title: Kras gene mutation and RASSF1A, FHIT and MGMT gene promoter hypermethylation: indicators of tumor staging and metastasis in adenocarcinomatous sporadic colorectal cancer in Indian population.
abstract: OBJECTIVE
  Colorectal cancer (CRC) development involves underlying modifications at genetic/epigenetic level. This study evaluated the role of Kras gene mutation and RASSF1A, FHIT and MGMT gene promoter hypermethylation together/independently in sporadic CRC in Indian population and correlation with clinicopathological variables of the disease.
  
  
  METHODS
  One hundred and twenty four consecutive surgically resected tissues (62 tumor and equal number of normal adjacent controls) of primary sporadic CRC were included and patient details including demographic characteristics, lifestyle/food or drinking habits, clinical and histopathological profiles were recorded. Polymerase chain reaction - Restriction fragment length polymorphism and direct sequencing for Kras gene mutation and Methylation Specific-PCR for RASSF1A, FHIT and MGMT genes was performed.
  
  
  RESULTS
  Kras gene mutation at codon 12 & 13 and methylated RASSF1A, FHIT and MGMT gene was observed in 47%, 19%, 47%, 37% and 47% cases, respectively. Alcohol intake and smoking were significantly associated with presence of Kras mutation (codon 12) and MGMT methylation (p-value <0.049). Tumor stage and metastasis correlated with presence of mutant Kras codon 12 (p-values 0.018, 0.044) and methylated RASSF1A (p-values 0.034, 0.044), FHIT (p-values 0.001, 0.047) and MGMT (p-values 0.018, 0.044) genes. Combinatorial effect of gene mutation/methylation was also observed (p-value <0.025). Overall, tumor stage 3, moderately differentiated tumors, presence of lymphatic invasion and absence of metastasis was more frequently observed in tumors with mutated Kras and/or methylated RASSF1A, FHIT and MGMT genes.
  
  
  CONCLUSIONS
  Synergistic interrelationship between these genes in sporadic CRC may be used as diagnostic/prognostic markers in assessing the overall pathological status of CRC.
authors.affiliation: Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India.
authors.forename: Rupal
authors.initials: R
authors.lastname: Sinha
authors.forename: Showket
authors.initials: S
authors.lastname: Hussain
authors.forename: Ravi
authors.initials: R
authors.lastname: Mehrotra
authors.forename: R Suresh
authors.initials: RS
authors.lastname: Kumar
authors.forename: Kapil
authors.initials: K
authors.lastname: Kumar
authors.forename: Pankaj
authors.initials: P
authors.lastname: Pande
authors.forename: Dinesh Chandra
authors.initials: DC
authors.lastname: Doval
authors.forename: Seemi Farhat
authors.initials: SF
authors.lastname: Basir
authors.forename: Mausumi
authors.initials: M
authors.lastname: Bharadwaj
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics* / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics* / Q000556:secondary; D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D004032:Diet; D005260:Female; D006801:Humans; D007194:India; D008019:Life Style; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D025521:Tumor Suppressor Proteins; D018631:ras Proteins; D000099170:Bis(5'-adenosyl)triphosphatase; C117307:KRAS protein, human; C411762:RASSF1 protein, human; C515491:MGMT protein, human