DECRIPT programme: Improving understanding of the role of genetics in paediatric cancers

In France, approximately 2,250 new cases of paediatric cancer are diagnosed each year. Advances in treatment and care now mean that nearly 80% of patients are cured, increasing the number of adults who have recovered from a cancer diagnosed in childhood.
This major improvement nevertheless brings a long-term challenge: some former patients remain at risk of late complications, particularly the development of a second cancer several years after the first. This risk does not depend solely on the treatments received. It may also be influenced by genetic factors, some of which are already known in a proportion of patients but remain largely unexplained in many cases.

Beyond these already known genes, other factors may be involved, such as the combined effect of several rare or common genetic variations, grouped into polygenic risk scores that measure the cumulative effect of many variations on the risk of developing a disease.

Improving understanding of these mechanisms is essential to identify children at risk of developing cancer, assess the long-term effects of treatment and organise follow-up that is better tailored to each patient's profile.

Objectives

The DECRIPT programme aims to improve understanding of why some children develop cancer and why some patients face a higher risk of a second cancer after the first. 

• Its main objective is to identify new genetic predisposition factors, whether linked to a single gene or to a combination of several genetic variations.

The programme focuses particularly on rare or still poorly understood variants, on major biological functions involved in protection against cancer, such as DNA repair and the immune system, and on interactions between genetic predisposition and cancer treatments.

Beyond understanding these mechanisms, DECRIPT has a highly practical ambition for patients: to estimate more accurately an individual's risk of cancer or a second cancer by considering their genetic profile, treatments received, and clinical characteristics together. Ultimately, this knowledge should allow care to be tailored more precisely, improve follow-up and support targeted prevention strategies for people at greatest risk.
 

Studying genetic predisposition to paediatric cancers is particularly difficult because these diseases remain rare. DECRIPT uses a large-scale approach made possible by resources developed over several decades of clinical and fundamental research conducted by Gustave Roussy in collaboration with Inserm.

The programme draws on two major structured cohorts:

• The GenEFCCSS cohort, which includes 2,696 patients treated for a solid tumour or lymphoma during childhood.
• The GENECAP cohort, comprising 301 patients selected based on their phenotype, in whom a genetic predisposition is suspected but no alteration has been identified in the main predisposition genes currently known.

They will be supplemented by other existing data available at Gustave Roussy.

Pooling these genetic and clinical data is essential to detect rare abnormalities, analyse combinations of variants and improve understanding of their links with the development of a cancer or a second cancer. In some cases, researchers have access to patients' germline genetic data, tumour data and sometimes family data. This allows them to refine the interpretation of results and identify new predisposition genes or mechanisms.

DECRIPT also forms part of an international research effort, which is essential in paediatric cancer. Collaborations with major international cohorts are already under way, notably to validate findings and further increase the statistical power of the analyses.

The programme pays particular attention to certain secondary cancers frequently seen in the cohorts studied, such as breast and thyroid cancers and tumours of the nervous system, including meningiomas, with the aim of improving risk estimates in these practical long-term follow-up situations. Among former patients cured of paediatric cancer, this risk may be influenced by the treatments received, particularly radiotherapy and certain chemotherapies that damage DNA, but also by genetic susceptibility factors.

Outlook

DECRIPT has a translational focus, with the ambition of turning research findings into useful tools for patients and healthcare professionals. The data generated by the programme should support the development of risk models integrating genetic factors, demographic data, treatments received and clinical characteristics.

Ultimately, these tools could help to adapt treatments, personalise follow-up arrangements and offer targeted prevention strategies to patients at greatest risk. The programme also includes health-economic studies to assess the value of these approaches in the organisation of care.

Finally, DECRIPT opens up possibilities for prevention trials in very-high-risk populations, such as people with CMMRD syndrome, a rare genetic predisposition associated with a very high risk of early and multiple cancers, for whom an immunotherapy-based prevention strategy could be explored in the future.