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 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 is sequencing retrospective (stored) samples for clinically important and hard to treat types of pancreatic, oesophageal, ovarian and brain cancers. A collaboration with AstraZeneca is exploring 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) leads 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 has been developing a new pan-cancer “clinical genome” assay, which focuses on the existence of "clinically actionable" genomic events and possible driver mutations controlling genome structural changes. This bioinformatics development activity has been led by Dr Susie Cooke at the University of Glasgow.
Professor Andrew Biankin (Director, Wolfson Wohl Research Centre, University of Glasgow) and Dr David Chang (Reader, Wolfson Wohl Research Centre, University of Glasgow) are leading 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 will explore this further.
Sequencing and analysis is ongoing.
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) are leading on 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 aims to determine the clinical consequences of ovarian cancer molecular subgroups. Sample collection, sequencing and analysis are ongoing.
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.
The samples for this study, which have been collected from 18 carcinosarcoma patients over many years, were prepared for panel-based sequencing. Data from this study have been analysed and findings are being reviewed.
Oesophageal proteogenomic analysis
Professor Russell Petty, Chair of Medical Oncology, University of Dundee, is leading 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 will carry 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. The analysis aims to demonstrate the functional relevance of genetic alterations/chromosomal instability, identify specific disease mechanisms and possible therapeutic targets for precision medicine approaches. It is hoped that this integrated proteo-genomic analysis will provide a therapeutically relevant molecular classification of oesophageal adenocarcinomas beyond what can be shown from genomic analysis alone. It may also suggest candidates for driver genes within large deletions or amplifications.
Sequencing for this study is complete, and data are being reviewed and interpreted.
Oesophageal adenocarcinoma - complete responders
Professor Grant Fullarton, Associate Professor of Surgery and Consultant Upper GI Surgeon, Glasgow Royal Infirmary, is leading 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 will characterise a cohort of 12 complete responders, making comparisons with 12 poor responders using a locally-developed custom genome analysis panel, which includes recurrent features of oesophageal adenocarcinoma tumours and allows analysis of large-scale structural genome changes.
This information may ultimately lead to more customised therapy and better outcomes for patients with oesophageal carcinoma.