Phenotypic mismatch repair hMSH2 and hMLH1 gene expression profiles in primary non-small cell lung carcinomas.
BACKGROUND
Defects in the human DNA mismatch repair genes (MMR) hMSH2 and hMLH1 are responsible for the development of sporadic and hereditary colorectal cancers. The role of MMR genes in the pathogenesis of lung cancer has not been elucidated. The aim of this study was to address the phenotypic mRNA expression profiles of mismatch DNA repair system in lung cancer.


METHODS
We evaluated the mRNA levels of the hMSH2 and hMLH1 components of the mismatch DNA repair (MMR) system in 29 unselected frozen pairs of primary non-small cell lung carcinomas (NSCLCs) and their adjacent normal tissue (ANTs) specimens by quantitative real-time PCR analysis relative to housekeeping Porphobilinogen deaminase (hPBGD) mRNA. To simplify and potentially improve the analysis of data, we defined for each individual MMR mRNA two possible phenotypes: a regular (R(2): hMSH2/hPBGD mRNAs> or =1 and R(1): hMLH1/hPBGD mRNAs> or =1) and a reduced (r(2): hMSH2/hPBGD mRNAs<1 and r(1): hMLH1/hPBGD mRNAs<1). The presence of MMR gene expression was evaluated after conversion of the molecular mRNA levels into clinically distinct phenotypic entities by these working criteria, based on the hypothesis that reduced mRNA and protein levels result in lower or non-functional MMR.


RESULTS
Phenotyping defined four distinct MMR system expression profiles, R(2)R(1), r(2)R(1), R(2)r(1) and r(2)r(1) by ascending tumor progression rate and identified a previously unrecognized disease-associated phenotypic entity (r(2)r(1)). The phenotype-based biological aspects of the MMR system suggested that its two components: (1) function independently and (2) are not directly involved in the onset of the transformation process, since healthy lung tissue was devoid of r(2)r(1) phenotypes.


CONCLUSIONS
These findings link MMR mRNA levels of paired lung tissue specimens to patients' clinical condition and suggest that phenotypic translation of molecular MMR data refines the biology of the MMR system with consequent diagnostic implications in the clinical assessment of lung cancer patients.
Vageli
Dimitra
D
Department of Pathology, University of Thessalia Medical School, Larissa, Greece. vagelidim@med.uth.gr
Daniil
Zoe
Z
Dahabreh
Jubrail
J
Karagianni
Eleni
E
Vamvakopoulou
Dimitra N
DN
Ioannou
Maria G
MG
Scarpinato
Karin
K
Vamvakopoulos
Nikos C
NC
Gourgoulianis
Konstantinos I
KI
Koukoulis
George K
GK
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000235:genetics*; D053843:DNA Mismatch Repair; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis*
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011163:Hydroxymethylbilane Synthase; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein