Discovery and Validation of Plasma DNA Methylation Biomarker for Detection of Stomach Cancer
Condition: Stomach Cancer; Gastric Cancer
MeSH terms: Stomach Neoplasms
Study type: Observational

Summary: 
      Background:

      Stomach cancer is common around the world. The US is a low-risk region. But the 5-year
      survival rate in the US is low. This is because the cancer is usually in a late stage by the
      time it is diagnosed. One way to detect it earlier is to screen many people with a procedure
      called endoscopy. But this may not be feasible in low-risk or developing countries.
      Researchers want to find a biomarker for early-stage disease to help them create an effective
      way of screening. DNA methylation is a chemical modification of DNA. It generates a signal
      for certain cancers, including stomach cancer. Researchers want to find a blood-based DNA
      methylation marker for stomach cancer.

      Objective:

      To study plasma DNA methylation as a potential biomarker for detection of stomach cancer.

      Eligibility:

      Participants from 2 studies already done in China

      Design:

      Researchers will use blood samples from participants in the 2 studies. The blood was
      collected in 1999/2000. They will use samples from some who developed stomach cancer between
      those years and 2006. The other samples will be from some who stayed cancer free in that
      time.

      Participants already gave written informed consent.

      Researchers will take DNA from the samples. They will look for methylation.
    

Detailed description: 
      Despite markedly declining incidence in recent decades, almost one million new cases of
      stomach cancer were estimated to have occurred in 2012, making it the fifth most common
      malignancy in the world after lung, breast, colorectal, and prostate cancer. More than 70% of
      cases (677,000 cases) occur in developing countries, and half occur in Eastern Asia (mainly
      in China). Although North America is considered to be a low-risk region, 22,000 cases are
      diagnosed in the US each year. Five-year survival for 2005-2011 in the US was less than 30%,
      since stomach cancer is generally asymptomatic in early stages and has often metastasized by
      the time of diagnosis. In contrast, 5-year survival rates are almost 70% in South Korea and
      Japan where mass screening programs have been implemented and a large proportion of stomach
      cancer is detected in early stages. UGI endoscopy has been considered as the gold standard
      for diagnosis of stomach cancer but endoscopy-based mass screening may not be feasible in
      relatively low-risk or less developed regions. Therefore, identification of biomarkers for
      early stage disease is crucial to in the development of effective screening strategies. With
      the recent advances in cancer genetics and assay technologies, this is an opportune time to
      discover minimally invasive, specific, and cost-effective biomarkers.

      A surprising discovery from the large scale cancer genome projects such as TCGA was the
      enormous variation in mutational patterns both across and within individual tumor types. Even
      the most commonly mutated genes were typically altered in less than half of cases of a given
      cancer. The two most frequently mutated driver genes in stomach cancer, TP53 (tumor protein
      p53) and ARID1A (AT rich interactive domain 1A), were mutated in only 44% and 17% of cases,
      respectively. Mutation rates for the remaining stomach cancer driver genes were even lower.
      Importantly, mutations of these genes are often spread across several exons which complicates
      detection of DNA-based sequence variation, since large numbers of samples and extensive
      genotyping will be required to achieve adequate sensitivity and power. In contrast, DNA
      methylation, which is a chemical modification of CpG dinucleotides that does not alter base
      pair sequence, generates a more robust signal as compared to genetic alterations. For
      example, methylation in the Stratifin promoter was found in 96% (24/25) of breast carcinomas,
      83% (15/18) of ductal carcinoma in situ, and 38% (3/8) of benign atypical hyperplasias, but
      was absent in breast tissues from healthy individuals, which suggests that methylation status
      of this locus is an early event of breast cancer that could serve as a breast cancer
      biomarker. Aberrant DNA methylation occurs in an early phase of carcinogenesis and
      contributes to development and progression. Notably, a comprehensive molecular
      characterization of 295 primary stomach cancers in TCGA classified the tumors into four
      molecular subtypes. All four types exhibited DNA hypermethylation to various degrees, with
      one type more heavily methylated than any other tumor group previously analyzed in TCGA.
      Moreover, other studies have also suggested that aberrant methylation may be associated with
      various pre-malignant conditions like Helicobacter pylori infection, severe gastritis,
      intestinal metaplasia, and dysplasia, implying a role for an epigenetic field effect which
      may reflect the earliest steps in neoplastic transformation of the stomach. Importantly,
      hypermethylation can be detected in circulating cell-free DNA (cfDNA) which is thought to be
      derived from preneoplastic or tumor tissues. Efforts to discover blood-based DNA methylation
      markers are underway in various types of cancers. In particular, plasma methylated SEPT9 DNA
      has been evaluated for detection of colorectal cancer, and a commercialblood test for this is
      under review for approval by the US Food and Drug Administration.
    

Observational model: Other
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        Nutrition Intervention Trials (NIT) - Community Sample Shanxi - Hospital and community
        samples@@@@@@
      
Biospecimen description: 
      Testing pre-existing serum samples from 2 ongoing studies covered by other SSIRB approvals -
      OH95-C-N027-G (Esophageal CA Genetic Studies) and PH99-C-N031-H (Nutritional Intervention
      Trials in Linxian China - Continued Follow-Up)
    
Keywords: Epidemiology; Cancer; Methylation; Genetics; Screening