R. Mathew et al., Esophageal squamous cell carcinomas with DNA replication errors (RER+) areassociated with p16/pRb loss and wild-type p53, J CANC RES, 127(10), 2001, pp. 603-612
Purpose: Microsatellite instability (MSI) as a determinant of propensity to
esophageal squamous cell carcinoma (ESCC at seven microsatellite markers a
t 2p (2p 15-16), 3p (3p13, 3p 14.1-3, 3p25, and 3p26) and 16q (16q12.1-3) w
as investigated to analyze their putative role as indicators of predisposit
ion to esophageal malignancies. Methods: Seven microsatellite loci were amp
lified by polymerase chain reaction, from surgically resected tumor tissues
from 30 ESCC patients from Indian population. to assess the loss of hetero
zygosity (LOH) and replication error repeats (RER) and to correlate these a
lterations with aberrations in major cell cycle regulatory proteins and his
topathological parameters. Results: LOH and RER analyses at these loci demo
nstrated moderate microsatellite alterations, suggesting the involvement of
MSI in esophageal tumorigenesis in a subset of the Indian population. MSI
defined as RER in at least two or more of the loci studied, was observed in
ten of 30 (33%) patients. Twenty-two of 30 patients (73%) showed LOH at on
e or more loci, while 17 of the 30 patients (60%) showed RER in at least on
e of the loci studied. RER-positive patients showed a trend towards better
prognosis when compared to RER-negative patients. NISI demonstrated a signi
ficant association with concomitant loss of p16 and pRb (p16-/pRb- phenotyp
e) (P=0.046). Interestingly, we observed an inverse correlation between MSI
and p53 mutations (P=0.03) suggesting that NISI may provide a p53-independ
ent pathway for esophageal tumorigenesis in RER+ patients. MSI showed a tre
nd towards longer survival and absence of distant organ metastasis (P=0.06)
. Conclusions: The present study demonstrates the probable role of MSI in e
sophageal squamous cell carcinoma in the Indian population. Instability ass
ociated with the repetitive sequences - the revealing marks of loss of DNA
replication fidelity may serve as an indicator of predisposition to esophag
eal cancer.