A germline mutation is any detectable and heritable variation in the lineage of germ cells, any biological cell that gives rise to the gametes of an organism in sexual reproduction. Mutations in these cells are transmitted to offspring, while those in somatic cells are not. A germline mutation gives rise to a constitutional mutation in the offspring which is present in virtually every cell. Interestingly, in humans, mutations are more likely to occur in sperm than in ova, due to the larger number of cell divisions are involved in the production of sperm.
Ultimately, researchers anticipate that systematic monitoring of patients and family members who have germline mutations in cancer predisposition genes will allow the detection of cancers at their earliest and most curable stage, thereby improving the outcomes for these children and family members. Now, researchers at the St. Jude Children’s Hospital state they have provided the most detailed analysis yet of the role germline mutations in genes associated with cancer predisposition play in the development of childhood cancer. The team state that this suggests comprehensive genomic screening may be warranted on all pediatric cancer patients, not just those with a family history of cancer. The study is published in the New England Journal of Medicine.
Previous studies have shown that the presence of such germline mutations in pediatric cancer patients was thought to be extremely rare and restricted to children in families with strong histories of cancer. The current study revealed that more than half of the children with germline mutations lacked any family history of cancer, with a frequency of 8.5% representing the current estimate of the number of pediatric patients with a hereditary cancer predisposition.
The current study conducted next-generation DNA sequencing of both the tumour and normal tissues from 1,120 pediatric cancer patients. The researchers sequenced the whole genome, whole exome, or both, of patients enrolled in the Pediatric Cancer Genome Project to check for germline mutations in 565 genes associated with cancer. In-depth data analysis was done on 60 of these genes associated with autosomal dominant hereditary cancer predisposition syndromes, with mutations in these genes known to increase cancer risk when one of the two copies of the gene is altered.
Results show that 95 patients, or 8.5%, had germline mutations in 21 of the 60 genes. Data findings show that only 1.1% of patients in a comparison group of 966 adults without cancer had alterations in the same genes. The group state that the frequency of germline mutations in cancer predisposition genes varied by the type of cancer the child had. They go on to add that the highest frequency, 16.7%, was found in children with non-central nervous system (CNS) solid tumours, followed by CNS tumours, at 9%, and leukemia, at 4.4%.
Data findings show commonly mutated genes in the affected patients were TP53, APC, BRCA2, NF1, PMS2 and RB1, with the lab explaining that many of these genes have been previously associated with rare families with multiple children who develop cancer. An unexpected finding was the identification of mutations in the breast and ovarian cancer genes BRCA1 and BRCA2 in a number of the pediatric cancer patients as these genes are not currently included in pediatric cancer genetic screening. The researchers state that another surprising finding to emerge from this study was the prevalence of germline mutations in six patients with Ewing sarcoma, a cancer of the bone and soft tissue that was not previously thought to be part of any cancer predisposition syndrome. They go on to conclude that the prevalence of these newly identified mutations in these genes suggests that the role of these genes in pediatric cancer needs to be further studied.
The team surmise that their paper marks an important turning point in the understanding of pediatric cancer risk and will likely change how patients are evaluated. For the future, the researchers state that any child found to have a germline mutation in a cancer predisposition gene will be referred to the new St. Jude Hereditary Cancer Predisposition Clinic, which evaluates and cares for children who are at increased genetic risk for cancer. They go on to add that the clinic is staffed by a team of doctors, researchers, nurses and genetic counselors who work with families to determine if a child’s cancer might be inherited and if any other family members are at risk.