High Frequency of Loss of Heterozygosity in Colorectal Signet Ring Carcinomas Compared to Mucinous and Nonmucinous Adenocarcinomas
N Madiraju, G Deng, L Cun, YS Kim, S Kakar. UCSF, San Francisco, CA; VA Medical Center, San Francisco, CA
Background: Signet ring cell carcinoma is a rare subtype of colorectal cancer associated with a poor prognosis.This study compares the molecular features of SRC with mucinous (MC) and nonmucinous adenocarcinoma(AC).The relationship of molecular abnormalities with survival in SRC is also examined.
Design: Microsatellite instability (MSI) and methylation status was determined in SRC (n=33),MC(n=26) and AC(n=57).For MSI, the 5 Bethesda markers were used; instability at >30% of markers was considered MSI.For methylation analysis,methylation specific PCR was used at 7 loci: hMLH1,p16,RASSF2, HIC1,MINT1,MINT31,MGMT. Methylation at 3 or more loci was considered CIMP+ and the remaining as CIMP-negative.Loss of heterozygosity(LOH)analysis was done at 4 loci: 5q,8p,17p,18q.Tumors with LOH at any locus were considered LOH+.BRAF and KRAS mutations were determined by PCR followed by sequencing.
Results: MSI,CIMP+ status and BRAF mutations were more often seen in SRC and MC compared to AC (see table).LOH status was available in 15 SRC and was present in 14 (94%) cases,including 5(100%)MSI cases and 9(90%)microsatellite stable(MSS)tumors.In SRC, BRAF and KRAS mutations were present in 33% and 52% respectively.BRAF mutations were significantly associated with CIMP+ status(p=0.002).BRAF mutations did not have any impact on overall survival.However, the 5-year survival was zero in patients with MSS cancers and BRAF mutations compared to 100% in MSI cancers with BRAF mutations(p=0.01).
All figures are precentages. p values reflect SRC vs MC and SRC vs AC
|MSI||LOH||MSI with LOH||CIMP+||BRAF mutation||KRAS mutation||5-year survival|
|p value||0.2, 0.08||0.02, 0.04||0.008, 0.008||0.3, 0.002||0.3, 0.04||0.05, 0.2||0.07, 0.02|
Conclusions: Loss of heterozygosity is more frequent in SRC compared to MC and AC. In contrast to MC and AC, LOH is observed in all MSI+ SRC.This may explain its aggressive behavior irrespective of MSI status.BRAF mutations and CIMP+ status are similar in SRC and MC but more frequent compared to AC.In SRC, BRAF mutations adversely affect survival in MSS,but not in MSI tumors.The high frequency of methylation and BRAF mutations suggests that many SRCs may be related to the serrated pathway of carcinogenesis.
Monday, March 9, 2009 1:00 PM
Poster Session II # 70, Monday Afternoon