N. Benachenhou et al., HIGH-RESOLUTION DELETION MAPPING REVEALS FREQUENT ALLELIC LOSSES AT THE DNA MISMATCH REPAIR LOCI HMLH1 AND HMSH3 IN NONSMALL CELL LUNG-CANCER, International journal of cancer, 77(2), 1998, pp. 173-180
To study the involvement of DNA mismatch repair genes in non-small cel
l lung cancer, matched normal and tumoral DNA samples from 31 patients
were analyzed for both LOH and microsatellite instability with 34 mar
kers at or linked to hMLHI (3p21), hMSH2 (2p16), hMSH3 (5q11-q13), hMS
H6 (2p16), hPMSI (2q32), and hPMS2 (7p22) loci. Chromosomal regions 3p
21 and 5q11-q13 were found to be hemizygously deleted in 55% and 42% o
f the patients, respectively. Sixty five percent of the patients delet
ed at hMLHI were also deleted at hMSH3. The shortest regions of overla
p for 3p21 and 5q11-q13 deletions delimited by D3S1561/D3S1612 and D5S
2107/D5S624, respectively, were restricted to genetic distances of onl
y 1 cM. Currently, the hMLHI (3p21) and hMSH3 (5q11-q13) genes are the
only known candidates located within these regions. The mutational an
alysis of hMLHI and hMSH3 in hemizygously deleted patients led to the
detection of 2 new polymorphisms in hMSH3. The consequence of these al
lelic losses remains unclear, but the lack of inactivating mutation mi
ght explain that replication error, the hallmark of mismatch repair ge
nes inactivation in cancer cells, was quasi-absent in tumors. We sugge
st that hMLHI and hMSH3 genes could be involved in lung tumorigenesis
through dosage effect in cellular functions other than replication err
or correction. (C) 1998 Wiley-Liss, Inc.