Clonal and parallel evolution of primary lung cancers and their metastases revealed by molecular dissection of cancer cells.
OBJECTIVE
Several models of cancer progression, including clonal evolution, parallel evolution, and same-gene models, have been proposed to date. The purpose of this study is to investigate the authenticity of these models by comparison of accumulated genetic alterations between primary and corresponding metastatic lung cancers.


METHODS
A whole-genome allelic imbalance scanning using a high-resolution single nucleotide polymorphism array and mutational analysis of the p53, EGFR, and KRAS genes were done on eight sets of primary and metastatic lung cancers. Based on the genotype data, the natural history of each case was deduced, and candidate metastasis suppressor loci were determined.


RESULTS
Five to 20 chromosomal regions showed allelic imbalance in each tumor. Accumulated genetic alterations were similar between primary and corresponding metastatic tumors, and the majority(>67%) of genetic alterations detected in metastatic tumors was also detected in the corresponding primary tumors. On the other hand, in seven of the eight cases, there were genetic alterations accumulated only in metastatic tumors. Among these alterations, allelic imbalances at chromosome 11p15 and 11p11-p13 regions were the most frequent ones (4 of 8, 50%). Likewise, four cases showed genetic alterations detected only in primary tumors.


CONCLUSIONS
The natural history of each case indicated that the process of metastasis varies among cases, and that all three models are applicable to lung cancer progression. According to the clonal and parallel evolution models, it is possible that a metastasis suppressor gene(s) for lung cancer is present on chromosome 11p.
Takahashi
Kenji
K
Biology Division, National Cancer Center Research Institute, Tokyo, Japan.
Kohno
Takashi
T
Matsumoto
Shingo
S
Nakanishi
Yukihiro
Y
Arai
Yasuhito
Y
Yamamoto
Seiichiro
S
Fujiwara
Toshiyoshi
T
Tanaka
Noriaki
N
Yokota
Jun
J
D000328:Adult; D000368:Aged; D000483:Alleles; D022981:Allelic Imbalance; D002880:Chromosomes, Human, Pair 11; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide