title: MLH1 V384D polymorphism associates with poor response to EGFR tyrosine kinase inhibitors in patients with EGFR L858R-positive lung adenocarcinoma.
abstract: A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short (< 3 months) and 16 had long (> 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Thoracic Oncology, Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chao-Hua
authors.initials: CH
authors.lastname: Chiu
authors.affiliation: Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Hsiang-Ling
authors.initials: HL
authors.lastname: Ho
authors.affiliation: Taipei VGH-Lihpao Laboratory of Cancer Genomic Medicine, Lihpao Life Science Corporation, Taipei, Taiwan.
authors.forename: Howard
authors.initials: H
authors.lastname: Doong
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Yeh
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Teh-Ying
authors.initials: TY
authors.lastname: Chou
authors.affiliation: Department of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Thoracic Oncology, Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Tsai
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; MLH1; lung adenocarcinoma; resistance; tyrosine kinase inhibitor
references.citation: Annu Rev Genet. 2000;34:359-399
references.pmid: 11092832
references.citation: J Clin Oncol. 2013 Mar 10;31(8):1070-80
references.pmid: 23401451
references.citation: N Engl J Med. 2004 May 20;350(21):2129-39
references.pmid: 15118073
references.citation: Science. 2004 Jun 4;304(5676):1497-500
references.pmid: 15118125
references.citation: Clin Cancer Res. 1998 Jan;4(1):1-6
references.pmid: 9516945
references.citation: Hum Hered. 1998 Mar-Apr;48(2):87-91
references.pmid: 9526167
references.citation: N Engl J Med. 2005 Feb 24;352(8):786-92
references.pmid: 15728811
references.citation: PLoS Med. 2005 Mar;2(3):e73
references.pmid: 15737014
references.citation: Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):839-44
references.pmid: 16467097
references.citation: Clin Cancer Res. 2006 Jul 1;12(13):3908-14
references.pmid: 16818686
references.citation: Cancer Res. 2007 May 15;67(10):4595-604
references.pmid: 17510385
references.citation: Science. 2007 May 18;316(5827):1039-43
references.pmid: 17463250
references.citation: Clin Cancer Res. 2007 Nov 15;13(22 Pt 1):6555-60
references.pmid: 18006754
references.citation: Clin Cancer Res. 2007 Dec 15;13(24):7515-21
references.pmid: 18094436
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20932-7
references.pmid: 18093943
references.citation: Eur J Cancer. 2009 Jan;45(2):228-47
references.pmid: 19097774
references.citation: Oncotarget. 2013 May;4(5):772-84
references.pmid: 23800712
references.citation: Oncotarget. 2013 Aug;4(8):1253-65
references.pmid: 23896512
references.citation: Rinsho Ketsueki. 2013 Oct;54(10):1714-9
references.pmid: 24064821
references.citation: Lung Cancer. 2013 Nov;82(2):370-2
references.pmid: 24012411
references.citation: Oncotarget. 2014 Jul 15;5(13):4920-8
references.pmid: 24952482
references.citation: Oncotarget. 2014 Aug 15;5(15):5908-19
references.pmid: 25115383
references.citation: Ann Oncol. 2009 Feb;20(2):298-304
references.pmid: 18836087
references.citation: Cancer Res. 2009 Apr 15;69(8):3256-61
references.pmid: 19351834
references.citation: N Engl J Med. 2009 Sep 3;361(10):947-57
references.pmid: 19692680
references.citation: Lancet Oncol. 2010 Feb;11(2):121-8
references.pmid: 20022809
references.citation: J Thorac Oncol. 2010 Mar;5(3):399-400
references.pmid: 20186026
references.citation: N Engl J Med. 2010 Jun 24;362(25):2380-8
references.pmid: 20573926
references.citation: Lung Cancer. 2011 Feb;71(2):241-3
references.pmid: 21168933
references.citation: Sci Transl Med. 2011 Mar 23;3(75):75ra26
references.pmid: 21430269
references.citation: J Clin Oncol. 2011 May 20;29(15):2121-7
references.pmid: 21482992
references.citation: Ann Oncol. 2011 Jul;22(7):1507-19
references.pmid: 21536661
references.citation: Lancet Oncol. 2011 Aug;12(8):735-42
references.pmid: 21783417
references.citation: J Thorac Oncol. 2011 Jul;6(7):1152-61
references.pmid: 21597390
references.citation: J Clin Oncol. 2012 Feb 1;30(4):433-40
references.pmid: 22215752
references.citation: Lancet Oncol. 2012 Mar;13(3):239-46
references.pmid: 22285168
references.citation: Nat Med. 2012 Apr;18(4):521-8
references.pmid: 22426421
references.citation: N Engl J Med. 2002 Jan 10;346(2):126-8
references.pmid: 11784881