Why identical mutations cause different types of cancer

Why do alterations in certain genes only cause cancer in specific organs of the human body? Scientists from the German Cancer Consortium (DKTK), the Technical University of Munich (TUM) and the Göttingen University Medical Center have now shown that cells from different organs are differentially susceptible to activating mutations in cancer drivers: same mutation in the precursor cells. of the pancreas or bile duct leads to different fundamental results. The team first discovered that tissue-specific genetic interactions are responsible for the differential susceptibility of the biliary and pancreatic epithelium to oncogene transformation. The new findings could guide more accurate therapeutic decision-making in the future.

There have been no significant improvements in the treatment of the pancreas and biliary tract cancer in recent decades and so far no effective targeted therapies are available. “The situation of patients with pancreatic and extrahepatic bile duct cancer is still very depressing, with approximately only 10% of patients surviving five years,” says Dieter Saur, DKTK translational cancer research professor at the university hospital. of TUM Klinikum rechts der Isar, associate site of DKTK Munich.

DKTK is a consortium centered around the German Cancer Research Center (DKFZ) in Heidelberg, which has long-term collaborative partnerships with oncology centers specializing in universities throughout Germany.

“To discover new therapeutic strategies that improve the prognosis of these patients, it is essential to understand the fundamental genetic networks and interactions that drive these tumors in a tissue-specific way. This will allow for very precise molecular interventions in the future.”

The research team examined the development of biliary and pancreatic cancer in mice, replacing the normal oncogenes PIK3CA and KRAS with a version that contained a mutation identical to that of human cancers. Expression of these oncogenes in the common precursor cells of the extrahepatic bile duct and pancreas led to very different results. Mice with the mutated PI3K gene developed mostly biliary tract cancer, while mice with the mutated KRAS gene developed exclusively pancreatic cancer.

This was unexpected because both genes are mutated in both types of human cancer. Subsequent analyzes uncovered the fundamental genetic processes underlying the differential sensitivity of different tissue types to oncogenic transformation.

“Our results are an important step toward solving one of the greatest mysteries of oncology: why alterations in certain genes cause cancer only in specific organs?” says Chiara Falcomatà the first author of the new publication. “Our studies in mice revealed how genes cooperate to cause cancer in different organs. We have identified the main actors, the order in which they occur during tumor progression, and the molecular processes of how they turn normal cells into threatening cancers. These processes are potential targets for new treatments. “

In mice, the team discovered a process by phases of genetic alterations, which lead to the development of these types of cancer. Some cooperating genetic events overactivate the PI3K signaling pathway, making them cancerous. Others disrupt regulatory proteins, inactivating their ability to suppress cancer progression.

“Understanding genetic interactions in different types of cancer will guide more accurate therapeutic decision-making in the future,” says Günter Schneider, professor of translational cancer research at Göttingen University Medical Center. “Our ability to design specific genetic alterations in mice allows us to study the function of cancer genes and model specific subtypes of cancer. These mouse models are also invaluable for testing cancer drugs before using them in clinical trials.” .

“What we showed is that the function of an oncogene is different depending on the type of tissue and what other genes are altered,” says Roland Rad Professor of TUM and researcher at DKTK. “These oncogenes must sequester the intrinsic signaling network of a specific tissue to allow the development of cancer. Interestingly, these networks only exist in specific tissue types, making them susceptible to cancer development.”

These findings have important implications for therapeutic interventions. “The concept that multiple tissue-specific genetic interactions drive cancer progression demonstrates that no single gene can predict the responsiveness of a cancer for a particular therapy, “says Saur.” In the future, it is key to mechanically understand the tissue-specific determinants of the therapeutic response and resistance to get precision medicine to the next level. ”

Several authors, including Dieter Saur and Roland Rad, are based at TranslaTUM, TUM’s Translational Cancer Research Center. At this interdisciplinary research institute, physicians work with colleagues in the fields of natural sciences and engineering in research into the causes, diagnoses, and potential treatments for cancer.