Cancer is a disease of the genome and the genomic features of every tumour are different.
Sequencing and analysis of tumour tissue comes with different challenges compared with sequencing of the "germline genome", which is our body's instruction manual and is in almost every cell of our body.
Comparing an individual's germline DNA (genome) with the tumour DNA (genome) can help researchers to understand what has caused the cancer, and to tailor a treatment to that particular cancer.
Members of the SGP Cancer Programme team at the Scientific Advisory Board meeting in April 2017.
The SGP Cancer Programme is now complete. It was led from the Wolfson Wohl Cancer Research Centre at the University of Glasgow, with research projects carried out by researchers in Glasgow, Dundee and Edinburgh.
The SGP Cancer Programme sequenced retrospective (stored) samples for clinically important and hard to treat types of pancreatic, oesophageal, ovarian and brain cancers. A collaboration with AstraZeneca explored whole genome sequencing for high grade serous ovarian cancer tumours using newly collected samples.
More information about each of the SGP cancer studies can be found below.
Analysing the cancer genome
Dr Susie Cooke (University of Glasgow) led the SGP bioinformatics activity to develop a new pan cancer "clinical genome" assay
A vital part of cancer genome research is how to analyse data quickly and in ways that support better clinical decision making. The SGP team developed a new pan-cancer “clinically actionable genome” series of assays, which focus on the existence of clinically actionable genomic events and possible driver mutations controlling genome structural changes. This bioinformatics programme was led by Dr Susie Cooke at the University of Glasgow and developed a comprehensive genomic profiling platform (HOLMES) for analysis of a range of advanced cancers. HOLMES has been tested successfully in a clinical service setting.
Professor Andrew Biankin (Director, Wolfson Wohl Research Centre, University of Glasgow) and Dr David Chang (Reader, Wolfson Wohl Research Centre, University of Glasgow) led the SGP Pancreatic research project
In Scotland, pancreatic cancer incidence rates have increased by 12% in the last 10 years and associated mortality rates by 6%.
Prof Biankin and Dr Chang are part of an international team that has published several landmark papers on molecular phenotyping of pancreatic cancer. The SGP study has been exploring intra-tumour heterogeneity.
Primary analysis is complete and the data will be published shortly.
High Grade Serous Ovarian Cancer: The Scottish Molecular Ovarian Cancer Collaboration
Professor Charlie Gourley (Professor of Oncology, University of Edinburgh) and Dr Alison Meynert (IGMM Bioinformatics Analysis Core Manager, University of Edinburgh) have led the clinical and analytical aspects of the High Grade Serous Ovarian Cancer project
Ovarian cancer is the 6th most common female cancer in the UK. High Grade Serous Ovarian Cancer (HGSOC) is the commonest subtype, accounting for 70% of all ovarian cancer cases.
Although the genomic landscape of ovarian cancer is well described, there is still much work to be done to understand which molecular abnormalities are relevant to specific therapies and disease outcomes.
The SGP collaboration with AstraZeneca has been determining the clinical consequences of ovarian cancer molecular subgroups. Publications are expected relating to the genomic landscape seen in these patients.
Ovarian Squamous Cell Carcinoma and Ovarian Carcinosarcoma
Professor Iain McNeish (now Professor of Oncology, Imperial College London) led the ovarian squamous cell carcinoma and carcinosarcoma projects while based at the Institute of Cancer Sciences at the University of Glasgow
Ovarian Squamous Cell Carcinoma
Mature cystic teratomas (MCTs) are the commonest ovarian tumours in adolescents and women of reproductive age. Most are entirely benign, but a small percentage (<1%) may become malignant, frequently with aggressive squamous cell carcinoma (SCC) and which have a very poor prognosis. The molecular drivers that push MCTs to develop into SCCs are unknown.
SCC samples and normal tissue, which have been collected from 25 patients over many years, were available for panel-based genomic analyses in this study. In addition, a small number of whole genome sequences of DNA, derived from newly collected fresh tissue, were generated.
Results from this study were published in Clinical Cancer Research in 2017 (https://eprints.gla.ac.uk/148750/).
Carcinosarcomas account for approximately 5% ovarian cancer cases in the UK, but were previously excluded from all large treatment-defining clinical trials. They present at late stage and their prognosis is at least as poor as the commonest type of ovarian cancer, called high grade serous carcinoma. Little is known of the genomics of this disease.
Findings from this study, and a follow on project on transcriptomics, will be submitted for publication shortly.
Oesophageal proteogenomic analysis
Professor Russell Petty, Chair of Medical Oncology, University of Dundee, led the Oesophageal proteomic analysis project.
Studies of oesophageal adenocarcinomas have provided a comprehensive characterisation of the genomic landscape and identified that it is a disease with high levels of chromosomal instability dominated by structural re-arrangements.
However, our understanding of how these genomic alterations influence production and modification of proteins and, in turn, observable changes to cells and clinical characteristics, is limited. This has made it difficult to identify and validate novel therapeutic targets.
This study has carried out an integrated proteomic and whole genome analysis of samples from 40 chemo-naïve oesophageal adenocarcinomas, previously subjected to mass spectrometry-based quantitative proteomic characterisation at the University of Dundee. This combined analysis has identified distinct genomic profile subsets not previously identified in genomic only studies. Potential new targets have been identified for clinical trials and data will be published once validation studies are completed.
Oesophageal adenocarcinoma - complete responders
Professor Grant Fullarton, Associate Professor of Surgery and Consultant Upper GI Surgeon, Glasgow Royal Infirmary, led the Oesophageal adenocarcinoma project.
Oesophageal adenocarcinomas generally exhibit an extremely poor outcome (the 5-year survival is 15%), but a small number of patients have a complete response to pre-surgery chemotherapy, with subsequent long-term survival. Large numbers of oesophageal cancers have been sequenced and the genomic landscape of oesophageal adenocarcinoma is well characterised. However, it is not clear how many exceptional responders are included in these studies and no predictors of response have been reported.
The SGP study characterised a cohort of 14 complete responders, making comparisons with 16 matched poor responders using a locally-developed custom genome analysis panel, which included recurrent features of oesophageal adenocarcinoma tumours and allowed analysis of large-scale structural genome changes.
The data, which will be published shortly, show that the genomic profile of complete responders and non-responders is different. This information may ultimately lead to more customised therapy and better outcomes for patients with oesophageal carcinoma.