Functional evaluation of missense variations in the human MAD1L1 and MAD2L1 genes and their impact on susceptibility to lung cancer
- Yongli Guo1,
- Xuemei Zhang2,
- Ming Yang1,
- Xiaoping Miao1,
- Yuankai Shi3,
- Jiarui Yao3,
- Wen Tan1,
- Tong Sun1,
- Dan Zhao1,
- Dianke Yu1,
- Junniao Liu1,
- Dongxin Lin1,2
- 1State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China
- 2Department of Etiology & Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China
- 3Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Correspondence to Dr Dongxin Lin, Department of Etiology & Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences, Beijing 100021, China; dlin{at}public.bta.net.cn
- Received 15 October 2009
- Revised 27 February 2010
- Accepted 2 March 2010
- Published Online First 1 June 2010
Abstract
Background Human MAD1 mitotic arrest deficient-like 1 (MAD1L1) and MAD2 mitotic arrest deficient-like 1 (MAD2L1) are two interactive proteins playing important roles in maintaining spindle checkpoint function. This study examined the functional relevance of missense coding single nucleotide polymorphisms (SNPs) in MAD1L1 and MAD2L1 and their association with susceptibility to lung cancer.
Methods SNPs in the MAD2L1 coding region were discovered by sequencing and impact of MAD1L1 and MAD2L1 variants on spindle checkpoint function was examined by flow cytometry and mitotic index assay. The associations of MAD1L1 and MAD2L1 variants with lung cancer were analysed in a case–control cohort of 1000 patients and 1000 controls. ORs and 95% CIs were estimated by logistic regression.
Results A novel C-to-A SNP at codon 84 of MAD2L1 (Leu84Met substitution) was discovered. Cells expressing MAD2L1-84Met and MAD1L1-558His had impaired spindle checkpoint function, with a lower 4N-DNA content and mitotic index when treated with nocodazole. Case–control analysis showed that the MAD2L1 Leu84Met SNP was associated with increased risk of lung cancer in an allele dose dependent manner, with the ORs being 2.55 (95% CI 1.95 to 3.33) for the Leu/Met and 2.68 (95% CI 2.05 to 3.48) for the Met/Met genotype compared with the Leu/Leu genotype. The MAD1L1 558 His/His genotype was also associated with 1.4-fold elevated lung cancer risk compared with the Arg/Arg genotype.
Conclusion These results suggest that genetic variants in MAD1L1 and MAD2L1 confer susceptibility to lung cancer, which might result from reduced spindle checkpoint function due to attenuated function of MAD1L1 and/or MAD2L1.
Footnotes
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YG, XZ and MY contributed equally to this work.
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Funding This study was supported by State Key Basic Research Program (grant 2004CB518701).
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Competing interests None.
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Patient consent Obtained.
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Ethics approval This study was conducted with the approval of the Regional ethics committee, Uppsala university, Cancer Institute and Hospital, Chinese Academy of Medical Sciences.
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Provenance and peer review Not commissioned; externally peer reviewed.
