Multilocus Inherited Neoplasia Allele Syndrome (MINAS): an update

Multi-locus Inherited Neoplasia Allele Syndrome (MINAS) refers to individuals with germline pathogenic variants in two or more cancer susceptibility genes(CSGs). With increased use of exome/genome sequencing it would be predicted that detection of MINAS would become more frequent. Here we review recent progress in knowledge of MINAS. A systematic literature search for reports of individuals with germline pathogenic variants in 2 or more of 94 CSGs was performed. In addition, participants with multiple primary tumours who underwent genome sequencing as part of the Rare Disease arm of the UK 100,000 Genomes Project were interrogated to detect additional cases. We identified 385 MINAS cases (211 reported in the last 5 years, 6 from 100,000 genomes participants). Most (287/385) cases contained at least one pathogenic variant in either BRCA1 or BRCA2. 108/385 MINAS cases had multiple primary tumours at presentation and a subset of cases presented unusual multiple tumour phenotypes. We conclude that, as predicted, increasing numbers of individuals with MINAS are being have been reported but, except for individuals with BRCA1/BRCA2 MINAS, individual CSG combinations are generally rare. In many cases it appears that the clinical phenotype is that which would be expected from the effects of the constituent CSG variants acting independently. However, in some instances the presence of unusual tumour phenotypes and/or multiple primary tumours suggests that there may be complex interactions between the relevant MINAS CSGs. Systematic reporting of MINAS cases in a MINAS database (e.g. https://databases.lovd.nl/shared/diseases/04296) will facilitate more accurate prognostic predictions for specific CSG combinations.

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations (“non-R132H IDH1/2 mutations”). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.

Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma

The clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncovered significant spatial and phenotypic immune–ITH from multiple tumour sectors and deciphered its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune–ITH was associated with RNA-ITH and distinct immune microenvironments. Tumours with low immune–ITH experienced higher immunoselective pressure and underwent escape mechanisms via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH were associated with a more immunosuppressive/exhausted microenvironment. This immune pressure gradient along with immune-ITH represents a hallmark of tumour evolution closely linked to the transcriptome-immune networks contributing to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature were predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides novel evidence on tumour-immune co-evolution along HCC progression.

Analysis of real-world PD-L1 IHC 28-8 and 22C3 pharmDx assay utilisation, turnaround times and analytical concordance across multiple tumour types

AimsProgrammed death-1/programmed death ligand 1 (PD-1/PD-L1) inhibitor therapy is accompanied by companion or complementary PD-L1 testing in some tumour types. We investigated utilisation of the Dako PD-L1 IHC 28-8 and 22C3 pharmDx assays and the Ventana PD-L1 (SP142) assay and evaluated concordance between the 28-8 and 22C3 assays in a real-world cohort of patients tested at a single US national reference laboratory.MethodsNeoGenomics Laboratories performed PD-L1 testing on tumour samples between October 2015 and March 2018. PD-L1 test results were matched with patient characteristics using unique identifiers. Concordance between the 28-8 and 22C3 assays was evaluated in matched tumour samples. Data were evaluated across multiple tumour types and in subgroups of patients with lung cancer, melanoma, squamous cell carcinoma of the head and neck, and urothelial carcinoma.Results62 180 individual PD-L1 tests were conducted on samples from 55 652 patients. PD-L1 test volume increased ~10-fold over the period evaluated. Test failure rates were typically low, and test turnaround time (TAT) ranged between 2 and 4 days. Concordance between the 28-8 and 22C3 assays was strong in the overall population and across tumour type subgroups (Kendall’s tau correlations of 0.94 and 0.92–0.98, respectively).ConclusionsTest failure rates for PD-L1 tests were low and TAT remained reasonable despite marked increases in test volume. Concordance was high between the 28-8 and 22C3 assays across a range of tumour types and biopsy locations. These findings add to the literature showing high concordance between the 28-8 and 22C3 assays.

Cancer immunity and immunotherapy

The development of a cancer in an immunologically intact host leads to an interaction between the host immune system and the tumour mass. The three phases of tumour/host interactions (Elimination, Equilibrium, and Escape) form the ‘immune editing hypothesis’, which serves as a valuable framework for understanding of the immune response to cancer and the approaches by which this might be manipulated for therapeutic benefit. Immunotherapy is emerging as an important treatment modality for many tumour types, including melanoma, lung cancer, kidney cancer, lymphoma, and bladder cancer. By the time you read this chapter it is highly likely that additional monotherapy and combination regimens will be approved in multiple tumour types, but an understanding of the basic mechanisms underlying an adaptive antitumour immune response will be valuable in understanding future agents, as well as their toxicities.