Molecular pathology of primary and metastatic ductal pancreatic lesions

Abstract

BACKGROUND The molecular pathology underlying the development and progression of ductal pancreatic adenocarcinoma is poorly understood relative to that of other major cancers in industrialized societies. The frequency, nature, and distribution of p53 abnormalities, their temporal relationship to the metastatic and clinicopathologic phenotypes of sporadic and familial pancreatic cancer, and their consequent effects on the genetics and expression of critical wild‐type p53‐regulated genes (mdm‐2 and p21/WAF‐1) warrant examination in pancreatic adenocarcinoma. This molecular and immunochemical study of the p53, mdm‐2, and p21/WAF‐1 genes and gene products examined the largest series of nonneoplastic, neoplastic, and metastatic ductal pancreatic lesions reported to date in relation to clinicopathologic profile. METHODS Histologically confirmed specimens of primary (n = 136) and metastatic (n = 23) sporadic and familial ductal pancreatic adenocarcinoma lesions were subjected to immunochemical analyses of p53 expression in which a panel of 3 antibodies was utilized. A panel of nonneoplastic but histologically abnormal pancreatic lesions (n = 77) from individuals with varied histories of cigarette smoking were subjected to similar immunohistochemical examinations. In addition, 3 specimens from patients with chronic pancreatitis, 2 specimens of normal fetal pancreata, and 16 specimens of normal adult pancreata were examined as control tissues. Suitable frozen and archival microdissected tumor lesions were evaluated for mutations in exons 4‐9 of the p53 gene by single strand conformation polymorphism (SSCP) and dideoxy sequencing analyses in which two distinct sets of outer and nested intron‐based amplification primers were used for each exon. A subset of 25 tumor specimens and 18 tumor‐derived cell lines for which the p53 mutation status was known were examined for amplification and/or overexpression of the mdm‐2 gene; amplification was determined by Southern hybridization and overexpression by immunohistochemical and Western blot analyses. Similarly, mutations in the coding region of p21/WAF‐1 gene were examined by SSCP and DNA sequence analyses, and steady‐state expression of the p21/WAF‐1 protein was assessed by Western blot analysis in these subsets of tumors and tumor‐derived cell lines. RESULTS Positive ductal nuclear p53 immunostaining was demonstrated in 56% of primary tumors and 54% of metastatic lesions. The frequency did not differ significantly between sporadic and familial lesions, and immunostaining was not observed in ductal, acinar, or islet cell elements of normal pancreata or histologically abnormal benign pancreatic lesions from cigarette smokers. A total of 70% of tumor samples revealed reproducible SSCP abnormalities for p53; 42% of these were found in exons 7 and 8. DNA sequence analysis of cases with greater than 35% epithelial cellularity (n = 25) revealed 17 missense mutations, 12 of which were transitions. Seventy‐five percent of these transitions were of G:C→A:T type. A total of 22% of ...

Association of MDM2 expression with shorter progression-free survival and overall survival in patients with advanced pancreatic cancer treated with gemcitabine-based chemotherapy

“…The percentages of MDM2 and p53 IHC expression in this study were similar to those from previous reports [19, 21, 22]. Under ordinary conditions, MDM2 and p53 form a negative regulation loop [23].…”

“…Therefore, functional p53-mediated apoptosis and cell cycle regulation may be inefficient, thus contributing little to gemcitabine-mediated cytotoxicity in pancreatic cancer patients. Furthermore, the status of p53 is not prognostic for pancreatic cancer [19–22], and the prognostic significance of MDM2 in resected pancreatic cancer is inconsistent [21, 22]. …”

Clinical Significance of p16 Protein Expression Loss and Aberrant p53 Protein Expression in Pancreatic Cancer

“…Zhang et al25 stated that p53 mutation occurs in relatively early stages of carcinogenesis because p53 protein overexpression is observed in intraductal papillary adenocarcinoma. Ruggeri et al19 reported similar results. However, researchers have proposed various results in the association between p53 mutation and clinicopathologic properties and survival rate.…”

Proteasome-Mediated Degradation and Functions of Hematopoietic Progenitor Kinase 1 in Pancreatic Cancer

“…With the progression of PanIN lesions to invasive PDA, there is a gradual accumulation of molecular abnormalities that are commonly seen in invasive PDA, including K-ras activation by point mutation (3) and inactivation of the tumor suppressor genes p16 (4), SMAD4/DPC4 (5), and p53 (6). Increased expression of the epidermal growth factor (EGF) family of mitogenic peptides, including EGF and transforming growth factor-α, cripto, amphiregulin, and β-cellulin, is a characteristic feature of PDA, along with elevated expression of their corresponding EGF receptor (EGFR)–related tyrosine kinase receptor subtypes, including EGFR and c-erb B/HER-2 (7). More recently, the mammalian Ste20-like serine/threonine kinase family has been shown to be involved in human malignancies (8–11).…”