Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer

Drastic genetic instability of tumors and normal tissues in Turcot syndrome

“…K-ras gene mutation was detected at codon 13 (GGC to GAC) in one of colon tumors (CoCa1). Such a high frequency of APC and p53 gene mutation has not previously been observed in our HNPCC carcinomas with germline mutation of hMSH2 or hMLH1 gene (Konishi et al, 1996). A p53 mutation and a K-ras mutation have also been detected in a colorectal carcinoma from a Turcot patient, but other genetic changes have not been described (Rochlitz et al, 1993).…”

“…Some PCR reactions of diluted DNA contained none or only one band, although PCR reaction of undiluted DNA always showed two normal bands. PCR products with abnormal mobilities were present in 4, 5, 6, 7, 8, 11, 15th and 16th lanes of the PCR products (from the left) in the case of Turcot patient, but the abnormal bands were not detected in 13 PCR reaction products in the case of HNPCC patient with hMSH2 germline mutation, nor in 16 PCR reactions in the case of HNPCC patient with hMLH1 germline mutation Primers and conditions for PCR, SSCP and direct sequencing in mutation analyses were those previously reported: hMSH3 and hMSH6 (Malkosyan et al, 1996); TGFbRII (Konishi et al, 1996); BAX (Rampino et al, 1997); E2F-4 (Yoshitaka et al, 1996); APC (Groden et al, 1991); p53 (Kikuchi-Yanoshita et al 1992). a As, Astrocytoma; CoAd, Colon adenoma; CoCa, carcinoma.…”

“…We conducted further tests to see if somatic mutation of APC, p53, and K-ras genes occurred in these Turcot tumors at a high frequency as in non-HNPCC (Miyaki et al, 1994), or at low frequencies, as in usual HNPCC (Konishi et al, 1996). All three colon carcinomas showed somatic mutations of APC gene.…”

“…Diluted DNA of normal mucosa was ampli®ed by PCR reaction of 35 cycles, containing DNA, primers for the microsatellite marker D2S123, and [ 32 P]dCTP, in 96-well system. Other PCR conditions were those described previously (Konishi et al, 1996). Products from 13 to 16 parallel PCR reactions were simultaneously electrophoresed through 6% polyacrylamide gel containing 7 M urea.…”

No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer

“…Evidence of these mechanisms in HNPCC tumor initiation can be found in the literature. Somatic mutations as second hits have been found in both MLH1-and MSH2-deficient tumors, albeit at low frequencies Konishi et al, 1996;Lu et al, 1996;Cunningham et al, 2001). MLH1 promoter hypermethylation has been detected in 17-46% of the HNPCC tumors (Cunningham et al, 1998;Herman et al, 1998;Kuismanen et al, 2000;Potocnik et al, 2001).…”