A specific mode of microsatellite instability is a crucial biomarker in adult T-cell leukaemia/lymphoma patients

Abstract

PurposeMicrosatellite instability (MSI) has been a long-standing biomarker candidate for drug resistance in tumour cells. Despite numerous clinical studies, the data in the literature are not conclusive. The complexity of the MSI phenomenon in some malignancies may, at least partly, account for the discrepancy. In addition, methodological problems are also pointed out in the assay techniques. We previously established a unique fluorescent technique in which the major methodological problems in conventional assays are overcome. Application of this technique has revealed two distinct modes of microsatellite alterations, i.e. Type A and Type B. More importantly, we demonstrated that Type A MSI is the direct consequence of defective DNA mismatch repair (MMR) that causes cellular resistance against antineoplastic agents.MethodWe first applied this technique to adult T-cell leukaemia/lymphoma (ATLL).ResultsThe MSI phenomenon was indeed observed in ATLLs (4/20, 20%). Intriguingly, the observed microsatellite alterations were invariably Type A, which implies that the tumours were MMR-defective. Indeed, clinical outcomes of patients with these MSI+ tumours were significantly worse. Furthermore, multivariate analysis revealed that Type A MSI is an independent prognostic factor.ConclusionThese observations strongly suggest the possibility of Type A MSI as a prognostic and potentially predictive biomarker in ATLL.

Correlations between microsatellite instability and the biological behaviour of tumours

“…In 2016, Miyashita et al (2017) first used five microsatellite markers (D2S123, D5S107, D10S197, D11S904, and D13S175) to detect MSI in tumours and normal tissues from 20 adult T-cell leukaemia/lymphoma (ATLL) patients. Expression of MMR proteins was also evaluated by immunohistochemistry (IHC).…”

Looking beyond the cytogenetics in haematological malignancies: decoding the role of tandem repeats in DNA repair genes

“…Early events of repeat polymorphisms in the intronic and exonic regions of DNA may lead to impaired repair mechanisms causing hematopoietic disturbances followed by cancer development. A few research groups have con rmed presence of tandem repeat variation in myeloid and lymphoid cancers while others have found it to be rare or absent in blood cancers [13][14][15][16]. These incongruencies motivated us to design a pilot study to investigate tandem repeat instability in MMR and MGMT gene structures in blood cancer cell lines.…”