SMAD4 Gene Mutations Are Associated with Poor Prognosis in Pancreatic Cancer

Abstract

Purpose: Recently, the majority of protein coding genes were sequenced in a collection of pancreatic cancers, providing an unprecedented opportunity to identify genetic markers of prognosis for patients with adenocarcinoma of the pancreas. Experimental Design: We previously sequenced more than 750 million base pairs of DNA from 23,219 transcripts in a series of 24 adenocarcinomas of the pancreas. In addition, 39 genes that were mutated in more than one of these 24 cancers were sequenced in a separate panel of 90 well-characterized adenocarcinomas of the pancreas. Of these 114 patients, 89 underwent pancreaticoduodenectomy, and the somatic mutations in these cancers were correlated with patient outcome. Results: When adjusted for age, lymph node status, margin status, and tumor size, SMAD4 gene inactivation was significantly associated with shorter overall survival (hazard ratio, 1.92; 95% confidence interval, 1.20-3.05; P = 0.006). Patients with SMAD4 gene inactivation survived a median of 11.5 months, compared with 14.2 months for patients without SMAD4 inactivation. By contrast, mutations in CDKN2A or TP53 or the presence of multiple (z4) mutations or homozygous deletions among the 39 most frequently mutated genes were not associated with survival. Conclusions: SMAD4 gene inactivation is associated with poorer prognosis in patients with surgically resected adenocarcinoma of the pancreas.Pancreatic cancer is the fourth leading cause of cancer death in the United States (1). Worldwide pancreatic cancer is responsible for more than 213,000 deaths each year (2). The 5-year overall survival rate for all patients diagnosed with pancreatic cancer is less than 4% (3). Surgical resection offers the best hope for long-term survival, with a 17% 5-year survival rate in most surgical series (4 -10). A number of pathologic features have been shown to correlate with outcome following surgery (4,(11)(12)(13)(14). For example, the completeness of resection (margin status), size of the cancer, degree of differentiation, vascular invasion, lymph node status, and tumor stage are all independent prognostic indicators following pancreaticoduodenectomy for pancreatic cancer (4, 11 -16). These factors have been useful guides in the clinical management of patients with pancreatic cancer. Genetic markers that could be used as prognostic indicators of outcome would be useful in establishing an individualized treatment plan for a patient. For example, a more aggressive surgical approach, such as vascular resection and reconstruction, may be considered for a patient with a reduced risk of systemic recurrence.In an attempt to establish such genetic makers, we took advantage of the recently completed mutational analysis of the pancreatic cancer coding genome (17). The results of this ''pancreatic cancer genome project'' provide a unique opportunity to determine if any genes with somatic changes correlate with patient outcome following surgical resection (17). This previous study included the sequencing of the protein-coding exons f...

Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells

“…Previous studies have established that Smad4 may interact with other signaling pathways, including Notch and MAPK, and function independently of TGF-β (20). Despite clear evidence of the association between Smad4 and pancreatic cancer (1,(4)(5)(6), the mechanism of the cross-talk between Smad4 and other signaling pathways that affect the development of pancreatic cancer remains unclear. JNK activity is reported to be pivotal in tumor development, particularly in gastrointestinal tumors, including hepatocellular carcinoma (12), colon cancer (26) and pancreatic cancer (27).…”

“…Smad4, also referred to as deleted in pancreatic cancer locus 4, is localized to chromosome 18q21, and was originally identified as a signaling mediator of the transforming growth factor-β (TGF-β) signaling pathway (3). It has been reported that tumor development is induced by a decrease in Smad4 in pancreatic cancer, and mutations of the Smad4 gene predict a poorer prognosis of patients with pancreatic ductal adenocarcinoma and pancreatic cancer (4)(5)(6). Furthermore, verbal evidence supports the role of Smad4 as a tumor suppressor gene in pancreatic tumorigenesis (7).…”

The genetic classification of pancreatic neoplasia

“…Blackford et al [59] analyzed sequence data on 39 genes frequently mutated in PDA in a well-characterized series of 90 tumors and correlated the results with patient outcome. They found that loss of SMAD4 in a pancreatic cancer was associated with a shorter overall survival (11.5 months compared with 14.2 months in patients whose tumors had intact SMAD4).…”

Biomarkers Screening Between Preoperative and Postoperative Patients in Pancreatic Cancer

“…overall survival is about 20-25%. A mass of markers, such as SMAD4 and SPARC were researched to evaluate risk of development of widespread metastasis and outcome after surgical resection (Tascilar et al, 2001;Infante et al, 2007;Blackford et al, 2009). Although these researches may improve clinical decision making, but might not be sufficiently informative.…”