Our investigator focus introduces you to CanGene-CanVar researchers, their academic interests and involvement in the programme. For our first investigator focus, during Men’s Health Week (June 15 to June 21,2020), we introduce our programme lead, Prof. Clare Turnbull, and her research in the area of testicular cancer.
Clare’s research centres around utilising genetic sequencing technologies to identify and characterise genetic predispositions to testicular, breast and ovarian cancer. In addition to the CRUK Catalyst Award, Clare is in receipt of funding from Movember to support her research in the area of testicular cancer.
Testicular cancer has some interesting characteristics that distinguish it from other tumour types:
Germ cell testicular cancer (TGCT), which accounts for around 95% of testicular cancer cases in the UK, is one of the most highly heritable tumour types (40% heritability estimated with population-based approaches).
5-year survival of testicular cancer is very high (above 97% for stages 1 and 2 and >80% for stages 3 and 4 testicular cancer). This is due to the exquisite sensitivity of tumour cells to platinum-based treatment.
Whilst cancer is often considered as a ‘disease of old age’, testicular cancer mostly affects men between 15 and 49 years of age, with the average age at diagnosis being ~32 years.
The first genetic mutations causing normal germ cells to develop into carcinoma-in-situ arise whilst still a foetus.
Heritability
Despite the highly heritable nature of TGCT, in 2009 less than one percent of this heritable risk had been accounted for. The first major advancements in identifying genes implicated in TGCT came from Genome Wide Association Studies (GWAS).
In a GWAS, several hundred thousand genomic variants are included on a genotyping chip: the frequency of each variant is then compared between men with TGCT and controls. Often the experiment is conducted once as a ‘discovery’ stage and then repeated in a different set of samples (the ‘replication series’) to confirm the findings.
Clare’s group lead the first GWAS in testicular cancer, published in 2009 and went on to publish an additional five analyses over the following years. By 2019, the number of genomic variants identified for TGCT is 49, of which Clare’s group identified 42. Together these loci accounted about a third of the heritability of TGCT, so much work is yet to do! By comparison, for breast and colorectal cancer, although many more GWAS variants have been identified, they explain <20% of the heritability of each cancer.
Clare’s team have also conducted whole exome germline sequencing in TGCT, with the purpose of looking for testicular cancer susceptibility genes; rare high penetrance variants in which may account for high-risk multi-case families. In their experiment, whole exome sequencing germline samples from ~1000 men with TGCT, they found families with rare deleterious variants in DNAAF1. A gene which causes seminoma in Zebrafish models. However, these families were highly infrequent and overall, from their experiments they concluded that there is no ‘major’ testicular cancer susceptibility akin to BRCA1 for breast cancer.
Platinum Resistance
Platinum resistance is observed in less than 10% of patients, but is associated with much poorer outcomes.
Although extensively investigated through somatic and germline pharmacogenomic studies, the mechanism for platinum resistance is poorly understood. Clare’s team have been researching the genetic basis for this mechanism.
Their latest publication describes the largest whole exome sequencing (WES) to date from patients with platinum resistant testicular cancer, which they combined with data from clinical testing of 624 tumours. The team were able to identify novel clinico-pathalogical associations relating to point mutations in particular genes. For example, KIT mutation is inversely associated with platinum resistance, TP53 mutations is associated with tumour location, and mutations in WNT signalling pathway genes are associated with development of metastatic disease.
However, despite the team examining multiple different types of genetic changes and their combination into ‘mutational signatures’, they were unable to nail down the platinum resistance to a single genetic cause. Therefore, in similar fashion to the search for genes implicated in heritability of testicular cancer, the results suggest there is no major gene implicated in platinum resistant tumours.
The conclusion?
Despite testicular tumours having these two unique characteristics, it would appear that the underlying genetic story is much more complex and additional study is required to further understand this fascinating tumour type.
Prof. Turnbull currently holds three appointments:
Professor of Cancer Genomics, Institute of Cancer Research;
Honorary Consultant in Clinical Cancer Genetics, Royal Marsden;
Honorary Consultant in Public Health Medicine, Public Health England.
Clare is also heavily involved with work in policy development work in clinical cancer genetics, including with the Cancer Genetics Group, Health Education England, NHS Improvements, Academy of Medical Royal Colleges and Public Health England.