Mutational analysis of Fas ligand gene in human non-Hodgkin lymphoma
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Wild-type Blocking PCR Combined with Sanger Sequencing for Detection of Low-frequency Somatic Mutation
Published on: August 23, 2024
Hong Sug Kim1, Sug Hyung Lee, Jong Woo Lee
1Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Abstract:
Among the systems triggering apoptosis, the Fas-Fas ligand (FasL) system is recognized as a major pathway for the induction of apoptosis in cells and tissues. Ligation of Fas by either an agonistic antibody or FasL transmits a 'death signal' to the target cell, potentially triggering apoptosis. Alterations of genes along the Fas-mediated apoptosis pathway have been reported in many human cancers. However, there have been no data regarding FasL gene mutations in human cancers. We hypothesized that FasL gene mutation might be involved in the development of non-Hodgkin lymphoma (NHL). In this study, we analyzed the entire coding region of the FasL gene for the detection of somatic mutations in a series of 111 NHLs and found that one tumor had a FasL gene mutation in the cytoplasmic domain. To evaluate the functional alterations of the mutant in apoptosis, we overexpressed the mutant in 293T cells, but couldn't find any significant loss of cell death compared to the wild-type FasL. Together, these data suggest that FasL is occasionally mutated in human NHL and that FasL mutations appear to play no role in the pathogenesis of the vast majority of NHLs.
Insights
FasL gene mutations are rare in non-Hodgkin lymphoma (NHL). Researchers found one mutation in 111 NHL cases, but it did not significantly impact apoptosis, suggesting FasL mutations do not drive most NHL development.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Immunology
Background:
- The Fas-Fas ligand (FasL) system is a key pathway for apoptosis induction.
- Alterations in Fas-mediated apoptosis genes are implicated in various human cancers.
- FasL gene mutations have not been previously reported in human cancers.
Purpose of the Study:
- To investigate the hypothesis that FasL gene mutations contribute to non-Hodgkin lymphoma (NHL) development.
- To analyze the FasL gene for somatic mutations in NHL patients.
- To assess the functional impact of any identified FasL mutations on apoptosis.
Main Methods:
- Sequencing of the entire coding region of the FasL gene in 111 NHL samples.
- Overexpression of the identified FasL mutant in 293T cells.
- Assessment of cell death in cells expressing wild-type versus mutant FasL.
Main Results:
- One NHL tumor exhibited a FasL gene mutation within the cytoplasmic domain.
- Overexpression of the mutant FasL did not result in a significant loss of cell death compared to wild-type FasL.
- The identified mutation did not appear to functionally impair apoptosis induction.
Conclusions:
- FasL gene mutations are infrequent in human non-Hodgkin lymphoma.
- The identified FasL mutation in NHL does not appear to play a significant role in the disease's pathogenesis.
- FasL mutations are unlikely to be a major driver in the majority of NHL cases.
