Genetic changes associated with relapse of mantle cell lymphoma

Mantle cell lymphoma is a rare form of cancer that often follows a chronic and sometimes aggressive course. For many patients, the first treatment works relatively well, but when relapse occurs, the disease becomes more difficult to control. Each time the lymphoma returns, the time to the next relapse becomes shorter, but the reason for this has been unclear.

In the current study, the researchers showed genetic changes occur in the tumour during the disease course, making it gradually more aggressive and worsening the prognosis. They also found that the treatment itself can influence this development.

“We analysed tumour samples from 70 patients with mantle cell lymphoma, taken at several different timepoints during the disease course. Using comprehensive DNA analysis, we were able to map both mutations and chromosomal changes in the tumour cells. One of our findings was that genetic alterations known to contribute to a faster disease progression – particularly in the TP53 and CDKN2A genes – often appeared in relapses in patients where they had not been detected previously,” says Anna Nikkarinen, researcher at IGP and first author of the article.

Genetic damage relates to treatment

Another important result was that all patients developed new mutations during the disease course. Those who developed many new genetic changes had a significantly shorter time to the next relapse and shorter survival compared to those who only developed a few new changes. The initial status of the tumour was less important – it was the new mutations that affected the prognosis most. This suggests that the development of the tumour during treatment is central to the aggressiveness of the disease.

“The third, and perhaps most important finding was that the number of new changes was related to the treatment the patient had received. Patients who had received chemotherapy developed on average more than twice as many new genetic changes compared to those who had been treated with targeted drugs or who had been monitored without treatment. This suggests that certain cancer treatments can contribute to genetic damage to the tumour and thereby affect how it develops over time,” says Anna Nikkarinen.

DNA-based methods important

The results also showed that traditional methods such as microscopy are not always sufficient to detect high-risk changes. DNA-based methods identified significantly more patients with TP53 and CDKN2A changes than pathology examinations did. This means that the risk at diagnosis may be underestimated if only standard methods are used.

“The study is based on a realistic patient group with a long follow-up period, which makes the results relevant for everyday clinical practice. In summary, our results show that mantle cell lymphoma is more dynamic than previously thought. This underlines the importance of performing new genetic analyses at each relapse and, in the future, considering treatment strategies that do not drive the tumour’s genetic instability,” says Ingrid Glimelius, who led the study.

The study has been published in the scientific journal Leukemia