Genetic Testing for Tumor Cuts Surveillance Costs

Written by on February 3, 2012 in Research & Technology - No comments
genetic testing

By Nancy Walsh

Genetic testing of children with retinoblastoma and their families greatly reduced unnecessary and expensive clinical surveillance among potentially at-risk family members, a study suggested. Analysis of the RB1 gene among 48 family members of affected children identified six individuals who carried a mutation predisposing them to retinoblastoma, although they were clinically unaffected. This meant that 42 were negative for the mutation and did not require repeated evaluations, according to Sharon E. Plon, MD, PhD, of Texas Children’s Cancer Center in Houston and colleagues. “If genetic testing had not been performed, these 42 individuals would have had to undergo expensive [examinations under anesthesia] as part of surveillance recommendations,” the researchers wrote in the November Archives of Ophthalmology.           

Retinoblastoma is an unusual malignant ocular tumor of early childhood that can affect one or both eyes. In the 40 percent of cases that are bilateral, a germline mutation in RB1 is responsible; the remaining 60 percent of cases, which present as unilateral, have either a somatic mutation in the gene – one that occurs during development – or, in about 15 percent of unilateral patients, a hereditary mutation. Retinoblastoma can occur if there are two mutations in RB1 or a single mutation plus inactivation of a second allele. Testing for the genetic mutation has been available and growing increasingly sensitive during the past 15 years, with the goal of determining risk for additional cancers among affected children and for the ocular tumor itself in family members.

The importance of being able to determine these risks as early as possible lies in the fact that prognosis in retinoblastoma is “highly dependent on prompt diagnosis and evaluation,” the researchers observed. Guidelines on surveillance for those at risk have been developed, but little is known about the implementation of recommendations in clinical practice, so Plon and colleagues reviewed the charts of 90 children evaluated at Texas Children’s Hospital between 2001 and 2008. The management process used by Plon’s team involved molecular analysis of blood and/or tumor tissue, and a multidisciplinary program of monthly meetings with geneticists, genetic counselors, pediatric neuro-oncologists and pediatric ophthalmologists in which each case was discussed and updated. These meetings also ensured that all cases were referred for genetic testing and the results disseminated to parents and other family members. In 42 percent of the children in this series, tumors were present in both eyes. Genetic testing was completed in 65 percent of children with bilateral tumors and in 62 percent of those with unilateral disease. For bilateral disease or in cases where there is a family history of retinoblastoma, the testing can be done on samples of blood, but in unilateral cases, analysis of the tumor DNA is needed following removal of the eye.

During the early years of the study, the laboratory analysis included only DNA sequencing, which provided a mutation yield of 79 percent. After 2004, however, the researchers also were able to obtain copy number analysis and determination of whether promoter methylation was present leading to inactivation of the gene, which improved the yield to 88 percent. Among the 29 unilateral cases, a mutation was identified in blood in five, indicating that it was a germline mutation. In seven of the unilateral cases, no mutations could be detected in blood but they were present in the tumor tissue, signifying sporadic mutations. The six individuals who had RB1 mutations but no clinical disease were likely to have mutations with limited penetrance or expression, the researchers explained.

Genetic testing was not done in 37 percent of cases, most often because patients did not return for the appointment. Other reasons cited for failure to complete testing were cost of the program and the deaths of four patients, which highlighted the importance of the genetic analysis being done as soon as possible after the diagnosis, according to Plon and colleagues.

As to the costs of their program, they noted that the price tag for DNA sequencing was $1,800 for the affected individual and $340 for family members. But the cost of each evaluation under anesthesia and related fees reached about $3,000, and a child at risk generally needs eight such evaluations in the first year of life, and up to 26 by age 6.

“Thus, the relatively inexpensive, simplified familial mutation testing allows a substantial decrease in the expensive and potentially morbid [evaluation under anesthesia] procedures,” the researchers noted. The multidisciplinary approach ensured that evaluations of all at-risk individuals were done promptly, when survival and preservation of vision were most likely to be achieved.

 

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