First large-scale Genomic analysis of stomach cancer confirms two Discrete Tumor types

Stomach cancer is actually two different disease variations based on the genetic makeup, and every else responds to chemotherapy, according to an international team of scientists led by researchers from Duke-National University of Singapore Graduate Medical School.

The finding, published in the edition of the journal Gastroenterology, August 1, 2011 is the first large-scale genomic analysis of gastric cancer to confirm the two discrete tumor types.

The researchers also found that a certain regime of chemotherapy more effective on a tumor type, while another drug works best on the other, the basis for a more efficient approach to the treatment of gastric cancer patients.

"Our study is the first to show that a proposed molecular classification of gastric cancer genomic subtypes that respond differently to therapies, can identify which is crucial in the efforts to customize treatments for patients," said Patrick Tan, MD, PhD, senior author of the study and associate professor in cancer and stem cell biology program at Duke-NUS Graduate Medical School.

An estimated 21,000 people in the United States will be diagnosed with stomach cancer this year, and 10,570 will die of the disease, according to the National Cancer Institute. Only lung cancer worldwide is more lethal.

Patients have been very different responses to treatments, suggest that perhaps their tumors underlying differences.

Allude to these differences a microscopic pathology test developed in the 1960s, broadly described how well the tumor cells clumped together, typing them as "intestinal" or "fugitive." Known as the format of Lauren, after the doctor who the distinction, first described briefly attacked the analysis as a reliable prognostic instrument.

"Most stomach cancer patients today is treated with a common uniform regime," said Tan, who also serves as group leader in the Genome Institute of Singapore and a senior researcher at the Cancer Sciences Institute of Singapore.

"One reason for this is that the Lauren format requires considerable stomach cancer experience and there is considerable variation in the classification of stomach cancers, even among qualified pathologists," said Tan.

But the genetic findings by Singapore-based researchers add more specificity to the microscopic classifications and, for the first time, a guide for doctors to write effective treatments.

The team first analyzed 37 gastric cancer cell lines, which were purely free cancer cells of blood, tissue and other counterfeit products that might skew the results.

Gene expression profiles yielded very different patterns that indicated the two subtypes. The genetic subtypes validated in 64% of cases, the classifications of Lauren-intestinal or diffuse. In the remaining 36 percent of the cases distinguish subtypes the genomic process where the pathology test could not.

Findings were confirmed using tumor samples of 521 cancer patients.

"It was very reassuring for us that genomic subtypes associated with Lauren's system were," said Tan. "There is a general assumption in the field that intestinal and diffuse stomach cancers (such as classified by Lauren) two very different versions of stomach cancer, and now represent genomic data confirms this by showing that the two genomic subtypes have very different molecular patterns."

Establishing the very precise definition of tumor subtypes enabled the researchers to observe the different responses to chemotherapy. The intestinal-type tumors showed significantly more responsive to the chemotherapy 5-fluorouracil and oxaliplatin, and are more resistant to cisplatin than the diffuse tumors.

"The exact mechanistic causes of this difference are currently unclear, and this is an area that we are actively working on," Tan said, adding that researchers are working to find molecular subtype-specific vulnerabilities to drugs.

The researchers have begun a prospective clinical trial, called the 3 G-study, where stomach cancer tumors genomically will be profiled, and treatments will be allocated on the basis of the type of tumor.

Comments:

In addition to Duke-NUS, research institutions included the National Cancer Centre Singapore; National University of Singapore; Singapore General Hospital; Genome Institute of Singapore; Yonsei Cancer Center, Seoul, South Korea; Peter MacCallum Cancer Centre, East Melbourne, Australia; Singapore, National University Health System; Kanagawa Prefecture Cancer Center, Yokohama, Japan; Leeds Institute of molecular medicine, Leeds, England; Yonsei University College of Medicine, Seoul, South Korea; MD Anderson Cancer Center, Houston, Texas.

The study was funded by the Biomedical Research Council and national medical research Council of Singapore, Duke-NUS Graduate Medical School and the Cancer Sciences Institute of Singapore.

The researchers reported no conflicts of interest.

Article reference:
Duke University Medical Center