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Testicular Cancer
“Despite being the 2nd most common cancer in young men, testicular cancer is often a forgotten cancer due to early detection and treatment. Our projects look at underinvested areas such as improving access to healthcare services and treatment options for relapse” Paul Villanti, Executive Director, Programmes.

Identifying Genes That Cause Testicular Cancer

United Kingdom
Implemented by
The Institute of Cancer Research
Report Card Date
31 July 2016
Reporting period
April 2013 to July 2016
Project Status
In Progress

GBP 1,050,000

Movember Funding to Date

What we seek to achieve

By using advanced genetic technologies including Next Generation Sequencing and Array SNP Genotyping, the aim of the project is to discover and better understand genetic factors which are linked to the development of testicular cancer.

How the project works

This research is being undertaken by Dr Clare Turnbull and her team at The Institute of Cancer Research (ICR), UK.

At ICR the testicular cancer research team have assembled blood samples and tumour samples from a significant series of men with testicular cancer. This is the largest collection of samples from men with testicular cancer in the world.

The team are using several advanced genetic technologies to study the genetic sequence of these men. These include “Next Generation Sequencing” and “Array SNP genotyping”. Next Generation Sequencing of the “exome” involves studying the full code of all genes. This totals about 20,000 genes, which equates to approximately 30 million bases of DNA. However, the genes only account for less than 2% of the human genome, and it is known that the remaining 98% is important but it is not yet well understood. Array SNP genotyping is another approach to studying the genetic code and enables us to study at scale genetic variants outside of the genes. Array SNP genotyping involves analysing hundreds of thousands of selected genetic variants (SNPs) which have been assembled onto a “SNP array”.  

The research team use the data they generate to compare patterns of genetic variants:
(i) between men with and without testicular cancer
(ii) across families with multiple cases of testicular cancer 
(iii) between the blood and the tumour of men with testicular cancer.

The research team will analyse the combined data to identify the specific genetic variants linked with development of testicular cancer. In all cases, large experiments are needed to distinguish ‘signal’ from ‘noise’, that is to identify the biologically important genetic changes from all of the innocent ‘spelling variations’ in the genes.

Complex analyses of these data integrated with other biological data (bioinformatics), studies of the patterns of disease within families and populations (genetic epidemiology) and mathematical modelling best enable us to understand the relevance of the genetic signals we see in our experiments.

There are two main reasons why identification of the genetic variants that underlie the development of testicular cancer is important:
(i) to enable development of genetic tests to better understand which men are at high risk of developing testicular cancer and/or, once a man develops testicular cancer, to better predict the behaviour of tumours 
(ii) to enable better biological understanding of how and why the disease develops, which may in turn facilitate better and more targeted treatment.

What we are doing / have done

The ICR testicular cancer research team:
(a) Have been recruiting 70-100 men per month with newly diagnosed testicular cancer from across the UK to join our research study. We have now recruited almost 8,000 men with testicular cancer to the UK study. In total, in our laboratory, we now hold DNA samples from approximately 10,000 men with testicular cancer and more than 2000 relatives. This is far and away the largest resource of samples from men with testicular cancer in the world and has enabled our ICR team to lead the field in research into the genetic basis of testicular cancer.   It is noteworthy that the ICR testicular cancer research team has lead or collaborated in every single study through which genetic factors involved in testicular cancer have been identified.

(b) Have used Next Generation Sequencing to sequence the exome (all 20,000 genes) from the blood of more than 1,000 men with testicular cancer. The research team have included in this study approximately 400 men from families in which there are multiple cases of testicular cancer and approximately 100 men who have had bilateral testicular cancer (as these are the cases which are most likely to be “genetic”). Because familial and bilateral testicular cancer are rare, the team have worked with collaborators from USA, Canada, Europe and Australia to assemble a larger series of DNA samples from such cases in the UK laboratory. We have undertaken complex analyses involving more than 60 billion data-points through which we have compared sequence data on more than 1,000 men with testicular cancer to data from more than 1,600 men without testicular cancer. Again, this is by far and away the largest exome sequencing project in testicular cancer in the world.  

We studied the families with Testicular Germ Cell Tumours to establish whether there was a high risk gene accounting for a high proportion of familial testicular cancer (akin to BRCA1 and BRCA2 in breast cancer). Our studies have shown that there is not a high risk testicular cancer gene and testicular cancer is highly polygenic, i.e there are many different genes involved which differ across different families, with mutations in the same gene being shared by only small numbers of families. We did note that looking across the testicular cancer families, there was an over-representation of mutations in genes relating to the workings of the cilia (the hair-like projections from the cell). We took these observations forwards by working with a Dutch group to show that knocking out these genes in zebrafish also causes the fish to develop testicular cancer. These findings add to our understanding of the biology of how testicular cancer develops and serve as a basis for further exploration of how these genes influence disease. 

(c) Have used array SNP genotyping to identify novel common variants associated with testicular cancer. This year the research team have been working with a large international cancer consortium, the Oncoarray Consortium, and have helped design a new SNP genotyping array (the Oncoarray) which contains more than 600,000 common variants related to cancer. The research team are studying samples from 4,000 men with testicular cancer using the oncoarray and comparing the data to more than 7,000 controls: this has already enabled us to discover 19 new genetic variants for testicular cancer. We are also working with researchers in the consortium specialising in prostate, breast, ovarian, colorectal and other cancers to perform studies to better understand how genetic factors cause risk across multiple types of cancer.

We have also worked with TeCAC (the Testicular Cancer Association Consortium), an international consortium focused on testicular cancer. By sharing data across several research groups from the USA and Europe, we have conducted a large ‘meta-analysis’ through which we identified 9 new genetic variants for testicular cancer. 

This brings the total of common genetic variants underlying testicular cancer to 51: all of these have been discovered by this research team through experiments which the ICR team have led or collaborated.

(d) Have sequenced the exome of tumour tissue from 50 men with testicular cancer and compared these data with the blood DNA of these men: the first large scale genetic study of testicular tumours published.  We have been working with a group from the Dana Faber Cancer Centre (Harvard, Boston) to integrate these data with other tumour data from testicular tumours: this analysis has revealed a pattern of breakage and rearrangement of the chromosomes unique to testicular tumours. The more we can understand why and how testicular tumours arise, the better we can prevent and treat them.

The major reason for the overall good prognosis in testicular cancer is that the tumours are typically exquisitely sensitive to platinum chemotherapy.  However approximately 10% of tumours are resistant to platinum and for these men the prognosis is much worse. The biological basis of platinum resistance is poorly understood. Working with hospitals across the UK, we have collected serial tumour tissue from men whose testicular cancer has proven resistant to platinum. We aim to analyse the samples using sequencing and array genotyping to compare the pattern of mutations in the blood, early tumour samples and late tumour samples in order to identify the genes and mutations that are causing the resistance to platinum.  Identifying genetic mechanisms of platinum resistance is key for development of new treatments for this group of patients.  

(e) Are collaborating with groups in Oxford, Finland and Sweden on a project to use automated image analysis of slides from tumours that prove to be platinum resistant/sensitive in order to see if there are any features that can help us predict platinum resistance. And a testicular cancer heritability collaboration with scientists and epidemiologists from Sweden and Germany.

(f) Have collaborated with a Copenhagen testicular cancer research group who have been developing semen analysis for early detection of testicular cancer. Combining their data on semen analysis and our data on genetic susceptibility factors for testicular cancer, we have developed models for the implementation of screening for testicular cancer. These models suggest that screening in the general population would not be effective, but that screening in families with a history of testicular cancer may be more viable. Improvement of the sensitivity of the semen analysis along with discovery of additional genetic factors for testicular cancer will be required to improve the effectiveness of screening. 

There are additional materials available for this project, please email for further information

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