Evolution from heterozygous to homozygous KIT mutation in gastrointestinal stromal tumor correlates with the mechanism of mitotic nondisjunction and significant tumor progression.
Activating mutation in KIT or platelet-derived growth factor-alpha can lead to gastrointestinal stromal tumors (GISTs). Eighty-four cases from two institutes were analyzed. Of them, 62 (74%) harbored KIT mutations, 7 of which are previously unreported. One exhibited duplication from both intron 11 and exon 11, which has not been reported in KIT in human cancer. A homozygous/hemizygous KIT-activating mutation was found in 9 of the 62 cases (15%). We identified three GIST patients with heterozygous KIT-activating mutations at initial presentation, who later recurred with highly aggressive clinical courses. Molecular analysis at recurrence showed total dominance of homozygous (diploid) KIT-activating mutation within a short period of 6-13 months, suggesting an important role of oncogene homozygosity in tumor progression. Topoisomerase II is active in the S- and G(2) phases of cell cycle and is a direct and accurate proliferative indicator. Cellular and molecular analysis of serial tumor specimens obtained from consecutive surgeries or biopsy within the same patient revealed that these clones that acquired the homozygous KIT mutation exhibited an increased mitotic count and a striking fourfold increase in topoisomerase II proliferative index (percentage cells show positive topoisomerase II nuclear staining compared to the heterozygous counterpart within the same patient. KIT forms a homodimer as the initial step in signal transduction and this may account for the quadruple increase in proliferation. Using SNPs for allelotyping on the serial tumor specimens, we demonstrate that the mechanism of the second hit resulting in homozygous KIT-activating mutation and loss of heterozygosity is achieved by mitotic nondisjunction, contrary to the commonly reported mechanism of mitotic recombination.
Chen
Lei L
LL
Department of Internal Medicine, Division of Hematology/Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA. lei.chen@hci.utah.edu
Holden
Joseph A
JA
Choi
Haesun
H
Zhu
Jing
J
Wu
Elsie F
EF
Jones
Kimberly A
KA
Ward
John H
JH
Andtbacka
Robert H
RH
Randall
R Lor
RL
Scaife
Courtney L
CL
Hunt
Kelly K
KK
Prieto
Victor G
VG
Raymond
Austin K
AK
Zhang
Wei
W
Trent
Jonathan C
JC
Benjamin
Robert S
RS
Frazier
Marsha L
ML
D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D018450:Disease Progression; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008938:Mitosis; D008969:Molecular Sequence Data; D009154:Mutation; D009630:Nondisjunction, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
D019009:Proto-Oncogene Proteins c-kit