The interplay between hereditary and somatic mutations in cancer development has been a difficult relationship for oncologists to unravel. While we now know that some cancers are indeed heritable, we don’t always know to what degree. Pediatric acute lymphoblastic leukemia (ALL) is one such disease, with a well-documented but still ambiguous hereditary component. A new study out of St. Jude’s Research Hospital – Somatic and germline genomics in paediatric acute lymphoblastic leukaemia (ALL) - expanded on the complex genetics of the cancer. I spoke with Dr. Ching-Hon Pui, one of St. Jude’s leading pediatric oncologists and an author behind the study, about what these findings mean and how he hopes they impact the future of ALL treatment.
Pui’s study goes into extraordinary detail about the mutations and diseases that predispose children to ALL, which was once thought to be an entirely non-hereditary cancer. I asked Pui to expand on the clinical significance of these findings; he says they’ve transformed the way he and his colleagues treat ALL. He approaches each patient’s disease as a genetic puzzle, screening them for both germline and somatic mutations which, taken together, can provide important clues about the heritability, etiology, and prognosis of their individual case. “We carry out comprehensive genetic evaluations on all new cancer patients. These evaluations include medical and family histories, genetics-oriented physical examinations and examination of tumor genomic findings. Based on the outcomes of these evaluations, patients and families are counseled and offered genetic testing to determine whether there is a hereditary basis for their child’s leukemia.”
Pui says this approach is one he hopes becomes standardized across all institutions, not only because it provides each patient (and, potentially, their at-risk relatives) with a highly personalized treatment plan, but also because each time a patient’s genome is sequenced, we gain a little more information about the genetic landscape of ALL. Pui says we have to be diligent about performing somatic and germline genomic testing on each and every patient. “This is the only way that we will eventually capture all germline variants that put children at a higher risk for developing this disease.”
Pui has been researching and treating pediatric ALL for over 40 years. At the start of his career, the disease was nowhere near as treatable. “When I first began to study ALL, only one third of patients could be cured and many survivors had shortened life span and poor quality of life due to late complications of treatment. With the advances in the understanding the biology of leukemia, the development of effective risk-adapted treatment with carefully designed protocols, and international collaboration, we can push the cure rate of childhood ALL above 90 percent in this decade.”
This dazzling progress is significant for more than just the obvious reasons. For childhood leukemia patients, there’s more hope on the horizon than ever before. “For those who are at increased genetic risk for leukemia, the future holds great promise to identify better ways to screen, treat and possibly even prevent leukemia from developing.” But it’s also hopeful for cancer patients across the board. Pui hopes the approach that St. Jude’s is now taking with ALL – conducting thorough genetic analyses, replacing toxic chemotherapy with targeted and immunotherapy, and reducing treatment intensity in low-risk patients – will serve as a paradigm for treating other cancer types.
Published: December 17th, 2019