Molecular genetic alteration and DNA ploidy in hereditary nonpolyposis colorectal cancer

Abstract

Background:To clarify the biologic characteristics of hereditary nonpolyposis colorectal cancer (HNPCC), an investigation was made of the association of this cancer with mutations of the TP53 (alias p53) and K-ras genes, and with DNA ploidy. Methods:Samples from 19 patients with HNPCC and from 56 patients with sporadic colorecta[ cancer were analyzed by polymerase chain reaction-single strand conformation polymorphism and flow cytometric analyses. Results:Mutations of the p53 gene were found in 7 (32%) of 22 samples from H NPCC patients, and Kras mutations were found in 8 (44%) of 18 samples from HNPCC patients. Aneuploidy was noted in 8 (44%) of 18 samples. Each incidence in HNPCC was similar to the corresponding incidence in the sporadic colorectal cancers. Conclusion:The results of this investigation indicate that HNPCC shows no difference from sporadic colorectal cancer in terms of p53 and K-ras alterations, or DNA ploidy.Int I Clin Onco11997;2:224-229

Classification of colorectal cancer based on correlation of clinical, morphological and molecular features

“…Notwithstanding the mutual exclusivity of these two forms of genetic instability, all CRCs were considered to evolve through a similar linear sequence of genetic alterations. Indeed, APC , KRAS and TP53 were all shown to be mutated in CRCs with MSI‐H from patients with Lynch syndrome and in malignant cell lines with MSI‐H 14–20 …”

“…Notwithstanding the mutual exclusivity of these two forms of genetic instability, all CRCs were considered to evolve through a similar linear sequence of genetic alterations. Indeed, APC, KRAS and TP53 were all shown to be mutated in CRCs with MSI-H from patients with Lynch syndrome and in malignant cell lines with MSI-H. [14][15][16][17][18][19][20] Need for an alternative pathway to explain sporadic CRCs with MSI-H Support for the existence of two largely independent pathways to sporadic CRC was slow to develop. Acceptance of such a notion had to supplant an attractive and elegant paradigm, in which APC inactivation and loss of DNA mismatch repair were envisaged to initiate and promote (respectively) an essentially similar evolutionary pathway in both sporadic and familial settings.…”

Evolution of colorectal cancer: Change of pace and change of direction

“…This observation supports the contention that mismatch repair deficiency is the primary event. With the exception of the K‐ ras mutation 15,17–20,26,29–32 (Table 4), further progression is infrequently associated with ‘classic’ genetic alterations, for example, mutation of TP53 15,17–20,29,30,33,34 (Table 5) or a loss of traditional tumor suppressor loci on 5q 17,18,26 and 17p 17,18,20,26 (Tables 3,6). Instead, short repetitive tracts in a number of target genes (for example, TGFbetaRII , IGF2R and BAX ) are implicated and probably occur with great rapidity as a result of the DNA mismatch repair defect 35–37 …”