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.
BACKGROUND:HumanMAD1 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.
Authors: Kristen N Stevens; Xianshu Wang; Zachary Fredericksen; V Shane Pankratz; James Cerhan; Celine M Vachon; Janet E Olson; Fergus J Couch Journal: Breast Cancer Res Treat Date: 2011-05-24 Impact factor: 4.872
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Authors: Kristen S Purrington; Seth Slettedahl; Manjeet K Bolla; Kyriaki Michailidou; Kamila Czene; Heli Nevanlinna; Stig E Bojesen; Irene L Andrulis; Angela Cox; Per Hall; Jane Carpenter; Drakoulis Yannoukakos; Christopher A Haiman; Peter A Fasching; Arto Mannermaa; Robert Winqvist; Hermann Brenner; Annika Lindblom; Georgia Chenevix-Trench; Javier Benitez; Anthony Swerdlow; Vessela Kristensen; Pascal Guénel; Alfons Meindl; Hatef Darabi; Mikael Eriksson; Rainer Fagerholm; Kristiina Aittomäki; Carl Blomqvist; Børge G Nordestgaard; Sune F Nielsen; Henrik Flyger; Xianshu Wang; Curtis Olswold; Janet E Olson; Anna Marie Mulligan; Julia A Knight; Sandrine Tchatchou; Malcolm W R Reed; Simon S Cross; Jianjun Liu; Jingmei Li; Keith Humphreys; Christine Clarke; Rodney Scott; Florentia Fostira; George Fountzilas; Irene Konstantopoulou; Brian E Henderson; Fredrick Schumacher; Loic Le Marchand; Arif B Ekici; Arndt Hartmann; Matthias W Beckmann; Jaana M Hartikainen; Veli-Matti Kosma; Vesa Kataja; Arja Jukkola-Vuorinen; Katri Pylkäs; Saila Kauppila; Aida Karina Dieffenbach; Christa Stegmaier; Volker Arndt; Sara Margolin; Rosemary Balleine; Jose Ignacio Arias Perez; M Pilar Zamora; Primitiva Menéndez; Alan Ashworth; Michael Jones; Nick Orr; Patrick Arveux; Pierre Kerbrat; Thérèse Truong; Peter Bugert; Amanda E Toland; Christine B Ambrosone; France Labrèche; Mark S Goldberg; Martine Dumont; Argyrios Ziogas; Eunjung Lee; Gillian S Dite; Carmel Apicella; Melissa C Southey; Jirong Long; Martha Shrubsole; Sandra Deming-Halverson; Filomena Ficarazzi; Monica Barile; Paolo Peterlongo; Katarzyna Durda; Katarzyna Jaworska-Bieniek; Robert A E M Tollenaar; Caroline Seynaeve; Thomas Brüning; Yon-Dschun Ko; Carolien H M Van Deurzen; John W M Martens; Mieke Kriege; Jonine D Figueroa; Stephen J Chanock; Jolanta Lissowska; Ian Tomlinson; Michael J Kerin; Nicola Miller; Andreas Schneeweiss; William J Tapper; Susan M Gerty; Lorraine Durcan; Catriona Mclean; Roger L Milne; Laura Baglietto; Isabel dos Santos Silva; Olivia Fletcher; Nichola Johnson; Laura J Van'T Veer; Sten Cornelissen; Asta Försti; Diana Torres; Thomas Rüdiger; Anja Rudolph; Dieter Flesch-Janys; Stefan Nickels; Caroline Weltens; Giuseppe Floris; Matthieu Moisse; Joe Dennis; Qin Wang; Alison M Dunning; Mitul Shah; Judith Brown; Jacques Simard; Hoda Anton-Culver; Susan L Neuhausen; John L Hopper; Natalia Bogdanova; Thilo Dörk; Wei Zheng; Paolo Radice; Anna Jakubowska; Jan Lubinski; Peter Devillee; Hiltrud Brauch; Maartje Hooning; Montserrat García-Closas; Elinor Sawyer; Barbara Burwinkel; Frederick Marmee; Diana M Eccles; Graham G Giles; Julian Peto; Marjanka Schmidt; Annegien Broeks; Ute Hamann; Jenny Chang-Claude; Diether Lambrechts; Paul D P Pharoah; Douglas Easton; V Shane Pankratz; Susan Slager; Celine M Vachon; Fergus J Couch Journal: Hum Mol Genet Date: 2014-06-13 Impact factor: 6.150
Authors: Nikta Pashai; Haiping Hao; Angelo All; Siddharth Gupta; Raghothama Chaerkady; Alejandro De Los Angeles; John D Gearhart; Candace L Kerr Journal: PLoS One Date: 2012-06-21 Impact factor: 3.240
Authors: Charles C Chung; Peter A Kanetsky; Zhaoming Wang; Michelle A T Hildebrandt; Roelof Koster; Rolf I Skotheim; Christian P Kratz; Clare Turnbull; Victoria K Cortessis; Anne C Bakken; D Timothy Bishop; Michael B Cook; R Loren Erickson; Sophie D Fosså; Kevin B Jacobs; Larissa A Korde; Sigrid M Kraggerud; Ragnhild A Lothe; Jennifer T Loud; Nazneen Rahman; Eila C Skinner; Duncan C Thomas; Xifeng Wu; Meredith Yeager; Fredrick R Schumacher; Mark H Greene; Stephen M Schwartz; Katherine A McGlynn; Stephen J Chanock; Katherine L Nathanson Journal: Nat Genet Date: 2013-05-12 Impact factor: 38.330