Scientists and clinicians in this part of the world have once again shone a brighter light on Natural Killer T-cell Lymphoma (NKTCL), an aggressive Asian-centric disease that was shrouded in mystery not too many years ago. NKTCL commonly develops outside the lymph node in the nasal area but can also occur in other parts of the body such as the skin and gastrointestinal tract.

New genetic variants that raise an individual’s risk of NKTCL have been discovered by a multidisciplinary team from the National Cancer Centre Singapore (NCCS), Singapore General Hospital (SGH), National University Cancer Institute Singapore (NCIS), A*STAR’s Genome Institute of Singapore (GIS) and an international lymphoma study group.
Involving over 21,000 participants from Singapore, Mainland China, Taiwan, Hong Kong SAR, South Korea and the USA, this is the largest scale genome-wide association study of NKTCL ever undertaken globally. The findings were published in medical journal The Lancet Oncology in December 2019.

Risk genes identified

After comparing the genetic materials of patients with NKTCL and people without, the team found two additional genes, IL18RAP and HLA-DRB1 that could significantly increase one’s risk of the cancer.

In particular, having the risk allele (a variant form of a gene) in IL18RAP genes makes someone 39 per cent more likely to develop NKTCL. The likelihood goes up to 53 per cent for those who carry the risk allele in HLA-DRB1 genes.

And individuals who have two of the same risk alleles in IL18RAP, HLA-DRB1 and HLA-DPB1 (a risk gene identified a few years earlier) are 18 times more likely to get NKTCL, compared to those without any of these genes.

Growing need for genetic consultation

The finding signals the increasing importance of precision medicine in treatment of NKTCL, which often relapses and has a low survival rate. Currently, the five-year survival rate across the world stands at 70 per cent for early stage NKTCL and under 50 per cent for late-stage. Treatment options are also limited currently.

With this growing knowledge of genetic risks and immunotherapy, – a relatively new treatment using the body’s own immune system to tackle cancer cells–genetic consultations can play a bigger role in controlling the cancer and improving health outcomes.

“Currently, few genetic consultations are being applied [to NKTCL patients],” observed participating researcher Professor Bei Jin-Xin of Sun Yat-sen University Cancer Center, and Center for Precision Medicine of Sun Yat-sen University in Guangzhou, China. Prof Bei is also a senior research fellow with the Division of Medical Oncology at NCCS. Instead, the measurement of Epstein-Barr virus (EBV) load is more commonly practiced instead as EBV has been known to be a key risk factor.

However, the research team hope things can evolve, especially since NKTCL can be caused by different genes in separate individuals. This means a more tailored approach can be adopted for patients with different genetic profiles. “In recent years, genetic studies have identified both inherited and somatic (mutated) genetic components that are responsible for the risk of developing NKTCL and its precise identification based on molecular traits When validated, these components will serve as biomarkers to stratify patients for precise treatments, resulting in better survival outcome,” noted Professor Bei.

Landmark partnership

With more than 140 collaborators from over 90 institutions, the success of this study came with massive efforts. “As the disease is prevalent in Asian populations, international collaboration with centres across Asia has been particularly helpful in enabling the study of NKTCL. Patients’ participation, international collaboration with investigators of multiple disciplines and grant supports are critical factors,” said Professor Lim Soon Thye, NCCS’ Deputy Medical Director (Clinical) and Senior Consultant Medical Oncologist.

The research was funded by the National Medical Research Council (NMRC) through the National Lymphoma Translational Research Programme and other supporting grants.

Building upon current discoveries, the researchers continue to explore remaining genetic factors that predispose individuals to NKTCL, diving down to the molecular level. Said Prof Bei, “These findings would provide solutions for risk prediction, precise subtyping, and precise treatment, which will eventually improve early diagnosis and precision medicine for NKTCL, reducing the burden of this disease.”