CTOS Op Ed

CTOS Op Ed

NF1 patients: risks for sarcoma and the expedited referral of concerning cases

David Viskochil, M.D., Ph.D.

Professor, Department of Pediatrics, Division of Medical Genetics, University of Utah

Co-Director of the NF Clinic and the University of Utah

Member, Sarcoma Team, Hunstman Cancer Center

Chair, Clinical Care Advisory Board, Children's Tumor Foundation

[Editor's Note: This is the fifth in the series of Op Ed pieces written by one of the members of the Board of Directors of the Connective Tissue Oncology Society (CTOS). These Op Ed pieces are intended to address important and controversial issues in the field. The “CTOS Questions, Comments & Counterpoint” column allows readers to express their opinions in response to these Op Ed pieces. Click here to send in an opinion.]

Personalized medicine through genetics is a hot topic these days. In one sense, it brings with it a hope, a plan to institute protocols or even lifestyle changes to prevent conditions from arising that one is deemed predisposed to acquire based on one’s respective DNA blueprint. This hope is tempered by a realization that predisposition to acquire a specific phenotype is just that, a predisposition underscored with significant lack of certainty. DNA sequence variants in specific sarcoma-related genes might some day lead to a statistically valid susceptibility-to-develop-sarcoma risk estimate, yet, however good, it will only provide a relative risk estimate. In the general population where the incidence of sarcoma is extremely low, any increased absolute risk estimate will not likely be viewed as a threat. Plane crashes and earthquakes will be higher on their respective radar screen than sarcoma. The potential to develop a sarcoma is carried by all, yet the random genetic changes arising throughout someone’s lifetime that are presently identified by intense molecular evaluation of sarcoma DNA almost always occur as somatic mutations, DNA changes in a subset of cells that are not reflected in one’s constitutional DNA blueprint. Prediction of who might be more likely to undergo those random changes is fraught with error and will likely not herald sarcoma prevention programs. On the other hand, there are certain hereditary conditions that are at much higher risk than the general population to develop sarcoma. This recognition will continue to influence oncologists to have a high degree of suspicion that a lump may be more than a simple cyst. Earlier, and more effective therapy might be instituted when such epiphanies occur in the clinical setting. It would be better if primary care providers in the trenches could make this connection, and better yet if individuals who have those rare conditions with predisposition to sarcoma were informed and could distinguish those lumps needing evaluation from those that are just a nuisance. There are but a few hereditary conditions that carry an increased risk for sarcoma, nevertheless, we as a community need to optimize the recognition of sarcoma associations in such conditions, and then act on it.

Li-Fraumeni syndrome is the most well-known, albeit quite rare, genetic condition that has a predisposition to sarcoma. Registry information indicates that about 1/3 of individuals with germ-line mutations in TP53 will develop sarcoma. Hereditary retinoblastoma, another rare genetic condition, serves as the “2-hit” paradigm of genetic conditions caused by inactivating mutations in a tumor suppressor gene, RB1. The risk of osteosarcoma is relatively low, except in those individuals whose childhood retinoblastoma was treated with high-dose radiation therapy. Even more rare genetic conditions such as Sotos syndrome and Costello syndrome have associations with non-translocation rhabdomyosarcoma. Costello syndrome is notable because it is a sporadic condition caused by germline activating mutations in the H-RAS gene, which was the first oncogene identified in the modern era of molecular diagnosis. The RAS pathway is also important in the most common genetic condition that has a familial predisposition to sarcoma, neurofibromatosis type 1 (NF1).

Neurofibromatosis type 1 affects approximately 1 in 3000 individuals worldwide. In longitudinal registries, approximately 10% of all individuals with NF1 develop a malignant peripheral nerve sheath tumor (MPNST) in their lifetime. Strictly interpreted, 1 in 30,000 individuals worldwide will develop an NF1-related MPNST. Individuals with NF1 are also prone to develop rhabdomyosarcoma in childhood, although at much lower incidence than MPNST. This predisposition to sarcoma is predicated on double inactivation of the NF1 gene, which leads to inappropriate increased signaling through activated RAS to downstream targets in cells derived from the peripheral nerve sheath. Genomic DNA extracted from MPNST tissue demonstrates numerous mutations in other genes important for cell growth regulation, and these genetic changes accumulate as benign plexiform neurofibromas progress through stages of malignant transformation. Given our knowledge of the biochemical pathways involved in MPNST progression, it is just a matter of time before our oncology teams identify medicinal agents to specifically treat these tumors in the future. However, successful treatment presently requires complete surgical resection. Success is determined, in part, by early diagnosis. This is where the application of personalized medicine through genetics can make a tremendous, immediate impact in sarcoma management, without extensive DNA fingerprint analysis.

Similar to Sarcoma Centers, there are a number of NF Clinics affiliated with academic centers throughout the US, Canada and Europe. These designated clinics primarily follow children with NF1 because there are a number of pediatric-related ophthalmologic, orthopedic, and school performance issues. Unfortunately, for myriad reasons, adults with NF1 tend to drop out of the medical system, and when young adults develop a lump they are outside the normal channels of referral and tend to be diagnosed with sarcoma at later stages. The Children's Tumor Foundation and NF, Inc are two national support organizations for families with NF1, NF2, and Schwannomatosis. Both groups strive to organize NF Clinics, and CTF is spearheading an effort to organize these clinics into a working network that will provide regional centers of care for all patients with NF1, including adults. Lofty goals of this network include the education of all NF1 patients and their primary care providers about the risks for sarcoma and the expedited referral of concerning cases to affiliated sarcoma centers for appropriate diagnostic management and care. The development of a medical infrastructure for early clinical diagnosis of a familial cancer condition, NF1, with recognition that sarcoma is a 10% lifetime risk in this genetically selected population, coupled with a referral system to optimize successful management of those who develop sarcoma goes a long way to personalize medical care, at least for those 200 or so individuals in the USA with NF1 who are anticipated to develop MPNST this year.