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Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group.

ABSTRACT: It is increasingly common in oncology practice to perform tumour sequencing using large cancer panels. For pathogenic sequence variants in cancer susceptibility genes identified on tumour-only sequencing, it is often unclear whether they are of somatic or constitutional (germline) origin. There is wide-spread disparity regarding both the extent to which systematic 'germline-focussed analysis' is carried out upon tumour sequencing data and for which variants follow-up analysis of a germline sample is carried out. Here we present analyses of paired sequencing data from 17 152 cancer samples, in which 1494 pathogenic sequence variants were identified across 65 cancer susceptibility genes. From these analyses, the European Society of Medical Oncology Precision Medicine Working Group Germline Subgroup has generated (i) recommendations regarding germline-focussed analyses of tumour-only sequencing data, (ii) indications for germline follow-up testing and (iii) guidance on patient information-giving and consent.

SUBMITTER: Mandelker D

PROVIDER: S-EPMC6683854 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group.

Mandelker D D Donoghue M M Talukdar S S Bandlamudi C C Srinivasan P P Vivek M M Jezdic S S Hanson H H Snape K K Kulkarni A A Hawkes L L Douillard J-Y JY Wallace S E SE Rial-Sebbag E E Meric-Bersntam F F George A A Chubb D D Loveday C C Ladanyi M M Berger M F MF Taylor B S BS Turnbull C C

Annals of oncology : official journal of the European Society for Medical Oncology 20190801 8

It is increasingly common in oncology practice to perform tumour sequencing using large cancer panels. For pathogenic sequence variants in cancer susceptibility genes identified on tumour-only sequencing, it is often unclear whether they are of somatic or constitutional (germline) origin. There is wide-spread disparity regarding both the extent to which systematic 'germline-focussed analysis' is carried out upon tumour sequencing data and for which variants follow-up analysis of a germline sampl ...[more]

PMID: 31050713

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Project description:BackgroundThe use of next-generation sequencing technologies has enabled the rapid identification of non-synonymous somatic mutations in cancer cells. Neoantigens are mutated peptides derived from somatic mutations not present in normal tissues that may result in the presentation of tumour-specific peptides capable of eliciting antitumour T-cell responses. Personalised neoantigen-based cancer vaccines and adoptive T-cell therapies have been shown to prime host immunity against tumour cells and are under clinical trial development. However, the optimisation and standardisation of neoantigen identification, as well as its delivery as immunotherapy are needed to increase tumour-specific T-cell responses and, thus, the clinical efficacy of current cancer immunotherapies.MethodsIn this recommendation article, launched by the European Society for Medical Oncology (ESMO), we outline and discuss the available framework for neoantigen prediction and present a systematic review of the current scientific evidence.ResultsA number of computational pipelines for neoantigen prediction are available. Most of them provide peptide major histocompatibility complex (MHC) binding affinity predictions, but more recent approaches incorporate additional features like variant allele fraction, gene expression, and clonality of mutations. Neoantigens can be predicted in all cancer types with high and low tumour mutation burden, in part by exploiting tumour-specific aberrations derived from mutational frameshifts, splice variants, gene fusions, endogenous retroelements and other tumour-specific processes that could yield more potently immunogenic tumour neoantigens. Ongoing clinical trials will highlight those cancer types and combinations of immune therapies that would derive the most benefit from neoantigen-based immunotherapies.ConclusionsImproved identification, selection and prioritisation of tumour-specific neoantigens are needed to increase the scope of benefit from cancer vaccines and adoptive T-cell therapies. Novel pipelines are being developed to resolve the challenges posed by high-throughput sequencing and to predict immunogenic neoantigens.

Project description:BackgroundIntegrating germline genetic testing (GGT) recommendations from tumor testing into hereditary cancer clinics and precision oncology trials presents challenges that require multidisciplinary expertise and infrastructure. While there have been advancements in standardizing molecular tumor boards, the implementation of tumor profiling for germline-focused assessments has only recently gained momentum. However, this progress remains inconsistent across institutions, largely owing to a lack of systematic approaches for managing these findings. This study outlines the development of a clinical pathway for identifying potential germline variants from an institutional tumor-sequencing research program at Princess Margaret Cancer Centre.MethodsBetween August 2022 and August 2023, a clinical pathway led by a germline Molecular Tumor Board (gMTB) was established to review tumor genetic variants (TGVs) flagged as potential germline findings in patients with advanced cancer via a multigene panel. Eligibility for hereditary cancer syndrome investigation ('germline criteria') followed Cancer Care Ontario's Hereditary Cancer Testing Criteria and clinical judgment. Germline-focused analysis of TGVs followed the European Society of Medical Oncology guidelines and similar published criteria ('tumor-only criteria').ResultsOf 243 tumor profiles, 83 (34.2%) had at least one TGV flagged by the genetic laboratory as potentially germline and were therefore referred to the gMTB for further review. Among these 83 cases, 47 (56.6%) met 'germline criteria' for GGT, regardless of the TGV assessment. A total of 127 TGVs were assessed in these 83 cases, of which 44 (34.6%) were considered germline relevant. Tier I TGVs, interpreted as pathogenic/likely pathogenic (P/LP) and found in most- or standard-actionable genes with high germline conversion rates (GCRs) in any context, were more likely to be considered germline relevant (p-value < 0.05). One confirmed germline variant was identified in nine patients meeting solely 'tumor-only criteria'. Overall, 27/44 germline relevant TGVs underwent germline testing. We found a germline P/LP variant in 9 cases of the entire cohort, with a GCR of 33% (9/27).ConclusionsIncorporating genetic counselors into gMTBs enhanced the integration of research findings into clinical care and improved the detection of disease-causing variants in patients outside traditional testing criteria.

Project description:Immunotherapy strategies targeting immune checkpoints such as the CTLA4 and CD274 (programmed cell death 1 ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) T-cell coreceptor pathways are revolutionising oncology. The approval of pembrolizumab use for solid tumours with high-level microsatellite instability or mismatch repair deficiency by the US Food and Drug Administration highlights promise of precision immuno-oncology. However, despite evidence indicating influences of exogenous and endogenous factors such as diet, nutrients, alcohol, smoking, obesity, lifestyle, environmental exposures and microbiome on tumour-immune interactions, integrative analyses of those factors and immunity lag behind. Immune cell analyses in the tumour microenvironment have not adequately been integrated into large-scale studies. Addressing this gap, the transdisciplinary field of molecular pathological epidemiology (MPE) offers research frameworks to integrate tumour immunology into population health sciences, and link the exposures and germline genetics (eg, HLA genotypes) to tumour and immune characteristics. Multilevel research using bioinformatics, in vivo pathology and omics (genomics, epigenomics, transcriptomics, proteomics and metabolomics) technologies is possible with use of tissue, peripheral blood circulating cells, cell-free plasma, stool, sputum, urine and other body fluids. This immunology-MPE model can synergise with experimental immunology, microbiology and systems biology. GI neoplasms represent exemplary diseases for the immunology-MPE model, given rich microbiota and immune tissues of intestines, and the well-established carcinogenic role of intestinal inflammation. Proof-of-principle studies on colorectal cancer provided insights into immunomodulating effects of aspirin, vitamin D, inflammatory diets and omega-3 polyunsaturated fatty acids. The integrated immunology-MPE model can contribute to better understanding of environment-tumour-immune interactions, and effective immunoprevention and immunotherapy strategies for precision medicine.

Dataset Information

Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group.

Publications

Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group.

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