A Lung Cancer

>> good afternoon everyone. dr. qing lan andmyself are extremely honored to speak today at the symposium honoring dr. fraumeni, andwe'll be talking about indoor air pollution and lung cancer in china. as bill just mentioned,chairman mao and president nixon met in february, 1972, and opened up the door to a whole seriesof scientific collaborations in china. we fast forward to 1982, and you can see bothbill blot and dr. fraumeni and his wife, and they literally leaped through that door andset up an extraordinary research program that has gone on since that time. it's multifaceted,covers many exposures and many tumors. now there were many reasons to set up a cancerresearch program in china. there were extraordinary opportunities with regard to different typesof diseases that presented in different ways,

different rates, different exposures drivingthose diseases. this is one example of why it was compelling to study lung cancer inchina, and here you see a wide spectrum, a wide variety of rates, lung cancer incidencerates, among women in select asian countries with very low rates of female smoking. thisis work that michael thun published, and you can see he's comparing rates off to the leftamong women in connecticut, and that's 1935 to 1940 before women began smoking, and youcan see a wide variation in rates, very high rates in china and geographic variation inthose rates. so, as bill said, this was a sign that there was something interestinggoing on, something that deserved our study. so dr. fraumeni and dr. blot along with ourcollaborator published a paper noting geographic

variation of female lung cancer in china in1986, and you can see here even within china even though rates overall were elevated, astrong variation for rates, some hot spots up in the northeast and also down in the southwestand also around shanghai. there was more than a 20-fold variation lung cancer rates in thepopulation. this led to a series of studies that dr. fraumeni and his colleagues conducted.dr. fraumeni was the lead investigator in a number of these and supported other work.there were four primary areas of study that he worked on, shanghai, gansu, shenyang, andxuanwei. shanghai was a very large population based study that dr. fraumeni conducted withgao yu-tang and wei zheng, who's here today, and one of the most notable findings was anincreased risk associated with exposure to

cooking fumes from oil that was heated tohigh temperatures, particularly a certain type of oil called rapeseed oil, and therewas some wonderful mechanistic work that followed up on that conducted by peter shields andcurt harris that showed a very high mutagenic activity to rapeseed oil. this finding wasreplicated in a case control study in gansu where individuals lived in homes that wereactually underground, had very poor ventilation. in work that was led by jay lubin, the findingwas replicated. this was also a study with jay and john boice identified some importantdose response relationships with indoor radon and lung cancer, but what i'm going to talkabout today, our studies in shenyang and xuanwei, where the focus was in particular on coal.now 800 million people worldwide use coal

for home cooking, heating still today, andcoal's used to generate electricity in many countries. so this was a very important studythat was conducted, very large for its time, population based study of lung cancer in shenyangin the very northern part of china, and one of the exposures that they focused on wasexposure to something called a kang. a kang is a very ingenious device that cooks coal,burns coal here, uses it for cooking, and then the heat is channeled through the bedand keeps it warm. it's very cold. this is what an actual kang looks like. there's thestove. there's the funneling underneath the bed, and they found a strong dose responserelationship between burning coal in a kang for women, not men, and then when they lookedat burning a kang in the home and actually

in the bedroom, so they were both cookingin the bedroom as well as burning fuel in the bedroom for heating, they found dose responserelationship for both men and women, and in contrast there was no association with lungcancer risk for people who were using central heating that was supplied by gas. now thiswas followed up in a collaboration between dr. fraumeni and dr. henderson where the femalecases and controls in cases from the shenyang study were combined with female cases andcontrols from a study in harbin, relatively close by, also in the northeast, very cold,and almost 1,000 cases and 1,000 controls this time of women, and again they found doseresponse relationship for burning a kang, particularly in the bedroom, for using coalstoves but not for using non-coal stoves.

so this was very important evidence that burningcoal for heating and cooking inside the home was associated with lung cancer. now anotherregion of china that dr. fraumeni was very interested in pursuing research on was inxuanwei. xuanwei is located in the southwest part of china in yunnan province and ratesthere among the very highest in china. in fact they may be among the very, very highestin the world. there are a number of different types of coal that are burned in xuanwei.something called locally smoky coal or a variation on bituminous coal, smokeless coal, a typeof anthracite coal, and wood. and, unlike in the northeast, this area is much poorer.so people just dig a hole, make a fire pit in the home, and then burn the coal therein homes that were generally unventilated

and got very high exposures. now xuanwei isa semi-mountainous, rural region. it's actually relatively cold even though it's in the southbecause it's fairly elevated. almost no women smoke. most of the men smoke though at lightlevels, and it's really a model and a stable population to study. there was only one problem,and that is that the u.s. epa got there before nci. [laughter] the u.s. epa had a team thatwas doing research in the late 80's, and it wasn't quite an opportunity to work there,but dr. fraumeni bided his time. he waited until 1999, and then instead of having togo to xuanwei, xuanwei came to him, [laughter] and came to him in the form of dr. qing lan.dr. fraumeni recruited qing in 1999 just after she had finished her ph.d. at chapel hillin a joint trend program with the chinese

academy of preventative medicine in beijing,and qing for her dissertation had established a very large cohort in xuanwei, and the goalof the cohort was to study the causes of lung cancer excess and also test if lung cancermortality decreased after installing stoves with chimneys. the chinese government in recognitionof the potential problem of people being exposed to very high levels of coal combustion productshad given a few dollars, made available a few dollars to each home to replace theirfire pits with a stove and a chimney, and there was an option whether to use it or not.not everybody did. so qing came here in 1999, brought the entire cohort dataset with herand also brought thousands of samples from a pilot molecular epidemiology study thatshe had done. the investigators from the epa

had retired and agreed to transfer the wholestudy to nci. so dr. fraumeni had the opportunity following to work in xuanwei and he workedwith qing to produce some really exciting results. so one of the initial observationswas that there's a striking increased risk of lung cancer in men and women associatedwith exposure to smoky coal. in women the risk was almost 100-fold. it was also quiteinteresting that the age started cooking was strongly associated with risk of lung canceramong women using smoky coal, and you can see the peak risk starts among women who startedcooking between the ages of 12 to 15. no men cooked in that population. equally importantwas a striking observation that qing made and on a paper that she published showingthat improved stove ventilation substantially

reduced the risk of lung cancer, almost adecrease of almost 60%, of almost 40% in both men and women. this is one of the very firstexamples of proof that an intervention such as improving ventilation in the home, thehomes with very high levels of indoor air pollution, actually works, actually reduceslung cancer, and her group also showed that the same intervention had a strong influencein reducing the risk of copd. now there are a series of ongoing projects taking placein xuanwei now, evaluating, trying to evaluate the causative agents in smoky coal and lungcancer and to get at the underlying mechanisms of this association. there are studies goingon looking at coal composition, coal control combustion studies, and there's a great dealof air and personal air monitoring exposure

assessment that's going on. mechanistic studiesare taking place with the goal to link all of this to lung cancer risk. this shows someinitial data that we've collected-personal air monitoring of non-smoking women in thisregion in china, and if you look at smoky coal, you can see that, yes, it seems likethere are very high levels of pah's, interestingly moderate levels of respirable quartz, pm 2.5,but then you look at what we detected in smokeless coal and in wood, and you say, well, there'ssome pah's in wood, some respirable quartz, more pm 2.5 and higher levels of so2 and smokelesscoal than either. so simply analyzing the coal is inadequate to try and get a handleon what's driving this extraordinary excess. in parallel we're conducting some mechanisticstudies to try to get at this question biologically.

this is work that qing set up through a collaborationwith avi spira at boston university, and here what we've detected is a 282 gene signaturein this gene expression profile that reflects a response to smoky versus smokeless coal.and you can see some genes are increased, some are decreased. these are individualswith smoky coal exposure. these are individuals with smokeless coal or low risk coal exposure.we then tried to take the exposures that had been measured on these individuals and triedto look at the relationship between those air monitoring levels and this gene expressionsignature, and what we found is that the very carcinogenic pah's, particularly dibenz(a,h)anthraceneand the marker benzo(a)pyrene, showed correlation, a significant correlation with this gene signature,but non-carcinogenic ph's and interestingly

pm 2.5 showed no association. we also foundthat the changes induced in smoky versus smokeless coal exposure were similar, showed enrichmentin some of the same genes that have been identified that distinguish the response in current versusnever smoking. now the impact of this research was quite important. dr. fraumeni's studyin shenyang and qing's study in xuanwei were the key contributors to iarc's decision toconclude that coal indoor air emissions from coal are group 1 carcinogenic compounds, andthis was affirmed in 2009. in addition, these findings played an important role in the developmentof new who guidelines for indoor air quality. these were adopted just last week and theypromised to, if implemented, make an important contribution to reducing the substantial morbiditymortality from indoor air pollution throughout

the developing world. in the next steps inthe xuanwei study will be integration of exposure data into the analysis of lung cancer in anew case control study, histologic and tumor marker characterization, and integration intocancer risk analysis, and the comparison of findings with lung cancer in other parts ofchina and asia and the west, and along these lines qing established a new consortium, thefemale lung cancer consortium in asia, and the goal of this first notes that lung cancerin asia as i noted before is, it takes place in women mostly among never-smokers, thatthe rates are relatively high compared to the west, interestingly a higher proportionis an adenocarcinoma, and it has distinct molecular characteristics with clinical ramifications.the genetic environmental risk factors for

lung cancer may differ among women in asiaversus the west. this is one of the driving hypotheses in the consortium, and the goalof the consortium was to study both the environmental and genetic etiology in this population. thiswas the first project the consortium conducted, a large scale gwas, the largest ever of never-smokingfemales, and this was done in collaboration between qing and stephen chanock and manycollaborators in asia done at nci, and there were 18 studies that were involved. 6,600never smoking female lung cancer cases, mostly adenocarcinoma and 7,500 controls, and wefound three novel gene regions. one of these three was particularly interesting in ros1since ros1 fusions in lung adenocarcinoma are considered to be one of the drivers ofoncogenesis. also what was quite interesting

was to look at findings that had been detectedin smoking caucasians that had been associated with risk of lung cancer, and we saw absolutelyno association among asian never-smoking females. this was a follow up of a previous reportthat dr. margaret spitz had published, and we see evidence that this locus, these associations,really do seem to be specific to smoking and lung cancer that in this population therewas no relationship, and then finally initial analysis to study potential gene environmentactions in this gwas has identified several, in fact three of the seven snps that showedassociation provided evidence of interaction. this is being followed up now. now if we takea step back and look beyond china and beyond just coal, we should note that half of theworld's population is exposed to smoke from

cooking and heating with solid fuels. in additionto coal, that includes wood, plants, and dung. this is a major risk factor for global diseaseburden, but cancer risks for non-coal fuel is unresolved, and there are an estimated3.9 million premature deaths annually. so the future course of this consortium is toexpand it to include studies in populations exposed to biomass in southeast and west asia,to define a spectrum of susceptibility alleles in search for interactions, and very importantlyto conduct tumor marker characterization in non-adenocarcinoma samples using sequencingin particular from diverse populations. this shows the expanded consortium and includesstudies from japan to mumbai, india from singapore up to beijing and shenyang and offers a strikingopportunity to compare the epidemiologic exposure

data, genetic data, and also leak tumor dataacross these diverse populations. before i finish i want to touch just a little bit aboutoccupational studies. dr. blot described important work that dr. fraumeni and his colleagueshad conducted in the united states on occupation. this is the same smokestack. i just wantedto note that this is a paper from another lee, anna lee, and dr. fraumeni, it was publishedin 1969 on risks of lung cancer among copper smelters, and i'd like to note that dr. fraumenitaught us to identify high risk occupations to set up high risk populations to set uphigh quality case control cohort studies to ensure that we have very high quality exposureassessment and that if we see associations and if we can replicate it to not just stopthere, to go on and to attempt to then use

the molecular tools in our armamentarium totry to understand underlying mechanisms because of the enrichment that molecular epidemiologyapproaches and epidemiology approaches have with each other and this synergy that canresult from that work. these are a number of studies that resulted from that motivationthat he provided us--cohort studies of diesel exhaust conducted by debra silverman in theu.s., of benzene, a large cohort study in the united states conducted by martha linetand bill blot, a big study of formaldehyde that aaron blair and laura beane freeman conductedin the u.s., and a series of mechanistic studies that qing lan to try to understand the underlyingbiologic basis of these associations. this shows examples of how etiologic work can laythe foundation for public health action. these

studies contribute importantly to iarc reviews,and all three instances, they provided either the key study in some instances, almost theonly studies that were used, the epidemiologic studies that were used by iarc and their reviewand conclusions about the carcinogenicity of these compounds and also these have hadan impact on regulation. they've had a public health impact, and we're particularly proudof some of the work that's resulted from our benzene studies. the benzene cohort studydirectly led to workplace reduction of benzene in china, and some molecular epidemiologystudies that qing conducted showing some important molecular changes in populations exposed tobenzene at very low levels resulted in reducing the workplace standard in the netherlandsjust last month to the lowest level in the

world and also directly led to the reductionof benzene in the formulated u.s. gasoline. i'd like to close with the chinese versionof we stand on the shoulders of giants. [foreign language spoken] when you drink the well...when you drink the water, don't forget who dug the well. so qing and i and our collaboratorsat nci and the many collaborators that we have in china who dr. fraumeni developed longstanding collaborations with, who we helped to train, we helped to mentor. in fact thereare multiple generations of chinese investigators, many who came to nci to be trained have expressedto us over the last few weeks to make sure to tell him how grateful they are and howthankful they are for his mentorship and the work that he did to establish these internationalcollaborations based upon mutual respect,

based upon honesty, transparency, and thatreally launched decades and generations of studies that we are still harvesting today.thank you. [ applause ]