p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions.
Pancreatic adenocarcinoma is a major cause of cancer death, and yet little is known about its molecular pathogenesis. We identified p53 mutations in 19 (70%) of 27 primary pancreatic adenocarcinomas. Most were missense point mutations, and the mutations were distributed primarily within the evolutionarily conserved domains. Transitions predominated over transversions, and many of the transitions were at CpG dinucleotides. Intragenic deletions accounted for 32% of mutations and were associated with decreased survival (P = 0.0016). A review of 1937 published p53 mutations revealed that the occurrence of small (1-2 base pairs) microdeletions varied among different types of human neoplasms and that pancreatic adenocarcinoma had one of the highest frequencies (13% of 47 mutations, P = 0.0036). Many small deletions occurred in iterations of single bases, but this did not fully account for their pattern of distribution, and there was evidence for the involvement of homocopolymer (polypurine:polypyrimidine) tracts. This may represent a more widespread phenomenon, because microdeletions occur in similar sequence patterns in reports of somatic and germ line mutations among genes other than p53.
Redston
M S
MS
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Caldas
C
C
Seymour
A B
AB
Hruban
R H
RH
da Costa
L
L
Yeo
C J
CJ
Kern
S E
SE
D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002886:Chromosomes, Human, Pair 17; D003062:Codon; D017124:Conserved Sequence / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D016158:Genes, p53 / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics*; D014407:Tumor Cells, Cultured
D003062:Codon