title: Prognostic significance and molecular associations of 18q loss of heterozygosity: a cohort study of microsatellite stable colorectal cancers.
abstract: OBJECTIVE
  Loss of heterozygosity (LOH) at chromosome 18q frequently occurs late during colon cancer development and is inversely associated with microsatellite instability (MSI). 18q LOH has been reported to predict shorter survival in patients with colorectal cancer, whereas MSI-high status has been associated with superior prognosis. However, it is unclear whether 18q LOH in colorectal cancer has any prognostic implication independent of MSI status and other potential predictors of clinical outcome.
  
  
  METHODS
  Among 555 non-MSI-high colorectal cancers (stage I to IV) in two independent prospective cohort studies, we examined 18q LOH in relation to other molecular events and patient survival. Cox proportional hazard models computed hazard ratio of death, adjusted for clinical and tumoral characteristics, including KRAS, BRAF, PIK3CA, beta-catenin, p53, CpG island methylator phenotype, LINE-1 methylation, and John Cunningham (JC) virus T antigen.
  
  
  RESULTS
  In multivariate logistic regression, 18q LOH was independently associated with JC virus T antigen (odds ratio [OR] = 1.93; P = .0077), body mass index > or = 30 kg/m(2) (obesity; OR = 2.01; P = .014), high tumor grade (OR = 0.40; P = .018), KRAS mutation (OR = 0.66; P = .40), and LINE-1 hypomethylation (for a 30% decrease; OR = 1.92; P = .045). Five-year colorectal cancer-specific survival was 75% among patients with 18q LOH-positive tumors and 74% among those with 18q LOH-negative tumors (log-rank P = .80). Five-year overall survival was 70% among patients with 18q LOH-positive tumors and 68% among those with 18q LOH-negative tumors (log-rank P = .54). Multivariate analysis did not show prognostic significance of 18q LOH.
  
  
  CONCLUSIONS
  In our large prospective study of patients with non-MSI-high colorectal cancer, 18q LOH or allelic imbalance was not associated with patient survival.
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 44 Binney St, Room JF-215C, Boston, MA 02115 USA. shuji_ogino@dfci.harvard.edu
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Natsumi
authors.initials: N
authors.lastname: Irahara
authors.forename: Kaori
authors.initials: K
authors.lastname: Shima
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kirkner
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
mesh_terms: D000368:Aged; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
references.citation: Mod Pathol. 2006 Jan;19(1):59-68
references.pmid: 16118624
references.citation: Cancer Res. 2003 Nov 1;63(21):7256-62
references.pmid: 14612521
references.citation: J Mol Diagn. 2006 May;8(2):209-17
references.pmid: 16645207
references.citation: Cell. 1990 Jun 1;61(5):759-67
references.pmid: 2188735
references.citation: J Clin Oncol. 1998 Feb;16(2):427-33
references.pmid: 9469325
references.citation: J Mol Diagn. 2008 Jan;10(1):13-27
references.pmid: 18165277
references.citation: Cancer Cell. 2006 Mar;9(3):199-207
references.pmid: 16530704
references.citation: J Clin Oncol. 2008 Jan 20;26(3):380-5
references.pmid: 18202413
references.citation: Lancet. 2002 Nov 2;360(9343):1381-91
references.pmid: 12423985
references.citation: N Engl J Med. 1994 Jul 28;331(4):213-21
references.pmid: 8015568
references.citation: J Natl Cancer Inst. 1999 Aug 4;91(15):1295-303
references.pmid: 10433618
references.citation: Gastroenterology. 2008 Oct;135(4):1079-99
references.pmid: 18773902
references.citation: Cancer Res. 2006 Sep 1;66(17):8462-9468
references.pmid: 16951157
references.citation: Neoplasia. 2006 Jun;8(6):458-64
references.pmid: 16820091
references.citation: Gastroenterology. 1998 Jun;114(6):1180-7
references.pmid: 9609754
references.citation: Lancet. 2002 Jan 19;359(9302):219-25
references.pmid: 11812558
references.citation: Mod Pathol. 2007 Jan;20(1):15-22
references.pmid: 17086168
references.citation: J Clin Oncol. 2008 Dec 10;26(35):5705-12
references.pmid: 19001320
references.citation: J Clin Oncol. 2008 Oct 20;26(30):4906-11
references.pmid: 18794541
references.citation: J Clin Oncol. 2005 Jan 20;23(3):609-18
references.pmid: 15659508
references.citation: Gut. 2009 Jan;58(1):90-6
references.pmid: 18832519
references.citation: Br J Cancer. 1999 Feb;79(5-6):903-8
references.pmid: 10070888
references.citation: Neoplasia. 2009 Jan;11(1):87-95
references.pmid: 19107235
references.citation: Eur J Cancer. 2005 Sep;41(14):2060-70
references.pmid: 16125380
references.citation: J Clin Oncol. 2008 Jun 1;26(16):2690-8
references.pmid: 18509181
references.citation: Gastroenterology. 1998 Jun;114(6):1188-95
references.pmid: 9609755
references.citation: N Engl J Med. 2007 May 24;356(21):2131-42
references.pmid: 17522398
references.citation: N Engl J Med. 2001 Apr 19;344(16):1196-206
references.pmid: 11309634
references.citation: Dis Colon Rectum. 2004 Sep;47(9):1467-82
references.pmid: 15486743
references.citation: Histopathology. 2007 Jan;50(1):113-30
references.pmid: 17204026
references.citation: Neoplasia. 2008 Jun;10(6):534-41
references.pmid: 18516290
references.citation: Am J Pathol. 2007 Nov;171(5):1509-19
references.pmid: 17982127
references.citation: Int J Cancer. 2008 Jun 15;122(12):2767-73
references.pmid: 18366060
references.citation: J Mol Diagn. 2007 Jul;9(3):305-14
references.pmid: 17591929
references.citation: J Clin Oncol. 2008 Dec 10;26(35):5713-20
references.pmid: 18955444
references.citation: J Clin Oncol. 2008 Jul 1;26(19):3213-21
references.pmid: 18591556
references.citation: Nat Rev Cancer. 2005 May;5(5):388-96
references.pmid: 15864280
references.citation: J Mol Diagn. 2006 Nov;8(5):582-8
references.pmid: 17065427
references.citation: J Clin Oncol. 2010 Jan 20;28(3):466-74
references.pmid: 20008640
references.citation: J Mol Diagn. 2005 Aug;7(3):413-21
references.pmid: 16049314
references.citation: Stat Med. 1989 May;8(5):551-61
references.pmid: 2657958
references.citation: J Clin Oncol. 2009 Mar 20;27(9):1477-84
references.pmid: 19237633
references.citation: J Clin Oncol. 2003 Mar 1;21(5):820-9
references.pmid: 12610180
references.citation: Nat Genet. 1996 Jul;13(3):343-6
references.pmid: 8673134
references.citation: Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8564-9
references.pmid: 16361538
references.citation: J Natl Cancer Inst. 2008 Dec 3;100(23):1734-8
references.pmid: 19033568
references.citation: Gut. 2006 Jul;55(7):1000-6
references.pmid: 16407376
references.citation: Neoplasia. 2007 Jul;9(7):569-77
references.pmid: 17710160
references.citation: Nat Genet. 2006 Jul;38(7):787-93
references.pmid: 16804544