Introduction:
Human T cell leukaemia virus type 1 (HTLV-1) is the most potent viral driver of cancer in humans, causing adult T cell leukaemia/lymphoma (ATL) in 5% of carriers. We developed a method to detect 'ATL-like' hyper-expanded T cell clones circulating in the blood of HTLV-1 carriers with no symptoms of ATL. Our previous studies suggest that these ATL-like clones represent the premalignant stage of ATL.
Methods:
We performed cross-sectional and longitudinal studies of HTLV-1 carriers attending the UK National Centre for Human Retrovirology. We evaluated the cumulative incidence of ATL in carriers with circulating ATL-like clones (n=23) and matched controls (n=98) using a flow cytometric assay of T cell clonality (667 patient-years follow-up). We developed a capture-sequencing protocol to quantify the mutational burden in ATL-like clones, and evaluates gene expression by RNA-Seq. Finally, we characterised antiviral cytotoxic T-cell (CTL) responses.
Objectives:
To evaluate the efficacy of our risk stratification approach, and to identify early cancer-driver events.
Results:
We observed incident cases of ATL only in the group with detectable ATL-like clones (n=6). However, the timing of the onset of ATL symptoms ranged from months to over 10 years. ATL-like clones carried known ATL-driver mutations and had a gene expression profile similar to malignant cells in ATL. Finally, the frequency of antiviral CTL in carriers with circulating ATL-like clones was significantly lower than in controls.
Conclusions:
Together, this evidence strongly supports that we can precisely risk stratify HTLV-1 carriers before any symptoms of ATL begin, raising the possibility of testing interventions to prevent or delay the onset of ATL.
