E-Poster Presentation 34th Lorne Cancer Conference 2022

Establishment of clinical curation principles for whole genome and transcriptome sequencing of cancers of unknown primary (#207)

Camilla B Mitchell 1 , Richard Rebello 1 , Tharani Sivakumaran 2 , Clare Fedele 1 , Owen Prall 2 , Catherine Mitchell 2 , Atara Posner 1 , Shiva Balachander 1 , SUPER-NEXT Study Team 1 2 , Tran Pham 1 , Penelope Schofield 2 3 , Oliver Hofmann 1 , Linda Mileshkin 2 , Sean Grimmond 1 , Joseph Vissers 1 , Richard Tothill 1 2
  1. Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, Victoria, Australia
  2. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  3. Swinburne University of Technology, Hawthorn, Victoria, Australia

Cancer of Unknown Primary (CUP) is diagnosed when a patient presents with metastatic cancer with no identifiable primary cancer, despite standardised diagnostic investigations including cancer imaging and histopathological evaluation. Treatment of metastatic disease is generally based on the primary cancer type. However, patients with CUPs are largely treated with non-targeted empirical chemotherapy, often with poor survival outcomes. The SUPER-NEXT study uses whole genome and transcriptome sequencing (WGTS) to interrogate the molecular landscape of CUPs, comparing directly to contemporary gene panel-based sequencing approaches. Understanding a cancer’s genomic profile can help resolve likely tissue of origin (ToO) or a more specific cancer diagnosis, find potentially actionable genomic targets, and facilitate access to tumour stream-specific and targeted treatment approaches.

Through curation, interpretation, and integration of WGTS findings with histopathological and clinical review, we aim to understand and optimise WGTS curation to help resolve a cancer’s ToO. We identified three main areas of WGTS interpretation which can be routinely used to inform cancer diagnosis.

  1. Curation of combinations of mutations known to be recurrent in certain cancer types. The genomic landscapes of many tumour types have been characterised in large cancer cohort studies (e.g. TCGA, ICGC, GENIE). CUP WGTS curation allows for comparison of individual tumour genomic profiles with known cancer genomics landscapes, to provide potential diagnoses.
  2. Detection of patterns of damage due to specific environmental exposures, such as UV or tobacco. Using whole genome sequencing, we can accurately determine the mutational signature of individual CUPs, to provide clues to the ToO and potential therapeutic vulnerabilities.
  3. Detection of pathognomonic mutations. Next-generation sequencing-based approaches have linked specific mutations and gene-fusion events to certain rare cancers or molecular subtypes of more common cancers. Detection of these genome alterations through WGTS can augment a diagnosis of rare cancer entity when combined with expert histopathological and multi-disciplinary clinical review and resolve cases outside the scope of current machine-learning based prediction algorithms.

Case studies illustrating each curation approach will be presented, which highlight the utility of WGTS deep curation in solving CUP diagnostic conundrums.