Peptide Receptors, Genetic Factors That Increase the Risk for Bronchial Carcinoma

deicient฀allele฀of฀the฀a 1 -antitrypsin฀gene฀Pi฀protease฀inhibitor฀are฀at฀an฀increased฀risk฀of฀ developing฀bronchial฀carcinoma.฀The฀Pi฀locus฀is฀polymorphic฀with฀more฀than฀70฀variants฀ reported.฀ There฀ are฀ at฀ least฀ ten฀ alleles฀ associated฀ with฀ a 1 -antitrypsin฀ deiciency฀ [118] .฀ ฀Non-smokers฀carried฀a฀deicient฀allele฀three฀times฀more฀frequently฀20.6฀than฀smokers.฀ Nevertheless,฀patients฀with฀bronchial฀carcinoma฀or฀SCC฀had฀higher฀carrier฀rates฀than฀expected฀ 15.9฀and฀23.8,฀respectively.฀It฀may,฀therefore,฀be฀concluded฀that฀patients฀with฀an฀a 1 -anti- trypsin฀deiciency฀allele฀have฀an฀increased฀risk฀for฀lung฀cancer฀speciically฀SCC฀ [118] .

5.2.3.4 Exogenous Factors and Lung Cancer

Dietary฀factors฀may฀be฀important฀for฀the฀development฀of฀lung฀cancer,฀and฀the฀consumption฀ of฀carotene-rich฀fruits฀and฀vegetables฀and฀high฀plasma฀levels฀of฀vitamin฀E฀and฀b-carotene฀ are฀reported฀to฀reduce฀the฀risk฀ [119] .฀b-carotene฀functions฀as฀an฀antioxidant฀and฀as฀a฀pre- cursor฀for฀vitamin฀A฀or฀retinol.฀Retinoids฀are฀responsible฀for฀the฀differentiation฀of฀epithe- lial฀cells฀and฀they฀may฀suppress฀the฀malignant฀transformation฀of฀epithelial฀cells฀ [120] .฀ These฀indings,฀originally฀made฀in฀retrospective฀studies,฀have฀not฀been฀conirmed฀in฀pro- spective฀studies฀involving฀almost฀30,000฀smokers฀treated฀with฀vitamin฀E฀or฀b-carotene฀ over฀a฀period฀of฀years.฀The฀incidence฀of฀cancer฀even฀increased฀+18฀with฀b-carotene.฀ The฀Beta-Carotene฀and฀Retinol฀Eficacy฀Trial฀CARET฀also฀concluded฀that฀mortality฀was฀ increased฀in฀the฀active฀treatment฀group฀ [79] . Several฀studies฀were฀also฀showing฀that฀smokers฀with฀a฀low฀body฀mass฀index฀have฀a฀ higher฀risk฀for฀developing฀lung฀malignancies฀as฀compared฀with฀smokers฀of฀average฀weight.฀ It฀is฀suggested฀that฀DNA฀adducts฀may฀play฀an฀important฀role฀in฀that฀mechanism.฀A฀current฀ study฀could฀show฀that฀overweight฀subjects฀BMI฀฀25฀with฀little฀weight฀gain฀after฀smok- ing฀cessation฀median฀weight฀gain฀of฀6฀had฀more฀persistent฀adduct฀levels฀as฀compared฀ with฀those฀with฀lower฀BMI฀and฀higher฀weight฀gain฀฀p฀=฀0.06.฀Smokers฀with฀a฀low฀body฀ mass฀index฀have฀a฀higher฀risk฀for฀developing฀lung฀malignancies฀as฀compared฀with฀smokers฀ of฀average฀weight,฀but฀there฀is฀no฀mechanistic฀explanation฀for฀this฀observation.฀Carcinogens฀ in฀cigarette฀smoke฀are฀thought฀to฀elicit฀cancer฀by฀the฀formation฀of฀DNA฀adducts,฀which฀ give฀the฀opportunity฀to฀additionally฀investigate฀the฀biological฀link฀between฀BMI฀and฀lung฀ cancer.฀Godschalk฀et฀al.฀published฀a฀study฀in฀2002฀in฀which฀DNA฀adduct฀levels฀in฀periph- eral฀blood฀lymphocytes฀of฀24฀healthy฀smoking฀volunteers฀0.76฀±฀0.41฀adducts฀per฀108฀ nucleotides฀positively฀correlated฀with฀cigarette฀consumption฀r฀=฀0.51;฀p฀=฀0.01฀and฀were฀ inversely฀related฀with฀BMI฀r฀=฀−0.48;฀p฀=฀0.02฀ [121] .฀A฀signiicant฀overall฀relationship฀ was฀observed฀when฀both฀parameters฀were฀included฀in฀multiple฀regression฀analysis฀r฀=฀ 0.63;฀p฀=฀0.007.฀Moreover,฀body฀composition฀may฀affect฀DNA฀adduct฀persistence฀because฀ lipophilic฀tobacco฀smoke-derived฀carcinogens฀accumulate฀in฀adipose฀tissue฀and฀can฀be฀ mobilized฀once฀exposure฀ceases.฀Therefore,฀DNA฀adduct฀levels฀and฀BMI฀were฀reassessed฀ in฀all฀of฀the฀subjects฀after฀a฀non-smoking฀period฀of฀22฀weeks.฀Adduct฀levels฀declined฀to฀ 0.44฀±฀0.23฀per฀108฀nucleotides฀฀p฀=฀0.002฀and฀the฀estimated฀half-life฀was฀11฀weeks฀on฀ the฀basis฀of฀exponential฀decay฀to฀background฀levels฀in฀never-smoking฀controls฀0.33฀±฀0.18฀ per฀108฀nucleotides.฀Overweight฀subjects฀BMI฀฀25฀with฀little฀weight฀gain฀after฀smok- ing฀cessation฀median฀weight฀gain฀of฀6฀had฀more฀persistent฀adduct฀levels฀as฀compared฀ with฀those฀with฀lower฀BMI฀and฀higher฀weight฀gain฀p฀=฀0.06.฀Overall,฀the฀authors฀con- cluded฀ that฀ leanness฀ is฀ a฀ host฀ susceptibility฀ factor฀ that฀ affects฀ DNA฀ adduct฀ formation,฀ which฀could฀underlie฀the฀observed฀relationship฀between฀BMI฀and฀lung฀cancer฀risk฀ [121] . Alcohol฀does฀not฀play฀a฀role฀in฀smokers฀in฀terms฀of฀the฀development฀of฀lung฀cancer.฀ This฀was฀demonstrated฀in฀a฀study฀in฀27,111฀male฀smokers,฀1,059฀of฀whom฀developed฀lung฀ cancer฀over฀a฀period฀of฀7.7฀years.฀Non-drinkers฀were฀at฀increased฀lung฀cancer฀risk฀com- pared฀with฀drinkers฀relative฀risk฀=฀−1.2;฀95฀CI:฀1.0–1.4฀ [122] .฀However,฀additional฀ alcohol฀consumption฀is฀important฀for฀the฀development฀of฀cancers฀in฀the฀oral฀cavity,฀phar- ynx,฀larynx฀and฀oesophagus,฀the฀risk฀being฀twice฀as฀high฀as฀in฀patients฀with฀a฀current฀his- tory฀of฀smoking,฀but฀without฀current฀daily฀drinking฀ [123] . According฀to฀one฀study฀from฀Italy฀ [122] ,฀patients฀with฀lung฀cancer฀and฀HIV฀infection฀ were฀younger฀38฀vs.฀53฀years฀and฀previously฀smoked฀more฀cigarettes฀per฀day฀40฀vs.฀20฀ than฀the฀control฀group฀of฀patients฀with฀lung฀cancer,฀but฀without฀HIV฀infection.฀The฀main฀ histological฀subtype฀was฀AC,฀with฀tumour฀stage฀TNM฀III–IV฀observed฀in฀the฀majority฀ 53฀of฀patients.฀The฀median฀survival฀of฀the฀HIV฀patients฀was฀signiicantly฀shorter฀than฀ that฀of฀the฀control฀group฀5฀vs.฀10฀months. The฀ development฀ of฀ lung฀ cancer฀ in฀ smokers฀ is฀ supported฀ by฀ exposure฀ to฀ asbestos฀ [124] ,฀with฀the฀risk฀being฀increased฀by฀many฀multiples฀20-fold฀increase฀compared฀with฀ non-smoking฀ asbestos฀ workers฀ and฀ 50-fold฀ increase฀ compared฀ with฀ non-smoking฀ and฀ non-asbestos-exposed฀persons฀ [25] .฀Other฀gaseous฀substances฀also฀encourage฀the฀devel- opment฀ of฀ bronchial฀ carcinoma:฀ arsenic฀ compounds,฀ chloromethyl฀ ether,฀ chromium,฀ nickel฀ and฀ polynuclear฀ aromatic฀ compounds฀ act฀ synergistically฀ with฀ cigarette฀ smoke฀ [100] .฀Radon฀exposure฀is฀also฀associated฀with฀an฀increased฀risk฀of฀bronchial฀carcinoma฀ due฀to฀its฀storage฀in฀lung฀tissue฀and฀high-energy฀a-radiation฀ [64] .฀Smokers฀employed฀in฀ uranium฀mining฀have฀a฀tenfold฀increased฀risk฀of฀bronchial฀carcinoma฀compared฀with฀non- smokers฀working฀in฀the฀same฀industry฀ [64,฀125,฀126] .฀Even฀radiation฀from฀underground฀ uranium฀can฀increase฀the฀lung฀cancer฀risk฀in฀cigarette฀smokers฀ [64] .฀Radiation฀levels฀of฀ 50฀up฀to฀140฀Bqm 3 ฀are฀measured฀in฀various฀residential฀areas฀ [127] ,฀leading฀to฀p53฀muta- tions฀and฀increased฀cancer฀risk฀OR฀=฀−1.4;฀CI:฀0.7–2.6;฀OR฀for฀non-smokers฀=฀3.2;฀CI:฀ 0.7–15.5฀ [127] . Finally,฀the฀risk฀for฀bronchial฀carcinoma฀may฀be฀increased฀simply฀as฀a฀result฀of฀urbani- sation,฀mainly฀due฀to฀air฀pollution฀ [34] .฀However,฀this฀idea฀has฀not฀been฀conirmed฀by฀ other฀studies฀ [6,฀18,฀66] . Readers฀are฀referred฀to฀ Chap.฀3 ฀for฀a฀discussion฀of฀bacterial฀endotoxins฀lipopolysac- charides฀contained฀in฀cigarettes฀and฀cigarette฀smoke.

5.3 Cigarette Smoking and COPD

COPD฀is฀the฀sixth฀most฀common฀disease฀worldwide,฀four฀places฀ahead฀of฀bronchial฀carci- noma฀rank฀10.฀In฀about฀20฀years’฀time,฀COPD,฀a฀condition฀that฀is฀smoking-related฀for฀the฀ most฀part฀and฀is฀characterised฀by฀increasing฀exacerbations฀necessitating฀hospital฀interven- tion,฀will฀have฀risen฀to฀third฀place฀in฀the฀league฀table฀of฀diseases.฀In฀Germany,฀3–4฀of฀the฀