Dr. Maria Isabel Achatz, newly appointed tenure-track investigator in the Clinical Genetics Branch (CGB), is a leading geneticist studying inherited cancer predisposition syndromes. In her last year of medical school, a patient with six different types of cancer came into her clinic. Curiosity led Dr. Achatz to the medical library and, some years later, to the identification of the high occurrence of a rare inherited syndrome caused by a founder mutation among families in Southern Brazil, Li-Fraumeni Syndrome (LFS), an inherited disorder that dramatically increases affected individuals’ risk for developing cancer.
Though considered rare, Dr. Achatz found a much higher than expected prevalence of LFS in Southern Brazil: 1 in every 300 individuals carries a distinctive founder mutation in the tumor suppressor gene TP53 known as p.R337H. As part of CGB, Dr. Achatz will continue her investigations to identify other corners of the world where LFS has yet to be identified, but could be causing disease. In addition, she plans to extend her work to search for possible inherited factors to explain cancer patterns among isolated communities.
“DCEG offers a whole-world perspective,” commented Dr. Achatz, “For me, it’s an amazing opportunity to work with the NCI LFS cohort, alongside Drs. Sharon Savage and Joseph Fraumeni.” In her new position, she will collaborate with international and national groups on building oncogenetic resources and conduct testing, especially for those areas of the globe where resources are too scarce for this type of investigation.
In particular, Dr. Achatz will look closely at the patterns of tumor heterogeneity, somatic mutations, and germline variants in patients with LFS. She also plans to follow-up on health outcomes in the Brazilian cohort, which differ from the pattern observed among LFS families in the U.S. due to the p.R337H TP53 founder mutation. This mutation, in exon 10 of TP53 is outside the domain observed in most LFS families from other parts of the world. Brazilian LFS patients often also have an intronic duplication that delays onset of cancer by roughly 19 years.
Even more surprising, patients with p.R337H appeared remarkably healthy. They do not report hypertension, Alzheimer disease, or osteoporosis. What is more, they look decades younger than their chronological age.
Dr. Achatz will extend her study of this phenomenon by exploring the biological mechanism that might explain these observations, including the role of telomere length in the Brazilian cohort. Telomeres, caps that protect the ends of our DNA strands, naturally shorten with aging, but in some inherited syndromes like LFS, patients have shorter than typical telomeres.
“Combining clinical observations with genetics and molecular markers is the centerpiece of the research in CGB,” said Branch Chief Sharon Savage. “We are excited to have Maria Isabel contribute her unique expertise to our group.”