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Loss of heterozygosity in spontaneous and x‐ray–induced intestinal tumors arising in F1 hybrid Min mice: Evidence for sequential loss of Apc + and Dpc4 in tumor development
Author(s) -
Haines Jackie,
Dunford Rosemary,
Moody John,
Ellender Michele,
Cox Roger,
Silver Andrew
Publication year - 2000
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/1098-2264(200008)28:4<387::aid-gcc4>3.0.co;2-h
Subject(s) - loss of heterozygosity , biology , adenomatous polyposis coli , locus (genetics) , cancer research , allele , familial adenomatous polyposis , genetics , microsatellite , tumor progression , deletion mapping , chromosome , comparative genomic hybridization , gene , colorectal cancer , cancer
Min (multiple intestinal neoplasia) mice carry a mutant allele of the murine Apc (adenomatous polyposis coli) locus and are predisposed to intestinal adenoma formation in the intestinal tract. Early studies have shown complete loss of function of Apc by whole chromosome loss on the tumor‐sensitive C57BL/6J genetic background and in AKR × B6 F1 hybrids. Gamma‐radiation–induced chromosomal losses focus the critical region on wt Apc , but because of the limited number of polymorphic markers used, no other critical regions of loss on chromosome 18 were identified. Using intestinal tumors arising spontaneously and induced by X‐rays in CBA/H × C57BL/6J F1 hybrid mice and high‐resolution microsatellite loss of heterozygosity (LOH) techniques, we provide mapping data for wt Apc loss, which confirms and extends earlier observations. In addition, high‐frequency loss events at the Dpc 4 locus were found in both spontaneous and radiation‐induced tumors. These data identified LOH of Dpc 4 as a critical secondary event following complete functional loss of Apc . LOH across the Trp 53 genomic region of chromosome 11 was not observed. No LOH was recorded for the Mom 1 candidate gene Pla 2 g 2 a or for 9 out of 10 polymorphic markers from the Mom 1 genomic region on murine chromosome 4. One marker mapping distal to Pla 2 g 2 a showed LOH in a small minority of spontaneous tumors. These data support the contention that Mom 1 does not act as a classical tumor suppressor. Overall, our data indicates a significant role for Dpc 4 mutation in intestinal tumor progression in the mouse and provides further evidence for the importance of interstitial chromosome losses in radiation tumorigenesis. Genes, Chromosomes and Cancer 28:387–394, 2000. © Crown copyright 2000. Reproduced with the permission of the Controller of Her Majesty's Stationary Office.