Genomic technology predicts risk for children predisposed to cancer

A review authored by Drs. Sharon E. Plon and Philip J. Lupo at Texas Children’s Cancer and Hematology Centers, surveys the evolving landscape of genes known to increase susceptibility to certain childhood cancers and supports the increasing use of genomic technology in cancer diagnosis. The article was published in the Annual Reviews of Genomics and Human Genetics.

Cancer predisposition syndromes are caused by genetic changes (sometimes called mutations or pathogenic variants) and place certain children at an increased risk of developing cancer. These conditions may result when a child inherits a genetic change from his or her parents. Work from Texas Children’s Hospital and many other research centers show these genetic changes account for 10% of all cancers in childhood. For many such cancers, the risk of developing the disease is usually earlier in life compared to the general population.

In the last few decades, researchers have gained a better understanding of the genes underlying cancer predisposition syndromes, which has also led to better and effective interventions for cancer surveillance, prevention and control. With rapid advancements in genomic technologies, and reducing costs of genotyping and sequencing clinical samples, more high-risk children and their family members are regularly monitored with MRI and ultrasound tests to evaluate their risk of developing certain cancers.

In this review, authors reviewed data from large-scale studies of unselected pediatric patients which consistently show 6-10% of children with childhood cancers carry pathogenic mutations in at least one copy of a cancer predisposition gene, which underscores the importance of expanding genetic analysis to all pediatric cancer patients in the near future.

The review describes two different approaches that are typically employed by researchers to identify disease-causing variants in cancer predisposition genes. The first approach is to identify rare variants in specific cancer predisposition genes. In this scenario, the cancer is usually due to a variant in a single gene. For instance, using this approach, researchers have shown the presence of certain variants in genes such as IKZF1, PAX5 and TP53 increase the risk of pediatric forms of specific subtypes of acute lymphocytic leukemia (ALL).

Another approach is to evaluate the role of common variants in genes through a scan of a person’s entire genome. These so-called genome-wide association studies (GWAS) analyze millions of genetic regions for cancer-associated variants in those with cancer compared to those without cancer. The review describes how large-scale GWAS studies helped researchers identify new susceptibility variants for several complex pediatric cancers such as ALL, neuroblastoma, Ewing sarcoma, Wilms tumor, osteosarcoma and Langerhans cell histiocytosis.

The article concludes that while the choice of genome analysis technique  depends on several factors and is determined on a case-by-case basis, the availability of a multitude of clinical sequencing tests in the recent years has revolutionized the diagnosis and care of at-risk children and relatives.