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Discovering the causes of cancer and the means of prevention

Christian Kratz Investigates Cancer Predisposition Syndromes

A Profile of Tenure-Track Investigator Christian Kratz, M.D.

March 2011 - Linkage Newsletter

by Erin M. Fults

To date, cancer predisposition syndromes have not been fully defined. Helping to fill in the gaps, however, is Christian Kratz, M.D., a tenure-track investigator in the Clinical Genetics Branch (CGB). "By studying individuals with rare genetic cancer predispositions, one can learn a lot about cancer biology in general," Dr. Kratz said.

Dr. Kratz is especially interested in Noonan, Costello, and cardiofaciocutaneous syndromes, all of which involve inherited mutations in oncogenes that are also frequently mutated in cancer cells. Because these defects are germline events, the changes have to be relatively mild or have effects later in life for the embryo to survive. Survival, however, does not mean normal development. "It's an interesting connection because not only do the patients I study have a predisposition for cancer, but they also have a developmental disorder," Dr. Kratz said.

Christian Kratz, M.D.One syndrome that Dr. Kratz is now studying is familial pleuropulmonary blastoma (PPB), a rare and little-studied disease that leads to childhood lung sarcoma and a range of other rare tumors. It is caused by a germline mutation in the DICER1 gene that disrupts microRNA production. MicroRNAs regulate gene expression in the body, and Dr. Kratz's research promises to offer insight into their biology and their role in cancer. In 2010, Dr. Kratz received an NIH Bench-to-Bedside Award to study PPB.

Dr. Kratz is also leading a study on familial testicular cancer. Compared to disorders that are due to a mutation in a single gene, familial testicular cancer appears to be a more complex disease that is caused by a combination of risk alleles in conjunction with environ-mental factors. The familial form of testicular cancer serves as a good disease risk model because the risk variants are stronger than those found in other cancers. Identifying the genetic causes of familial predisposition to testicular cancer may help researchers better understand the biology of this tumor and identify men with an increased risk.

Dr. Kratz was originally trained as a pediatrician in Germany, where he became particularly interested in patients with developmental syndromes associated with cancer. He took a postdoctoral research fellowship in the Department of Pediatrics at the University of California, San Francisco, where he performed molecular studies on childhood myeloid malignancies. Upon returning to Germany, Dr. Kratz worked as an attending physician at the University of Freiburg, continuing to treat children with cancer. During that time, he also studied genetic syndromes predisposing to leukemia and identified germline mutations in the KRAS oncogene as a cause of both Noonan and cardiofaciocutaneous syndromes. At CGB, which Dr. Kratz joined in 2009 as a tenure-track investigator, he enjoys the opportunity to devote himself more fully to research.

Dr. Kratz plans to initiate a clinical protocol for cancer patients with rare underlying genetic syndromes. "If someone with a genetic syndrome develops cancer, this is usually not random," Dr. Kratz said. By characterizing the syndrome in a clinical setting, it may be possible to identify a causal genetic defect that may have significance beyond the rare syndrome. For example, one of Dr. Kratz's patients Kratzhad Börjeson-Forssman-Lehmann syndrome and developed T-cell leukemia. Dr. Kratz and his colleagues hypothesized correctly that the gene underlying the syndrome, PHF6, was relevant to the leukemia. Ultimately, Dr. Kratz and another group found that mutations of PHF6 represent an important factor in leukemogenesis.

Studying cancer predisposition syndromes may have implications beyond cancer. We can learn how conserved molecular pathways contribute not only to oncogenesis, but also to growth, cognitive function, and development. Moreover, such disorders may serve as model diseases in which the underlying germline mutation represents the cancer-initiating event that leads to cancer through acquisition of additional genetic hits. Studying cancer risks in these patients is also important for appropriate genetic counseling and early cancer detection. Finally, there is a chance that newly developed targeted cancer therapies may be used to improve the clinical course in patients with certain genetic syndromes.