Photo by Bill Branson
Many young cancer patients—not just those with a family history of cancer—may benefit from comprehensive genomic screening, according to a study published in NEJM.
The research revealed germline mutations in cancer-predisposing genes in 8.5% of the children and adolescents studied.
Information on family history was available for roughly 60% of these cancer patients, and, in this group, only 40% of patients had a family history of cancer.
Prior to this study, the presence of such germline mutations was thought to be extremely rare and restricted to children in families with strong histories of cancer.
“This paper marks an important turning point in our understanding of pediatric cancer risk and will likely change how patients are evaluated,” said James R. Downing, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“For many pediatric cancer patients, comprehensive next-generation DNA sequencing of both their tumor and normal tissue may provide valuable information that will not only influence their clinical management but also lead to genetic counseling and testing of their parents and siblings who may be at risk and would benefit from ongoing surveillance.”
To conduct this research, Dr Downing and his colleagues performed next-generation sequencing of both the tumor and normal tissues of 1120 cancer patients younger than 20 years of age.
The investigators sequenced the whole genome in 595 patients, the whole exome in 456 patients, and both in 69 patients.
The team analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations.
A total of 95 patients, or 8.5%, had germline mutations in 21 of the 60 genes. In comparison, only 1.1% of individuals in a non-cancer cohort had alterations in the same genes.
Fifty-eight of the cancer patients who had a cancer-predisposing mutation also had available information on their family history. Forty percent (n=23) of these patients had a family history of cancer.
The frequency of germline mutations in cancer-predisposition genes varied by the type of cancer a patient had. The highest frequency, 16.7%, was in patients with non-central nervous system (CNS) solid tumors, followed by CNS tumors, at 9%, and leukemia, at 4.4%.
The most commonly mutated genes were TP53 (n=50), APC (n=6), BRCA2 (n=6), NF1 (n=4), PMS2 (n=4), RB1 (n=3), and RUNX1 (n=3).
The investigators were surprised to find mutations in the breast and ovarian cancer genes BRCA1 and BRCA2 in a number of the patients. These genes are not currently included in pediatric cancer genetic screening.
“Another surprising finding to emerge from this study was the prevalence of germline mutations in 6 patients with Ewing sarcoma,” said study author Kim Nichols, MD, also of St. Jude. “[This cancer] was not previously thought to be part of any cancer-predisposition syndrome.”
