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Familial Bladder Cancer in an Oncology Clinic Henry T. Lynch, William J. Kimberling, Jane F. Lynch, and Kathleen Brennan ABSTRACT: We have evaluated family history and cigarette smoking history an 49 consecutively ascertained patients with urinary bladder carcinoma and compared them with 956 consecu- tively ascertained patients with histologically verified cancer (all sites), all of whom were being treated in the same oncology clinics. Data was collected through interviews, question- naires, and primary medical and pathology documents. Cancer risks were compared on the basis of anatomic sites involved and with cumulative risk estimated from data in the Third National Cancer Survey. A permutation test was also employed. Significant heterogeneity of risk (z = 4.85, p ~- 0.02) for bladder cancer was found in relatives of probands with bladder cancer. Significant heterogeneity or increase in risk of bladder cancer was not observed when families with lung, other smoking related cancer, and nonsmoking related cancer were ana- lyzed. Though based on a limited number of verified bladder cancer patients, we have pro- vided statistical evidence in support of our hypothesis that bladder cancer may have a stronger familial etiologic component than heretofore recognized. INTRODUCTION Environmental factors have been considered by many to be the sole etiologic factor in smoking associated cancers. However, recent attention to cancer genetic investi- gations has provided new clues to the etiologic role of host factors in concert with environmental perturbation [1]. Carcinoma of the urinary bladder is of historical interest in that environmental etiologic hypotheses were prompted in a major way by findings that arylamines showed strong links to this disease [2]. More recently, cigarette smoking has been variably reported to associate with this disease [3]. Our purpose is to describe family history and cigarette smoking history on 49 consecutively ascertained patients with urinary bladder carcinoma. Our internal comparison sample included a total of 956 patients with histologically verified can- cer (all sites) who were being treated in oncology clinics at two Omaha, Nebraska medical schools. This same comparison group was further subdivided into smoking associated (n = 392) and nonsmoking associated (n = 564) cancers based on the type From the Department of Preventive Medicine/Public Health (H. T. L.. J. F. L., K. B.), and the Department of Otolaryngology (W. J. K.), Creighton University School of Medicine, and the Hereditary Cancer Institute, Omaha, NE. Address requests for reprints to Dr. Henry T. Lynch, Department of Preventive Medicine/ Public Health, Creighton University School of Medicine, California at 24th Street, Omaha, NE 68178. Received August 22, 1986; accepted November 13, 1986. 161 © 1987 Elsevier Science Publishing Co., Inc. Cancer Genet Cytogenet 27:161-165 (1987) 52 Vanderbilt Ave., New York. NY 10017 0165-4608/87/$03.50

Familial bladder cancer in an oncology clinic

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Familial Bladder Cancer in an Oncology Clinic

Henry T. Lynch, William J. Kimberling, Jane F. Lynch, and Kathleen Brennan

ABSTRACT: We have evaluated family history and cigarette smoking history an 49 consecutively ascertained patients with urinary bladder carcinoma and compared them with 956 consecu- tively ascertained patients with histologically verified cancer (all sites), all of whom were being treated in the same oncology clinics. Data was collected through interviews, question- naires, and primary medical and pathology documents. Cancer risks were compared on the basis of anatomic sites involved and with cumulative risk estimated from data in the Third National Cancer Survey. A permutation test was also employed. Significant heterogeneity of risk (z = 4.85, p ~- 0.02) for bladder cancer was found in relatives of probands with bladder cancer. Significant heterogeneity or increase in risk of bladder cancer was not observed when families with lung, other smoking related cancer, and nonsmoking related cancer were ana- lyzed. Though based on a limited number of verified bladder cancer patients, we have pro- vided statistical evidence in support of our hypothesis that bladder cancer may have a stronger familial etiologic component than heretofore recognized.

I N T R O D U C T I O N

E n v i r o n m e n t a l factors have been cons ide r ed by m a n y to be the sole e t io logic factor in smok ing assoc ia ted cancers . Howeve r , recent a t ten t ion to cancer genet ic invest i - gat ions has p r o v i d e d n e w clues to the e t io logic role of host factors in concer t w i th e n v i r o n m e n t a l pe r tu rba t ion [1].

Ca rc inoma of the u r ina ry b ladder is of h i s tor ica l in teres t in that e n v i r o n m e n t a l e t io logic hypo theses were p r o m p t e d in a major w a y by f indings that a ry lamines s h o w e d strong l inks to this d isease [2]. More recent ly , c igaret te smok ing has been var iab ly r epor t ed to associa te w i th this d isease [3].

Our pu rpose is to descr ibe fami ly h is tory and cigaret te smok ing his tory on 49 c o n s e c u t i v e l y ascer ta ined pat ients w i t h u r ina ry b ladder carc inoma. Our in terna l c o m p a r i s o n sample i n c l u d e d a total of 956 pa t ien ts w i t h h i s to log ica l ly ver i f ied can- cer (all sites) w h o were be ing t reated in onco logy c l in ics at two Omaha , Nebraska med ica l schools . This same c o m p a r i s o n group was fur ther s u b d i v i d e d into smoking assoc ia ted (n = 392) and n o n s m o k i n g assoc ia ted (n = 564) cancers based on the type

From the Department of Preventive Medicine/Public Health (H. T. L.. J. F. L., K. B.), and the Department of Otolaryngology (W. J. K.), Creighton University School of Medicine, and the Hereditary Cancer Institute, Omaha, NE.

Address requests for reprints to Dr. Henry T. Lynch, Department of Preventive Medicine/ Public Health, Creighton University School of Medicine, California at 24th Street, Omaha, NE 68178.

Received August 22, 1986; accepted November 13, 1986.

161

© 1987 Elsevier Science Publishing Co., Inc. Cancer Genet Cytogenet 27:161-165 (1987) 52 Vanderbilt Ave., New York. NY 10017 0165-4608/87/$03.50

162 H.T. Lynch et al.

of cancer in the proband. All pat ients were consecut ively ascer tained from the same oncology cl inics and s imilar ly evaluated. A descr ip t ion of this resource is given in a recent report [1].

MATERIALS AND METHODS

Each pat ient was in terviewed in a s tandard ized manner by a t rained interviewer. Next of kin were also in terviewed when they accompanied the patient. Detailed information was obtained on smoking, family, general medical , and cancer history for first- and second-degree relatives. Detai led quest ionnaires were sent to these relatives. Of all l iving pr imary relatives, 4.8% returned a quest ionnaire, whi le 9.8% of all l iving second-degree relat ives (grandparents, aunts, uncles) re turned a ques- t ionnaire. In addi t ion, this informat ion was augmented by direct te lephone inquiry. Pathology confirmation was vigorously sought in relat ives of each proband. Death certificates were ut i l ized only when all other methods for documenta t ion had been exhausted. Of all relat ives wi th cancer, 45.3% were verified through pathologic re- port, 16.2% through death certificates, and the remainder were taken as affected solely on the basis of family report. All probands were in terviewed personally, as were 5% of their pr imary relatives. Data were entered into the Medical Genetics Acquis i t ion and Data Transfer System (MEGADATS) [4]. We calculated the cumu- lative risk in pr imary relatives in the same manner as previously reported [1, 5]. The risks were compared be tween four groups defined on the basis of the organ(s) involved, and wi th cumula t ive risk es t imated from data in the Third National Can- cer Survey [6]. Compar ison of r isk wi th popula t ion data is not ent i rely appropr ia te because any conclusions wil l be confounded by differences in cancer rates, mortal- ity, and diagnosis between t ime periods.

The second method of analysis was a permuta t ion test. This test a l lows for the evaluat ion of an hypothes is that empir ic cancer probabil i t ies, est imated from the sample, are homogeneous and independen t of family membership . Rejection of this null hypothes is is evidence for the presence of families at a dis t inct ly higher risk for the specific cancer. Details for the use of this approach to detect heterogeneity of genetic r isk are descr ibed e lsewhere [7, 8]. The sample Z-score variance is an indica t ion of heterogenei ty of risk. The statist ical significance is de termined by compar ison of the sample Z-score wi th Z-scores calcula ted from 99 permuta t ions of the sample.

The combinat ion of these two t e s t s - - r i sk analysis and permuta t ion a na ly s i s - - a l lowed the evaluat ion of two questions: a) whether or not certain groups of rela- tives are at increased risk for b ladder cancer or any other cancer; and b) whether or not this risk is heterogeneous; that is, more highly focused in some families than in others. The combinat ion of answers to these two quest ions would al low for the evaluat ion of whether or not there is any under ly ing familial l iabil i ty, and second, if an under ly ing famil ial l iabi l i ty is found, whether it appears to be quali tat ive and, therefore, megaphenic . All analyses were control led for both sex and smoking status in relatives.

RESULTS

Table 1 reports our findings of the analysis of the risk of b ladder cancer in families with b ladder cancer, lung cancer, all smoking related cancers (combined), and all nonsmoking related cancers (combined). These results show significant heteroge- neity of r isk (Z = 4.85, p -< 0.02) for b ladder cancer in relat ives of probands with b ladder cancer. Specifically, three of the 49 b ladder families showed increased risk. We also found an increase in the cumulat ive risk, calculated out to age 80, for

Famil ia l Bladder Cancer 163

Table 1 Bladder cancer in relat ives by cancer site in proband

Number of families Z-Score Families at Cumulative Relative

Cancer in proband analyzed variance Percentile high risk (%) risk risk

Lung 254 0.88 0.58 0.043 0.007 1.08 Bladder 49 4.85 0.98 0.064 0.014 1.63 Smoking-related cancers 138 0.44 0.21 0.018 0.005 1.01

(not including lung and bladder)

All nonsmoking-related 564 0.95 0.54 0.026 0.005 cancers

relat ives of all 49 b ladder cancer probands. We failed to find significant heteroge- nei ty or increase in risk of b ladder cancer when families of the other three groups (namely, lung, other smoking related cancer, and nonsmoking related cancer) were analyzed.

We did examine heterogenei ty of b ladder cancer risk by specific anatomic sites, wi th in the smoking related and nonsmoking related cancer groups. No significant heterogenei ty of risk was found for pancreas, oral cavity, colorectal, breast, or ovar- ian cancer. These results are not presented in a table because they lacked signifi- cance. No other cancer sites were analyzed because they have not yet been coded and computer ized.

DISCUSSION

Approx imate ly 3% of all cancer deaths in the United States are at tr ibutable to uri- nary b ladder cancer, the most common mal ignant neoplasm involving the ur inary system. There has also been a ma le - fema le sex p redominance in most reported series of ur inary b ladder cancer patients. Myriad environmenta l factors, inc luding indust r ia l chemicals (part icular ly the ment ioned aromatic amines), parasites, pre- dominan t ly Schistosoma haematobium, and variable habit patterns, of which sac- charin, cyclamates, coffee, and cigarettes have all been variably impl ica ted in its etiology. Tryptophan metabol i tes also have been investigated, al though their etio- logic role remains obscure [9].

The first report of familial b ladder carc inoma was that of Fraumeni and Thomas [10], involving a father and three sons. Blattner et el. [11] provided fol low-up on this original family. Of interest was the fact that the proband, as well as one of his brothers wi th b ladder cancer, deve loped secondary pr imary lung cancers. These apparent ly represented the first familial aggregation reported with dual pr imary lung and b ladder tumors. Lynch et el. [12] repor ted two families prone to carcinoma of the ur inary b ladder and reviewed the per t inent l i terature through 1978.

Kantor et el. [13] have provided the most comprehensive, contemporary review of the l i terature on familial b ladder cancer. In addit ion, they conducted a popula- t ion based, case-cont ro l s tudy of 2982 b ladder cancer patients and 5782 controls. There was l imited data on affected family members , however, and there was no confirmation of tumor type from medical records. The risk of b ladder cancer asso- ciated with a posi t ive family history of cancer was found to be elevated among ind iv idua ls wi th suspected environmenta l exposures, par t icular ly heavy cigarette smoking. They observed a relative risk (RR) of b ladder cancer associated with fam- ily his tory of b ladder cancer to be higher for those who smoked 40-59 cigarettes

164 H.T. Lynch et al.

per day (RR = 2). This RR rose to 10.7 among those who smoked 60 or more ciga- rettes per day. Patients with a negative family history of bladder cancer, who never smoked cigarettes, were compared with patients who were moderate or heavy smokers, with positive family histories of bladder cancer. The RR was found to be further elevated in the presence of a family history, particularly for the relatively small group of smokers who consumed more than three packs per day (RR - 28.1).

Our findings are unique in that they involve the study of host factor-cigarette smoking interaction in a bladder cancer cohort wherein a high degree of verification of family history, cigarette smoking, and cancer (all sites) has been performed. These findings provided material for a critical internal comparison with similarly ascertained patients manifesting putative cigarette smoking and non-cigarette smok- ing associated cancer.

Attention was drawn to the possibility of a relationship between families with lung and bladder cancer in a previously published study of lung cancer [11. Fami- lies of probands with bladder cancer showed significant heterogeneity with regard to their risk for lung cancer. We were especially interested in whether or not fami- lies of lung cancer probands showed a corresponding heterogeneity with regard to bladder cancer risk. This was not observed. In the present investigation, however, we have observed both significant heterogeneity of risk and an overall increase in risk of bladder cancer in relatives of bladder cancer probands.

This evidence suggests that the familial risk of bladder cancer varies between families. The cause of this familiality might be found in either common environ- mental agents other than cigarette smoking, or it could be due to the presence of a susceptible genotype that predisposes to bladder carcinoma. We have shown pre- viously that families of bladder cancer problands were heterogeneous with regard to risk of lung cancer [1]. Here, however, we find that lung cancer families do not show a "complementary" heterogeneity with regard to bladder cancer. Because of the limited number of families available for this study, any interpretation of etio- logic association between bladder and lung cancer must be viewed cautiously.

In conclusion, our results, though based on a limited number of verified bladder cancer patients, have provided statistical evidence in support of our hypothesis that this disease may have a stronger familial etiologic component than heretofore rec- ognized. The genetic basis in bladder cancer etiology, should it exist, appears to relate more specifically to a b ladder-b ladder cancer axis and possibly also to a b ladder - lung cancer axis. In accord with the multistage concepts of carcinogenesis, the deleterious cancer-prone genotype may be variably perturbed by enviroffmental interactive factors, inclusive of cigarette smoking, as evidenced in the large popu- lation-based case-control study by Kantor et a|. [13]. Importantly, our findings clearly indicate the need for meticulous documentat ion of both family history and environmental exposures when searching for evidence in support of etiologic hy- potheses for carcinoma of the urinary bladder.

Supported by Grant #1297BR1 from the Council for Tobacco Research, USA, Inc., and a grant from the Health Futures Foundation, Inc.

REFERENCES

1. Lynch HT, Kimberling WJ, Markvicka SE, et al. (1986): Genetics and smoking-associated cancers: A study of 485 families. Cancer 57:1640.

2. Clayson DB, Cooper EH (1970): Cancer of the urinary tract. Adv Cancer Res 13:271. 3. Najem GR, Louria DB, Seebode JJ, Thies TS, Prusakowski JM, Ambrose RB, Fernicola AR

(1982): Lifetime occupation, smoking, caffeine, saccharine, hair dyes, and bladder carci- nogenesis. Intl J Epidemiol 11:212.

F a m i l i a l B l a d d e r C a n c e r 165

4. Gersting JE (1976): MEGADATS--A computer system for family data acquisition, storage, and analysis. In Registers for the Detection and Prevention of Genetic Disease, AEH Emery, RJ Miller (eds.). Stratton Intercontinental Medical Book Corp, NY.

5. Lynch HT, Harris RE, Organ CH, et al. (1977): The surgeon, genetics, and cancer control: The cancer family syndrome. Ann Surg 185:435.

6. Cutler SJ, Young JL (1975): Third National Cancer Survey, incidence data. NCI Monogr 41:1.

7. Lynch HT, Fain PR, Goldgar D, Albano WA, Mailliard JA, McKenna PJ (1981): Familial breast cancer and its recognition in an oncology clinic. Cancer 47:2730.

8. Kalvin S, Williams PT, Carmelli D, Cameron E (1985): Permutation methods for the struc- tured exploratory data analysis (SEDA) of total cholesterol measured in five Israeli popu- lations. Am J Epidemiol 122:163.

9. Leklem JE, Brown RR (1976): Abnormal t ryptophan metabolism in a family with a history of bladder cancer. J Natl Cancer Inst 56:1101.

10. Fraumeni JF, Thomas LB (1967): Malignant bladder tumors in a man and his three sons. J Am Med Assoc 201:507.

11. Blattner WA, Greene MH, Goedert JJ (1983): Interdisciplinary studies in the evaluation of persons at high risk of cancer. In Human Carcinogenesis, C Harris (ed.). Academic Press, NY, p. 913.

12. Lynch HT, Walzak MP, Fried R, Domina AH, Lynch JF (1979): Familial factors in bladder carcinoma. J Urol 122:458.

13. Kantor AF, Hartge P, Hoover RN, Fraumeni JF (1985): Familial and environmental inter- actions in bladder cancer risk. Intl J Cancer 35:703.