A genome-wide analysis shows that alterations in gene pathways that govern cellular metabolism and those that maintain the DNA and proteins that make up chromatin contribute to development of the most common form of adult kidney cancer called clear cell renal cell carcinoma, said The Cancer Genome Atlas consortium led by researchers at Baylor College of Medicine’s Human Genome Sequencing Center in a report that appears in the journal Nature.
Members of the consortium surveyed more than 400 of these human kidney tumors to identify 19 mutated genes. Among these are those that are part of the PI3K/Akt pathway, which has been frequently associated with cancer.
Cells undergo metabolic shift
“The metabolic perturbation is important,” said Dr. Richard Gibbs, director of the BCM Human Genome Sequencing Center and a major contributor to the report. "When combined with knowledge of alterations in genes such as PBRM1, that are important to maintaining the stability of chromatin, we have more insight into the causation of this cancer," he said. "We found a generalized pattern of metabolic transformation in the cells that extends beyond the few cases marked by heritable mutations in metabolic genes."
"We were excited about the finding that high grade, high stage clear cell kidney tumors undergo a metabolic shift suggestive of the Warburg effect in cancer," said Dr. W. Marston Linehan, chief of the Urological Oncology Branch at the National Cancer Institute in Bethesda, Maryland. "These findings, which are consistent with those described in different types of kidney cancer associated with mutation of Krebs cycle enzymes, potentially provide the foundation for the development of novel approaches to therapy for this disease."
The Warburg effect in cancer cells refers to the fact that cancer cells generate energy in the absence of oxygen. While normal cell produce energy through the use of oxygen, they are serving the needs of cell functions. Cancer cell energy production is directed at growth and spread of the tumor. The Krebs cycle, carried out in the mitochondria or battery of the cell, is critical to converting carbohydrates and fats into energy the cell can use.
"What is striking is the centrality of the metabolic alterations to cancer," said Dr. Michael Ittmann, professor of pathology and immunology at BCM and an expert in urologic cancers, who was not involved in the research. "I think this paper points out how central that kind of alteration is in the biology of renal cell carcinoma. This is a more integrated analysis and presents a more comprehensive picture of the interlinking aspects and the impact on cellular metabolism. People are talking about using metabolically targeted drugs such as the diabetes drug metformin to treat or prevent cancers. It’s important to be able to understand the biology of the metabolic alterations. It means we can be more precise in targeting these metabolic alterations."
"In the kidney cells, only a fraction have inherited mutations in metabolic genes that go on to be the hallmarks of cancer," said Gibbs.
"A lot of the story builds around DNA methylation," said Dr. Chad Creighton, associate professor in the NCI-designated Dan L. Duncan Cancer Center at BCM. Creighton, an expert in bioinformatics, headed the analysis work to integrate all the diverse molecular data types generated for the project. DNA methylation in particular refers to a chemical change that can turn off a gene.
Aberrant methylation patterns
"There are widespread aberrant methylation patterns with kidney cancer," said Creighton. "More aggressive cancers have a methylation pattern that is distinct from less aggressive kidney cancers, and aberrant DNA methylation appears to have a role in activating the PI3K/Akt pathway."
Dr. Preethi Gunaratne, associate professor of biology and biochemistry at the University of Houston, and of pathology and immunology and the Human Genome Sequencing Center at BCM, said, "The finding that microRNA-21 is induced and could be a driver of the PI3K/AKT pathway in more advanced clear cell renal tumors is exciting and provides a new therapeutic target for RNA therapy for patients presenting with advanced stages of this cancer in the future."
The findings prove the value of projects such as The Cancer Genome Atlas.
Opportunity to work with Cancer Genome Atlas
"In my view, we are developing scientifically answerable questions rather than hit or miss hypotheses," said Gibbs. "We can now really ask, given the landscape of what happens in tumors, what perturbations are possible in the background of different drugs that inhibit chromatin state genes or metabolic genes. We have all the pointers and handles to answer these fundamental questions."
"Having worked on the genetic basis of kidney cancer for nearly 30 years, the opportunity to work with The Cancer Genome Atlas group on this project was the dream of a lifetime," said Linehan.
Gibbs and Linehan were project leaders of the group. Other BCM contributors included David A Wheeler; Donna Muzny; Caleb Davis; Margaret Morgan; Liu Xi; Kyle Chang; Nipun Kakkar; Lisa R. Treviño; Susan Benton; Jeffrey G. Reid; Donna Morton; Harsha Doddapaneni; Yi Han; Lora Lewis; Huyen Dinh; Christie Kovar; Yiming Zhu; Jireh Santibanez; Min Wang; Walker Hale and Divya Kalra.