Precision Oncology | Professor Sean Grimmond

Sean’s lab is committed to the continued systematic surveying of upper GI cancers as part of Australia’s contribution to the International Cancer Genome Consortium (ICGC) pancreatic program. Longitudinal studies, surveying the disease from pre-malignant lesions through to metastatic disease, will provide a better understanding of the timing of oncogenic events and their persistence and/or relevance at each stage of cancer progression. A better understanding of mechanisms behind punctuated evolution, non-coding oncogenic switches and metastatic potential are also required.

Mutational signatures and other surrogate makers of DNA repair deficiency have recently been described. Sean’s lab is actively pursuing the consequences of mutations to core DNA damage response (DDR) pathways, shedding insights into the germline and somatic contribution to cancer formation. These studies will redefine the way pathogenicity of germline variants of unknown significance and somatic damage is assessed in all major DNA damage repair pathways. Current efforts focus on Homologous Recombination Vs Mis-match Repair or Base-Excision Repair defects.

The Queensland Centre for Medical Genomics (QCMG) has contributed more than 350 patients for this international program (Pancreatic, ovarian, neuroendocrine & melanoma), second only to The Cancer Genome Atlas (TCGA). It is expected that the UMCCR will contribute similar levels of patients to this program.

ICGC efforts identified a wealth of potentially druggable segments in pancreatic cancers, which warrant further preclinical analysis and potentially clinical trials. These include: DNA damage repair defects (BRCA1, BRCA2, ATM, PALB2 mutations in 12 percent of patients), Wnt Signaling (RNF43 loss seven percent), G1/S cell cycle defects (CCNE1 amplification seven percent) ribonucleic acid (RNA) processing defects (SF3B1, U2AF1, RBM10 15 percent) and immunogenicity (>20 percent). Prospective studies, pairing organoids production with mutation detection will create the tools for evaluation these preclinical models for patients within the VCCC alliance network.

Advanced recalcitrant cancers require rapid accurate genome and transcriptome analysis to maximize the chances of accurately subtyping patients and stratifying them for targeted therapies. As whole genome sequencing costs continue to drop dramatically, this type of analysis will become the assay of choice in the future. Sean’s lab is working on how to crystallise clinically relevant information from cancer genomes and transcriptomes (messenger RNA) and to prove their value in a clinical setting.