Bronchioloalveolar Carcinoma Of The Molecular Biology Research

BackgroundBronchioloalveolar carcinoma(BAC),as defined by WHO,is a subtype of pulmonary adenocarcinoma,with a pure bronchioloalveolar growth pattern and no evidence of stromal,vascular,or pleural invasion.It is reported that the prognosis of BAC with focal invasion and adenocarcinoma with BAC features is better than non-BAC adenocacinoma,which is similar to pure BAC.Recent data from some developed countries suggest an increase in the incidence of BAC.Targeted therapy has become one focus of oncology in recent years.The observation that patients with adenocarcinoma or BAC are more likely to be sensitive to EGFR-TKIs in some large clinical trials has led to an increased interest in this subtype of NSCLC,especially in its relationship with EGFR. Human papillomavirus(HPV) is a type of oncogenic DNA virus and selectively infects the epithelium of skin and mucous membranes.As the technique in molecular biology developes,reports of the detection of HPV DNA-associated sequences in lung cancer samples have accumulated;however,the carcinogenesis role of HPV in lung cancer has not been confirmed yet.ObjectiveTo evaluate EGFR mutation,gene copy number and protein expression of both EGFR and HER2 in BAC,to investigate their relationship with the pathogenesis, treatment response and prognosis of BAC,and to determine the carcinogesis role of HPV in BAC.MethodsEGFR mutations in the paraffin-embedded BAC samples were analysed by PCR and DNA sequencing.EGFR mutations in the peripheral blood of BAC patients were analysed by PCR and EGFR Mutation Test Kit.Gene copy number and protein expression of EGFR and HER2 in the paraffin-embedded BAC samples were evaluated by FISH and IHC,respectively.PCR and DNA ISH were used to detect HPV DNA.The results were analyzed by the statistic software of SPSS 14.0.ResultsEGFR mutations were detected in 50%(16/32) of BAC samples.Among them,7 cases(43.8%) were exon 19 deletions,1 case(6.2%) was D807N,and 8 cases(50%) were L858R.EGFR mutation was not related to gender(p=0.476),smoking status (p=0.414),pathological subtype(p=0.151),or EGFR expression(p=0.231),but EGFR gene copy number(p=0.001).EGFR mutations in peripheral blood were detected in 5 out of 8 cases(62.5%),including 1 case of G719X,1 L858R,1 insertion and 2 cases of T790M.14 out of 34 cases(41.2%) were found to have increased EGFR gene copy numbers,which was not related to gender(p=0.681),smoking(p=0.288) or pathological subtype(p=0.056).26 out of 34 cases(76.5%) were found to have positive EGFR expression,which was not related to gender(p=0.702),smoking(p=0.724),pathological subtype(p=0.842),or EGFR gene copy number(p=0.252).2 cases demonstrated both increased HER2 gene copy number/gene amplification(2/35,5.7%) and positive HER2 expression(2/34,6.1%),their EGFR FISH and IHC results were also positive.HPV 6/11, 16,18 DNA were detected in no cases by PCR,and only 1(1/24,4.2%) had positive HPV 16/18 DNA by ISH.ConclusionsThe study shows that BAC has relatively higher incidence of EGFR-TKI sensitive mutation,increased EGFR gene copy number,positive protein expression,and possibly EGFR/HER2 co-expression.This may indirectly explain the better treatment response of EGFR-TKIs in BAC patients.Testing free DNA in the peripheral blood for EGFR mutations may help predict responses of EGFR-TKIs in BAC patients and monitor resistance.HPV infection appears to play a limited role in the carcinogenesis of bronchioloalveolar carcinoma.