Epigenetic difference in twins explains different risk of breast cancer

ScienceDaily (Oct. 17, 2012) — It can be detected an epigenetic alteration associated with an increased risk of breast cancer in the sick twin a few years before the clinical diagnosis.

Monozygotic twins have the same genome, that is, the same DNA molecule in both siblings. Despite being genetically identical, both twins may have different diseases at different times. This phenomenon is called "twin discordance." But how can people who have the same genetic sequence present different pathologies and at different ages? The explanation partly lies in the fact that the chemical signals added in the DNA to "switch off" or "switch on" genes can be different. These signals are known as epigenetic marks.

The research team led by Manel Esteller, director of the Cancer Epigenetics and Biology Program at the Bellvitge Biomedical Research Institute (IDIBELL), Professor of Genetics at the University of Barcelona and ICREA researcher, has identified an epigenetic change in the twin who will develop breast cancer but not in the healthy one. The finding has been advanced this week in the journal Carcinogenesis.

The research group led by Dr. Esteller studied the levels of DNA methylation (the best known epigenetic mark) in the blood of 36 pairs of twins diagnosed with breast cancer or healthy. Researchers analyzed half a million pieces of the genome in each twin and compared them with each other, and they found that women who have developed breast tumours showed a pathological gain of methylation in the DOK7 gene. " an epigenetic alteration associated with an increased risk of breast cancer can be detected in the sick twin a few years before the clinical diagnosis," said Dr. Esteller about the research results.

The next step for the researchers will be knowing the exact function of the DOK7 gene. "We believe it is a regulator of tyrosine kinases, an antitumor drug target already used for the treatment of breast cancer. If DOK7 performs this function, new studies to test drugs with tumour chemopreventive effects in breast cancer could be planned in the future," concludes the research coordinator.

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The above story is reprinted from materials provided by IDIBELL-Bellvitge Biomedical Research Institute.

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Journal Reference:

Heyn H, Carmona FJ, Gomez A, Ferreira HJ, Bell JT, Sayols S, Ward K, Stefansson OA, Moran S, Sandoval J, Eyfjord JE, Spector TD, Esteller M. DNA methylation profiling in breast cancer discordant identical twins identifies DOK7 as novel epigenetic biomarker. Carcinogenesis, 2012

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Epigenetic analysis of stomach cancer finds new disease subtypes

ScienceDaily (Oct. 17, 2012) — Researchers at the Duke-NUS Graduate Medical School in Singapore have identified numerous new subtypes of gastric cancer that are triggered by environmental factors.

Reported in the Oct. 17, 2012, issue of the journal Science Translational Medicine, the findings are based on the science of epigenetics, a study of gene activity. The insights into the complexities of stomach cancer could lead to better treatment approaches for the second leading cancer killer in the world, behind lung cancer.

"Gastric cancer is a heterogenous disease with individual patients often displaying markedly different responses to the same treatment," said Patrick Tan, M.D., Ph.D at Duke-NUS and lead author of the study. "Improving gastric cancer clinical outcomes will require molecular approaches capable of subdividing patients into biologically similar subgroups, and designing subtype-specific therapies for each group."

Like many cancers, stomach cancer is caused by genetic mutations, but also by external factors that affect the way genes work. These factors, called epigenetic alterations, work by methylation, a chemical process in which specific locations along the DNA, called CpG sites, are modified through the addition of a methyl group. Methylation silences a gene's behavior without actually altering the DNA sequence.

In their study, Tan and colleagues used 240 primary tumors and cell lines to conduct the first full survey of the DNA methylation landscape in gastric cancer, known as the methylome. Their goal was to identify new molecular subgroups of gastric cancer not caused by primary genetic mutations, particularly those that might be targeted with therapies.

The researchers found that the gastric cancer methylome was widespread, with more than half of the CpG sites analyzed demonstrating altered methylation patterns in cancer. Many of the methylation alterations were associated with significant changes in gene expression, suggesting that the methylation alterations may be functionally important in the development of gastic cancer.

The researchers also identified a subgroup of gastric cancers with extremely high levels of methylation. The CIMP subgroup (CpG Island Methylator Phenotype) had been previously proposed, but its clinical significance remained unclear. The Duke-NUS-led team confirmed the CIMP subgroup, correlating it with younger patients who had a poor prognosis. They also demonstrated in laboratory experiments that these tumors may have increased sensitivity to demethylating drugs.

"Our study does provide clarity in unambiguously demonstrating the presence of this subgroup and its features," Tan said. "What's more, we are encouraged that there may be potential utility in testing the sensitivity of CIMP tumors to more potent DNA demethylating agents and possibly other epigenetic drugs."

The study also discovered long-range regions of epigenetic silencing, some targeting a generalized region and others that targeting a single gene. The finding may help identify novel genes where methylation events play a role in tumor growth.

"Our results strongly demonstrate that gastric cancer is not one disease but a conglomerate of multiple diseases, each with a different underlying biology and hallmark features," Tan said. "If gastric cancer is the result of multiple interacting factors, including both environmental factors and host genetic factors, we need better ways to diagnosis and treat it.

"These findings move us forward, and additional work will focus on developing simple diagnostic tests to detect gastric cancer at earlier stages, plus drugs and drug targets that might exhibit high potency against different molecular subtypes of disease," Tan said.

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Journal Reference:

Hermioni Zouridis, Niantao Deng, Tatiana Ivanova, Yansong Zhu, Bernice Wong, Dan Huang, Yong Hui Wu, Yingting Wu, Iain Beehuat Tan, Natalia Liem, Veena Gopalakrishnan, Qin Luo, Jeanie Wu, Minghui Lee, Wei Peng Yong, Liang Kee Goh, Bin Tean Teh, Steve Rozen, and Patrick Tan. Methylation Subtypes and Large-Scale Epigenetic Alterations in Gastric Cancer. Sci Transl Med, 17 October 2012 DOI: 10.1126/scitranslmed.3004504

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