RT Journal Article
SR Electronic
T1 Functional evaluation of missense variations in the human <em>MAD1L1</em> and <em>MAD2L1</em> genes and their impact on susceptibility to lung cancer
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 616
OP 622
DO 10.1136/jmg.2009.074252
VO 47
IS 9
A1 Guo, Yongli
A1 Zhang, Xuemei
A1 Yang, Ming
A1 Miao, Xiaoping
A1 Shi, Yuankai
A1 Yao, Jiarui
A1 Tan, Wen
A1 Sun, Tong
A1 Zhao, Dan
A1 Yu, Dianke
A1 Liu, Junniao
A1 Lin, Dongxin
YR 2010
UL http://jmg.bmj.com/content/47/9/616.abstract
AB 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.