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646 Statement of Henry Rothschild, M.D., Ph.D. Introduction I am Henry Rothschild, a medical doctor and doctor of philosophy specializing in genetics, molecular biology and oncology, currently Professor of Medicine and Anatomy at the School of Medicine, Louisiana State University, New Orleans, .i Louisiana. Since 1962 I have been engaged in research involving the genetic basis of ` disease and am director of the Louisiana Ethnogenetic Disease Association. I currently serve as consultant to the Louisiana Department of Health and Human Resources and am a member of the Research Committee of the American :' Heart Association of Louisiana. I have published over 40 scientific articles. My Curriculum Vitae and list of publications are attached. Discussion Studies conducted in Louisiana have demonstrated an unusual distribution of ; lung cancer mortality. The lung cancer mortality in white males in Louisiana is the highest in the nation, and in particular the 27 southern preponderantly rural ~ parishes ranked in the top 3% nationally from 1950 through 1976 and has risen since - then. Studies that I have been conducting since 1975 on this population indicate 4 that genetic factors may play a significant role in this excess mortality from lung u cancer. In our initial investigation we interviewed the next-of-kin of 284 of the 813 persons who died of lung cancer during 1971 through 1977 in the 10 southern, nonurban parishes. We found that 108 (38%) of the decedents had been employ for at least six months as sugarcane-farm workers at some time during their lives and that the relative risk estimate of lung cancer mortality for sugarcane-farni , workers was more than twice that of the controls. Neither employment in other ,- industries nor tobacco consumption could account for the elevated risk of lung~ < cancer mortality associated wi We then began to exp including a group from the Na there may be "an inherited prec :here are genetic factors assc found, for example, that first- .ng cancer have higher rates c 'actors such as age, sex, birth c non-smoking first-degree rel. `ourfold risk of dying of lur i oKuhata and Lillienfield, 19( :~creased risk of lung cancer rr ~Fraumeni, et al., 1975) The argument for the pot( ~t al., 1974) is supported by re ~.ffer in their incidences for s, saectrum of different genetic ':stribution curve of genetic sus Studies of distribution o -aport this proposition. Comp ' oidly accelerating incidence c '•:exican and Chinese extraction I•+e a higher incidence, and A =wer incidence. Chinese in F ' ~e^ocarcinoma of the lung, a _~^iamaric, 1969). !n analyzying our data we "^ponent for lung cancer in th, 0 W ~ ~ ~ N j

647 schild, Y.D., Ph.D. ion >r and doctor of philosophy specializing , currently Professor of Medicine and ;iana State University, New Orleans, !search involving the genetic basis of nogenetic Disease Association. : Louisiana Department of Health and Research Committee of the American blistied over 40 scientific articles. My attached. ion iemonstrated an unusual distribution of -tality in white males in Louisiana is the the 27 southern preponderantly rural m 1950 through 1976 and has risen since since 1975 on this population indicate : role in this excess mortality from lung .ewed the next-of-kin of 284 of the 815 1971 through 1977 in the 10 southern, ?6) of the decedents had been employed workers at some time during their lives ig cancer mortality for sugarcane-farm controls. Neither employment in other ! account for the elevated risk of lung cancer mortality associated with sugarcane farming. We then began to explore the thesis expressed by many investigators including a group from the National Cancer Institute (Goffman, et al.,, 1982) that there may be "an inherited predisposition to lung cancer." Studies have shown that there are genetic factors associated with lung cancer pathogenesis. It has been found, for example, that first-degree relatives of individuals diagnosed as having lung cancer have higher rates of lung cancer that cannot be accounted for by other factors such as age, sex, birth cohort, or cigarette smoking. It was also shown that a non-smoking first-degree relative of an individual with lung cancer has about a fourfold risk of dying of lung cancer when compared to control relatives. (Tokuhata and Lillienfield, 1963, Tokuhata, 1964) A similar study reported an increased risk of lung cancer mortality in siblings of individuals with lung cancer (Fraumeni, et al., 1975) The argument for the potential genetic regulation of tumor incidence (Bodeau et al., 1974) is supported by results of studies indicating that many mouse strains differ in their incidences for specific tumor types (Murphy, 1966). In humans, a spectrum of different genetic predispositions for each tumor implies that a distribution curve of genetic susceptibilities exists for each tumor (Reif, 1981). Studies of distribution of cancer among different ethnic groups further support this proposition. Compared with whites, for example, blacks have a more rapidly accelerating incidence of lung cancer in the United States, Americans of Mexican and Chinese extraction (Buell et al., 1968; Fraumeni and Mason, 1974) also have a higher incidence, and American Indians (Creagan and Fraumeni, 1972) a lower incidence. Chinese in Hong Kong have an unusually high prevalence of adenocarcinoma of the lung, a relatively infrequent cell type in other areas (Belamaric, 1969). In analyzying our data we obtained results that establish a strong genetic component for lung cancer in the Louisiana population. (Ooi et al., 1981). Of the

648 446 white residents of the target parishes who died of lung cancer during 1976- 1979, we interviewed the next-of-kin of 328 cases. Of the 328 case families, 54 (16.5%) had first-degree relatives with lung cancer, compared with 16 (5.3%) in 304 control families. There were 61 (2.2%) lung cancers among the 2767 case first- degree relatives, compared with 18 (0.8%) in 2389 control relatives. This aggregation of lung cancer could not be attributed to differences in age at death, family size, or mortality. Six (1.8%) of the case families had two or more first- degree relatives with lung cancer. First-degree relatives of persons with lung cancer had, therefore, a lung cancer risk more than twice that of control relatives. Comparing case and control relatives by stepwise logistic regression indicated that a person's relationship to the person with lung cancer, and the square of a person's age, are the two strongest predictors of lung cancer outcome, even after controlling for the effects of age and sex. . We are in the process of further investigating this population to attempt to ascertain whether any major genes can be isolated as being involved in the pathogenesis of lung cancer. If we can isolate such genes, it will be major step forward in unravelling the mystery of lung cancer causation. t Henry Roth hild, M.D., Ph.D. Belamaric J: Cance Bodeau P, de Saint- Buell PE, Mendez W Creagan ET, Fraume Fraumeni JF Jr, Mw Fraumeni JF, Wertei Goffman TE, Hassinl %lurphy ED: Charact Ooi WL, Rothschild 1- Reif AE: OncoloAy I Tokuhata GK: Am J. Tokuhata GK, Lilienf

who died of lung cancer during 1976- cases. Of the 328 case families, 54 :ancer, compared with 16 (5.3%) in 304 ; cancers among the 2767 case first- 6) in 2389 control relatives. This ibuted to differences in age at death, case families had two or more first- egree relatives of persons with lung e than twice that of control relatives. •es by stepwise logistic regression :erson with lung cancer, and the square dictors of lung cancer outcome, even :x. tigating this population to attempt to e isolated as being involved in the ate such genes, it will be major step 649 Literature Cited ' Belamaric J: Cancer 4:560-573, 1969 Bodeau P, de Saint-Maur P, Herreman G, et al: Sem Hop Paris 50:1161-1168, 1974. Buell PE, Mendez WM, Dunn JE Jr: Cancer 22: 186-190, 1968. Creagan ET, Fraumeni JF Jr: 3 Natl Cancer Inst. 49:959-967, 1972. Fraumeni JF Jr, Mason TJ: J Natl Cancer Inst 52:659-665, 1974. Fraumeni JF, Wertelecki W, Blattner WA, et al: Am J\4ed 59:145-151, 1975. Goffman TE, Hassinger DD, ltulvihill JJ: JAMA 247: 1020-1023, 1982. Murphy ED: Characteristics of tumors: Ingreen (ed), Biology of the Laboratory Ooi WL, Rothschild H, Chen VW, et al: Clin Res 29:862A, 1981. Reif AE: Oncolog y 38:76-85, 1981. Tokuhata GK: Am J. Epidemiol. 89:139-153, 1964. Tokuhata GK, Lilienfeld AM: J Natl Cancer Inst 30:289-312, 1963.