predictive value of clinical toxicities of chemotherapy with fluoropyrimidines and oxaliplatin in colorectal cancer by DPYD and GSTP1 gene polymorphisms

2020 ◽  
Author(s):  
Xunwei Deng ◽  
Jingyuan Hou ◽  
Qiaoting Deng ◽  
Zhixiong Zhong
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Direct Sequencing ◽  
Dihydropyrimidine Dehydrogenase ◽  
Severe Toxicity ◽  
Nucleotide Polymorphisms ◽  
Mutant Type ◽  
Severe Vomiting ◽  
Significant Difference ◽  
The Impact

Abstract Background: Fluoropyrimidines and platinum are still widely used for colorectal cancer (CRC) management. Several studies have reported that mutations of dihydropyrimidine dehydrogenase (DPYD) and glutathione S-transferase pi-1 (GSTP1) polymorphisms are related to Chemotherapy-related adverse events. In the present study, we purposed to assess the impact of DPYD and GSTP1 variants on the toxicity of adjuvant chemotherapy risk among the Hakka population, minimize adverse events, and to maximize therapy outcome for individualized treatment.Methods: Genotyping was examined in 104 patients diagnosed with CRC cases and receiving fluoropyrimidine and platinum drugs based chemotherapy regimen by direct sequencing of DPYD and GSTP1 polymorphisms. Three DPYD variants including *2A, *5A, *9A, and GSTP1 c.313A>G were analyzed and clinical outcomes were assessed.Results: The data suggest that the incidence of DPYD*5A, DPYD*9A, and GSTP1 c.313A>G variants were 38.4%, 24%, and 32.7%, respectively. DPYD*2A variant was not found. A total of 23 patients (22.1%) suffered severe vomiting and 19 patients (18.3%) suffered severe anemia. DPYD*5A polymorphism was found significantly associated with grade 3/4 ulceration (p = 0.001). GSTP1 was determined to be an independent risk factor for severe vomiting and skin ulceration (p = 0.042 and p = 0.018, respectively). Patients with GSTP1 c. 313A>G mutant type contributed to a higher risk for grade severe toxicity compared with wild genotype (p = 0.027). Nevertheless, no significant difference was found between patients with DPYD*2A, *5A, *9A for chemotherapeutic toxicity.Conclusions: The results demonstrated that GSTP1 polymorphisms were useful predictors of severe events. Screening of single nucleotide polymorphisms of GSTP1 in colorectal cancer patients before chemotherapy may help to realize personalized therapy.

scholarly journals Interactions of Human hMSH2 with hMSH3 and hMSH2 with hMSH6: Examination of Mutations Found in Hereditary Nonpolyposis Colorectal Cancer

1998 ◽  
Vol 18 (11) ◽  
pp. 6616-6623 ◽  
Author(s):  
Shawn Guerrette ◽  
Teresa Wilson ◽  
Scott Gradia ◽  
Richard Fishel
Keyword(s):  
Colorectal Cancer ◽  
Protein Interactions ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Missense Mutations ◽  
Protein Protein Interaction ◽  
Static Interaction ◽  
Repair Protein ◽  
Hereditary Nonpolyposis ◽  
Interaction Regions ◽  
Mismatch Repair Protein

ABSTRACT Mutations in the human mismatch repair protein hMSH2 have been found to cosegregate with hereditary nonpolyposis colorectal cancer (HNPCC). Previous biochemical and physical studies have shown that hMSH2 forms specific mispair binding complexes with hMSH3 and hMSH6. We have further characterized these protein interactions by mapping the contact regions within the hMSH2-hMSH3 and the hMSH2-hMSH6 heterodimers. We demonstrate that there are at least two distinct interaction regions of hMSH2 with hMSH3 and hMSH2 with hMSH6. Interestingly, the interaction regions of hMSH2 with either hMSH3 or hMSH6 are identical and there is a coordinated linear orientation of these regions. We examined several missense alterations of hMSH2 found in HNPCC kindreds that are contained within the consensus interaction regions. None of these missense mutations displayed a defect in protein-protein interaction. These data support the notion that these HNPCC-associated mutations may affect some other function of the heterodimeric complexes than simply the static interaction of hMSH2 with hMSH3 or hMSH2 with hMSH6.

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