Abstract IA01: New frontiers in childhood cancer predisposition: Harnessing genomics for early detection and tumor interception

Abstract

The challenges and opportunities for early cancer detection and interception in the context of pediatric cancer predisposition are exemplified by the paradigm cancer predisposition disorder, Li-Fraumeni syndrome. More than 85% of patients with Li-Fraumeni Syndrome harbour germline TP53 mutations. The genetic and phenotypic heterogeneity within and between families is remarkable and indicates that modifiers must play an important role in defining the phenotype of each patient and each family. A clinical surveillance protocol for early detection of tumours in TP53 mutation carriers has proven to be of great clinical utility (Villani et al Lancet Oncol 2016). However, it does not consider the genetic and phenotypic heterogeneity of the disease. Results from deep (epi)genome sequencing of mutation carriers provide insight into the influence of modifiers on tumor onset, spectrum and response to therapy. Data will be presented to describe molecular algorithms that may be used to more precisely reflect the unique (epi)genetic signatures of LFS patients. It is anticipated that these algorithms can then be used to more effectively refine and guide the creation of personalized surveillance strategies for these patients. In addition, we have taken advantage of recent advances in sequencing technologies to develop and integrate multi-omic liquid biopsy assays to complement conventional surveillance programs. These approaches offer opportunities to consider ‘cancer interception’ therapies to be implemented at the earliest stages of tumor initiation and progression in LFS patients – leading to improved survival with improved quality of life.