Prevalence and clinical significance of combined K-ras mutation and p53 aberration in pancreatic adenocarcinoma.
CONCLUSIONS
This study could not attribute survival differences to the coincident acquisition of two common genetic alterations, K-ras mutation and p53 overexpression in pancreatic adenocarcinoma patients. Additionally, our data indicate the converse to be true: Those patients lacking both K-ras mutation and aberrant p53 expression showed the shortest survival when compared with cases showing either alteration or both. This study also showed the negative effect of K-ras mutation and p53 expression on pancreas cancer patients' survival after treatment with either radiation therapy or chemotherapy.


BACKGROUND
Mutations of the oncogene K-ras at codon 12 are reported to be the most common genetic alteration in pancreatic carcinoma, whereas either overexpression or mutation of the tumor suppressor p53 gene is considered the most common genetic alteration in neoplasia of all types. p53 overexpression has been attributed to survival differences in pancreatic carcinoma, but such association is still controversial. No studies have fully documented the combined incidence of K-ras and p53 alterations in pancreatic adenocarcinoma, or their combined effect on patient survival in a large case series. The influence of radiation or chemotherapy in groups showing both, either, or neither mutation is also undocumented.


METHODS
Paraffin-embedded tissue sections from 76 cases of pancreatic adenocarcinoma were cut for DNA extraction for K-ras analysis and immunohistochemical staining for aberrant p53 expression. K-ras mutation was determined by single-strand conformation polymorphism (SSCP) and slot-blot allele-specific oligonucleotide (ASO) hybridization of PCR-amplified DNA product p53 expression was scored on the basis of percent nuclear staining with the MAb DO7.


RESULTS
Sixty-four of 76 cases (84%) showed K-ras mutation, p53 expression, or both, K-ras was mutated in 55 of 76 cases (72%). p53 was expressed in 33 of 76 cases (43%). Twenty-four of 76 cases (31%) showed both K-ras mutation and p53 expression. The presence of both alterations was not related to significant differences in tumor grade, stage, or survival compared to either alteration alone. A sizable subset (16% of cases) lacked either alteration, and surprisingly, this group showed the shortest median survival compared to those with K-ras mutation, p53 expression, or both (p = 0.024). Patients whose tumors were K-ras-negative showed the greatest difference in median survival with radiation therapy (median survival 30.8 mo vs 7.8 mo with no radiation, p = 0.005).
Dergham
S T
ST
Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Dugan
M C
MC
Kucway
R
R
Du
W
W
Kamarauskiene
D S
DS
Vaitkevicius
V K
VK
Crissman
J D
JD
Sarkar
F H
FH
D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D011379:Prognosis; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D017931:DNA Primers; D016159:Tumor Suppressor Protein p53