Session 2: This session, delivered by Dr. Polona Le Quesne Stabej, begins with a recap of the fundamentals presented in Session 1. This provides the foundation for a deeper dive into the process of genomic variant annotation and interpretation. The session introduces cancer clinicians to the databases used during the variant annotation process and the standards used for the classification of variant oncogenicity. The standard operating procedure for somatic variant classification in cancer, formulated by Horak et al. (2022) and Li et al. (2017) is presented. Several key databases, including GnomAD, ClinVar, ONKOkb, Cancer Hotspot, cBioPortal, CIViC, COSMIC and ClinGen are discussed with reference to the evaluation of evidence required to assess the clinical significance of a given variant. Session 2 ends with an interactive example of variant interpretation based on the case first presented in Session 1.      A video recording of Session 2 can be found here.

Session 3: This session, delivered by Dr. Sandra Fitzgerald, discusses the pros and cons of genomic tests conducted on biopsy tissue and blood plasma. Tests of differing comprehensiveness available to NZ clinicians are first compared, including Biocartis Idylla and Agena Biosicence MassArray OncoFocus panels, which assess a few select genes for a large number of variants,  the AmpliSeq for Illumina Focus Panel, which provides targeted sequencing of 52 genes relevant to solid tumours, and larger-scale panels such as FoundationOne CDx/Liquid CDx and the TSO-500 panel being developed locally. The talk then turns to the significance of read-depth and variant allele frequency (VAF) in relation to liquid biopsy of circulating tumour DNA (ctDNA) and also highlights processes complicating the interpretation of VAFs, including aging-related CHIP (Clonal Hematopoiesis of Indeterminate Potential). Discussion at the end of the presentation considers how clinical decisions can be informed by tumour mutational burden (TMB) and microsatellite instability (MSI).  A recent report by Tie et al., (2022) is also mentioned, in which ctDNA data was used to guide treatment of stage II colon cancer, allowing a reduction in adjuvant chemotherapy use without impacting recurrence-free survival.  A video recording of Session 3 can be found here.

Session 5: This session on Inherited Cancer Predisposition was delivered by Dr Alex Henderson, (National Clinical Leader, Te Aho o Te Kahu/Cancer Control Agency, Cancer Genetics; Capital & Coast DHB), Kelly Sullivan (Auckland DHB Genetic Counsellor) and Dr Polona Le Quesne Stabej (University of Auckland). The classification and interpretation of germline versus somatic variants is discussed, referencing the ACMG guidelines proposed by Richards et al., (2015). Two hypothetical cases of familial predisposition to cancer are used to illustrate the databases and forms of evidence that inform clinical genetic counselling and treatment. Useful guidelines on criteria for germline follow-up testing in the context of clinical oncology are provided by EVIQ and by Mandelkar et al., (2019). More information about national clinical genetic testing services in Aotearoa New Zealand can be accessed here.  A video of Session 5 can be found here.

Session 6: Drs Polona Le Quesne Stabej, Anassuya Ramachandran and Laird Cameron present the final session of the 2022 Genomics For Cancer Clinicians course, in which they describe and analyse genomic test results that shaped the therapeutic journey of a patient with stage 4 lung cancer. As discussed by Laird, NGS-based information included the identification of an EGFR p.L858R variant which prompted treatment with Erlotinib. The response to treatment was less robust than hoped for, resulting in stable disease but eventual progression. Polona interactively recaps learnings from earlier sessions on variant curation, examining the NGS findings with reference to GnomAD, Cancer Hotspot, COSMIC and ClinVar databases (see this file containing databases to query and input terms), then addresses the actionability of the EGFR p.L858R variant by querying the CiViC and ONCOKb databases. Ana highlights hallmarks of cancer pertinent to this case, as well as the protein structural basis of the p.L858R change which results in constitutive EGFR activity (and the sensitivity to Erlotinib of cells carrying this variant). Ana then turns to the problem of treatment-driven Darwinian selection of tumour drug resistance which, in the case of this patient, was first acquired by c-MET amplification. This was addressed with the Type I MET inhibitor, Crizotinib – a treatment which ultimately resulted in the emergence of a resistant MET p.Y1230H mutation.  A video of Session 6 can be found here.