Pancreatic cancer: the genome reveals who is most at risk
The largest study to date, which has already sequenced 3,000 genomes, is from Italia: the aim is to identify the most vulnerable people and select the most effective treatments
It is the largest study ever conducted worldwide on whole-genome sequencing of germline DNA in pancreatic cancer and could pave the way for identifying people at the highest risk of developing the disease, improving early diagnosis and, in the long term, helping doctors to choose the most effective treatments for each patient. The project is coordinated by Daniele Campa, Professor of Genetics at the Department of Biology of the University of Pisa, and has been carried out thanks to the Human Technopole National Genomics Platform, one of the innovative, high-tech infrastructures that the Milan-based research institute makes available to the Italian scientific community, dedicated to the development of advanced technologies for biomedical research. Thanks to these technologies, 3,000 complete genomes have already been sequenced in just four months – an analytical capacity that demonstrates how genomics can now operate on a population scale with speeds and volumes that were unthinkable just a few years ago.
The aim is not to study the tumour’s DNA: ‘We are talking about the germline genome, that is, the individual’s DNA,’ Campa explains. The stakes are high. Exocrine pancreatic cancer, the most common and aggressive form of the disease, continues to have one of the worst prognoses in oncology and, despite advances in treatment, only a minority of patients are eligible for surgery at the time of diagnosis.
Exocrine pancreatic cancer is particularly insidious because it grows silently. “It is an almost entirely asymptomatic condition. It gives no specific warning signs and, by the time it is diagnosed, it is often already at an advanced stage,” explains Campa. “At that point, the tumour may no longer be operable. And even today, surgery, combined with specific chemotherapy regimens, remains the only truly curative option.” Over the last fifty years, survival rates have doubled, but they remain among the lowest of all cancers. Unlike breast or colorectal cancer, there is still no effective screening strategy for pancreatic cancer. ‘There is no marker sensitive and specific enough to be used in the general population,’ explains Campa. ‘The best one we have, CA19-9, does not perform well enough for mass screening.’
There is also another problem: the cancer is relatively rare. “The incidence in Europe is around 11 new cases per 100,000 inhabitants each year, and universal screening is not the best solution.” This is why researchers are exploring a different approach: rather than screening the entire population, they aim to identify those who already have a higher-than-average risk. These include people with late-onset type 2 diabetes, those with pre-neoplastic pancreatic cysts, and those with a strong family history of the disease. “These groups are at much greater risk than the general population, and it would make sense to identify biological and genetic markers for them,” says Campa. However, this is not straightforward because pre-neoplastic pancreatic lesions, for example, are often so-called ‘incidentalomas’: they are discovered by chance during examinations carried out for other reasons. ‘Until a few years ago, we thought they were very rare. Today we know that in people over the age of sixty, they may be present in 15 per cent of the population, although only a small proportion will progress to cancer.”
The project, coordinated by the University of Pisa, is a retrospective case-control study. The study will analyse 1,500 patients with pancreatic cancer and 1,500 healthy controls, recruited through the international Pancreatic Disease Research Consortium, founded over 10 years ago and now co-coordinated by Campa himself. The aim is to compare the frequency of genetic variants between the two groups and to identify which ones are associated with an increased risk. One of the most innovative features of the project is whole-genome sequencing. For Campa, limiting the analysis to protein-coding regions alone would mean losing a great deal of information: ‘Looking only at the coding region is a bit like peering through the keyhole rather than opening the door: you don’t get the full picture of the problem, but only a very limited perspective’. Only around 1–1.5 per cent of DNA produces proteins. The remaining 98 per cent or so comprises regulatory regions and genes that produce RNA, which profoundly influence how cells function.
