How wild-type TP53 is inactivated in undifferentiated-type gastric carcinomas: analyses of intratumoral heterogeneity in deletion and mutation of TP53.
OBJECTIVE
In undifferentiated-type gastric carcinoma (UGC), inactivation of TP53 is infrequent at early stages and comparable to tubular adenocarcinomas (TUBs) at advanced stages. To clarify how TP53 inactivation relates to histogenesis of UGCs, we examined p53 alterations in multiple samples of individual UGCs.


METHODS
We used 27 UGCs including 12 mixed types with minor tubular component (TC) and 16 with a layered structure (LS), a histological remnant of incipient signet ring cell carcinoma (SIG). We examined p53 expression immunohistochemically and analyzed loss of heterozygosity (LOH) with four microsatellite markers within 17p13.1 in multiple microdissected samples. DNA sequence of mutation hot spots in TP53 was determined in representative samples of each tumor.


RESULTS
In the mixed-type UGCs, 5 and 1 of the 8 tumors without LS showed global and regional loss of wild-type TP53, respectively, through mutation and LOH, and one fourth of the tumors with LS showed the regional loss. In the tumors with the mutation, the mutation pattern was identical between TC and poorly differentiated major component.


CONCLUSIONS
The inactivation of wild-type TP53 is an earlier event before dedifferentiation of TUB to mixed-type UGC, but is less frequent and a later event in a subset of mixed-type UGC deriving from SIG. .
Yoshimura
Akinobu
A
Department of Pathology, Shiga University of Medical Science, Otsu, Japan.
Sugihara
Hiroyuki
H
Ling
Zhi-Qiang
ZQ
Peng
Dun-Fa
DF
Mukaisho
Ken-ichi
K
Fujiyama
Yoshihide
Y
Hattori
Takanori
T
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*