Molecular Profiling of Gastric Cancer: Toward Personalized Cancer Medicine

Gastric cancer is the fourth most common cancer worldwide and the second leading cause of global cancer deaths. The prognosis of patients diagnosed with gastric cancer continues to be dismal, despite improving surgical and adjuvant treatment approaches, with a 5-year overall survival less than 25%. The high disease incidence and poor outcomes continue to make gastric cancer a topic of active clinical and basic scientific research. Notwithstanding these efforts, relatively little is known about the molecular changes that contribute to the development of this deadly disease and how they may influence outcomes and therapeutic results. Gastric cancer can be considered a multifactorial disease because many inherited and environmental factors play a role in its carcinogenesis, including the genetic background of the host, infectious agents such as Helicobacter pylori, and dietary habits. Gastric cancer is a heterogeneous disorder that can be divided into at least the following two main histologic types on the basis of the Lauren classification: intestinal and diffuse types. These two types have distinct morphologic, clinical, and epidemiologic features and may also represent a different molecular mechanism of tumor development and progression. The identification of germline E-cadherin (CDH1) mutations in families with hereditary diffuse gastric cancer provided early insight into the initial changes that promote gastric tumorigenesis and established CDH1 as a bona fide tumor suppressor. Subsequent studies indicated that, although germline CDH1 mutations are common in hereditary gastric cancer of the diffuse, but not intestinal, type, somatic mutations in CDH1 are frequently identified in sporadic gastric cancer of both major histologic subtypes. In addition, somatic epigenetic alterations, such as CDH1 promoter hypermethylation, are present in diffuseand intestinal-type tumors and result in gene silencing. This epigenetic silencing of CDH1 gene expression represents the “second hit” in approximately 50% of hereditary diffuse gastric cancers, whereas the prevalence of CDH1 promoter hypermethylation in sporadic gastric cancers ranges in estimates from 11% to 46% depending on the histologic subtype. Relatively small sample sizes and a focus on hereditary cancers or a single histologic subtype have hampered previous studies that evaluated the prevalence of CDH1 somatic mutations in gastric cancer overall. The current study by Corso et al evaluated a large set of familial and sporadic gastric cancers to provide a more comprehensive analysis of the prevalence of CDH1 somatic mutations and their correlation with patient survival. The authors analyzed 246 patients with sporadic (n 174) or familial (n 72) gastric cancer for CDH1 structural changes (either mutation or loss of heterozygosity) or epigenetic alterations (CDH1 promoter hypermethylation). The results indicated that, overall, 31% of gastric cancers carried CDH1 alterations, two thirds of which were epigenetic alterations and one third of which were structural alterations. Patients with CDH1 structural alterations displayed a poorer overall survival than in patients with either no changes or epigenetic changes only. In addition, the authors report that CDH1 alterations (both structural and epigenetic) were found in 27.5% of intestinal-type and 38.4% of diffuse-type gastric cancers. Although these alterations were not associated with a worse overall survival in patients with diffusetype tumors, there was a strong association between CDH1 structural alterations and poorer overall survival in patients with intestinaltype tumors. The major finding by Corso et al that nearly one third of gastric cancers harbor somatic CDH1 alterations and those with structural alterations carry a poorer prognosis raises the question of whether somatic CDH1 alterations should influence the clinical management of gastric cancer. Although the findings in this study significantly clarify the extent of somatic CDH1 alterations in gastric cancer, there continues to be insufficient evidence to warrant regular CDH1alteration analysis as a standard prognostic indicator or for predictive use in therapeutic decision making. However, the incorporation of this and other molecular features to more specifically characterize gastric cancers should certainly be part of the design of prospective studies of surgical and adjuvant therapy for this disease. The role of epigenetic changes and tumor-suppressor silencing through promoter hypermethylation in human cancers has raised the specter of the use of demethylating agents such as 5-azacytadine as a therapeutic intervention. Large-scale changes in DNA methylation have been noted in the gastric cancer genome, and the CpG island methylator phenotype may predict a poor outcome independent from the tumor stage. A large number of genes that are suppressed by hypermethylation have been reported in gastric cancer in addition to CDH1, including the DNA mismatch repair genes, CDKN2A (p16), and MGMT (O6-methylguanine DNA methyltransferase). Whether therapeutic demethylation of some or all of these genes in gastric cancer may lead to tumor responses has yet to be tested. The use of demethylating agents has also been considered a potential chemoprevention strategy for carriers of the germline CDH1 mutation to slow or reverse the epigenetic second hit that inactivates CDH1 expression. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 7 MARCH 1 2013