British Journal of Urology (1979), 51, 13-11
Genetic Associations of Transitional Cell Carcinoma D. W. HERRING, R. A. CARTWRIGHT and D. D. R. WILLIAMS Department of Surgery, Dr yburn Hospital, Durham; Yorkshire Regional Cancer Organisation, Cookridge Hospital, Leeds; Department of Anthropolog y, University of Durham, Durham
Summary-A series of 1 0 1 cases of transitional cell carcinoma (TCC) w a s contrasted with a control series for several genetic parameters. Three genetic associations were demonstrated with the TCC patients having A gene frequencies, HLA 85 and HLA CW4 genes all higher than might be expected by chance. A classification of the natural history of the disease is used t o show that the HLA frequencies vary with the more or t h e less severe forms of the disease.
Transitional cell carcinoma of the urothelium has well-described environmental causes related to the dyeing and rubber industries (Case et a/., 1954; Case, 1966; Case, 1969) and to smoking cigarettes (Hoover and Cole, 1971). However, not all people subjected to these environmental stimuli develop the disease, while a few who do develop TCC have never smoked or had industrial contact with the appropriate carcinogens. This paper is concerned with the possibility that individual genetic variability influences the appearance of the disease and contributes to the differing natural histories seen in TCC. The best understood attributes of individual variability are inherited factors such as blood groups. The general relationships between such factors and disease have been reviewed by Mourant (1976). lndividual variability is particularly relevant in cancer studies in that immune competence, in the recognition of cell surfaces, is suppressed in such diseases. Human cell surface variability is measured, to a certain degree, by red and white cell groups. The results do not depend on the use of genetics in the classical sense and although there have been 3 reports showing familial transmission of TCC (Fraumeni and Thomas, 1967; McCullough el a/., 1975; Sharma el a/., 1976), it is unlikely that the disease is commonly a unifactorially inherited attribute. This paper attempts to indicate how improved identification of those at risk in the community might take place.
Received 10 August 1977. Accepted for publication 2 August 1978.
73
Patients and Methods
All patients treated by surgeons in the Durham Hospital Area over the last 5 years were identified and contact was attempted with all living patients when they presented to the hospital for routine review, or they were asked by letter to attend an out-patient session. Each patient was asked for his address and occupation and for details of any change in each. A record was also made of sex, age, smoking habits and family history of bladder disease and other diseases. This was supplemented in each case by information from the notes on the site of the tumour, its histology and staging and the action taken at the first and each subsequent cystoscopies. Finally a blood sample was taken for analysis. The red blood cells were grouped for a variety of antigens including the ABO system, whilst the white cells were typed for a range of HLA specificities using the NIH method. A control group was assembled having about 2 controls for each case matched for social class, within 3 years of the age of the propositi and from the same village. The controls were not matched for sex. The control group comprised either trauma patients with no other known pathology or the neighbours of diabetics used originally in another study. Blood from the controls was analysed in the same way as that from the disease group. The characteristics of the TCC were defined by cystoscopy and on a broad histopathological basis. The grading of the tumour was recorded using the standard TNM classification. An important aspect of this study was to see
74
BRITISH JOURNAL OF UROLOGY
if the natural history of the disease (incorporating interventional treatments), as measured by repeated cystoscopies, is influenced by individual genetic variation. An attempt has been made to measure this by devising an artificial classification reflecting the varying invasiveness and aggressiveness of TCC. Patients who had at least 3 cystoscopies and who had been under review for at least 6 months were incorporated into this part of the study. Each patient was grouped into one of the following types:
These patients had 1 to 3 well differentiated carcinomas with no recurrence or few recurrences over at least 6 months. The carcinomas were either sessile or papillary in configuration. These were mainly TI grade at first cystoscopy. These patients had more than 3 carcinomas and/or more than 3 recurrences. The disease took longer to settle down. These tumours were either T1 or T2 at first cystoscopy. These patients had tumours which started off as type A or B but which became more aggressive over the first year of follow-up. More commonly these were patients who presented with deeply invasive tumours or spread beyond the urothelium. All data were computerised and the analyses performed using the Northern Universities Multiple Access Computer, an IBM 370/137.
Results One hundred and five patients were eligible for the study in that they were alive between September and December 1976. Four refused to participate, leaving a sample of 101 which was contrasted with 207 controls (Table 1). The mean Table 1 The Contrast between the Control and Patient Samples which shows no Statistical Difference between the Groups
Table 2 The TNM Staging Based on the Biopsy Results from the First Cystoscopy Showing Absolute Numbers and the Percentages for each Sex in Brackets Males
Females
TI
39 (56.6)
I S (62.5)
T2
18 (26.1)
3 (12.5)
T3
9 (13.0)
5 (20.8)
T4
3 14.4)
I
14.2)
age at presentation was 52.25 years, with a standard deviation of 12.10. The tumours were mainly sited in the bladder except for 2 from the ureter and 3 in the urethra. The staging at first cystoscopy is shown in Table 2. There was no significant sex difference (x2 0.23 for males v. females, T1 v. rest, P > 0 . 5 ) . The duration of the disease from the occasion of the first cystoscopy until January 1977 is given in Table 3. The range in this cross-sectional sample is considerable, being from 1 month to 16 years, the mean duration being 3.3 years. Table 3 also contrasts spread with the duration of the disease. Consideration was given to the ABO blood groups in patients presenting with TCC, contrasting the findings with the matched control group. Detailed results are given in Table 4 and these indicate a statistically significant increase in blood group A in TCC patients. HLA typing of the sample group with TCC and the control group was undertaken. The results are given in Table 5 where they are also contrasted with the results of Terasaki et al. (1977). These results, together with the results given in Table 4, are statistically homogenous for sex. Contrasting the disease and control groups in Table 5 by a series of chi-squared tests (2 x 2) showed 2 significant results which are asterisked. No corr6ction was made for the number of chi-square tests perTable 3 Tumour Spread and the Duration of Disease from First Cystoscopy until January 1977; the Numbers of Cases are given Under Each Heading
TCC
Control
Under 1 year
Mean age (years)
63.83
63.55
1-2 years
Standard deviation
11.09
1 1.45
Range (years)
37-86
35-89
2-3 years 3-4 years
Males (To)
73.50
42.50
Over 4 years
TI
T2
10 5 8, 4
23
T3
T4
4
3
2
4
4
2
3 3 5
1 2
-
2
-
75
GENETIC ASSOCIATIONS OF TRANSITIONAL CELL CARCINOMA
ABO Blood Groups in TCC Patients and Controls: Total Numbers and their Percentage Frequencies are given in Brackets
Table 4
~
TCC Control
37 (36.6)
12 (11.9)
49 (48.5)
6 (5.9)
5 (5.0)
41 (40.6)
101
64 (31.1)
13 (6.3)
71 (37.4)
20 (9.7)
6 (2.9)
103 (50.0)
206
The chi-squared test contrasting the aggregated groups A and Ab with 0 and B gives a significant value of 4.84, P=O.O2-0.05 for I d.f.
formed. The chi-square value for the significantly increased frequency of HLA-I35 amongst TCC patients is 4.46 and that for HLA-CW4 is 4.70. The sample sizes in Table 5 are 101 for the TCC group, and as some were not HLA tested, 202 for the controls and 264 for the Californian series of Terasaki et al. (1977), unless otherwise stated. The natural histories of the diseased group, incorporating interventional treatment, in ABO and HLA types were then classified into types A, B or C as previously defined. The results are shown in Table 6. Some specificities have been omitted because of small subsample sizes. The table gives the percentage frequencies of the phenotypes. It was not possible t o classify all the TCC sample into these types. The sex ratio of the
3 natural history subgroups is of interest in that type A, the least aggressive group, incorporates 36 males (87.8%) while the other 2 types have more females (55.2 and 72.7% males respectively in types B and C). It is impossible to establish if these are significant differences because of small samples. However, there are apparently considerable genetic differences between the 3 groups.
Discussion Transitional cell carcinoma is a complex disease. The role of environmental carcinogens has been extensively studied but clearly the host response plays an important part not only in the acquisition of the disease but also in the progress of the Table 5 HLA Types in TCC Patients and Controls disease once acquired. This paper deals in the and TCC Patients from California main with the relationship between the natural Control
TCC
N ~~
N
(%) ~
Terasaki
et al. (1977)
(%I
~~
(%I
The Natural History Typology Contrasted with the ABO and HLA Blood Groupings Table 6
~
HLA antigens
6.9
75 82 61 24 28 18
40.6 30.2 11.9 13.9 8.9
25 45 30 22 14 11
18.8 27.7 19.8 34.7 5.9 6.9 6.9 t14.9 8.9
19 53 62 74 8 18 16 19 14
9.4 26.2 30.7 36.6 3.9 13.9 7.9 9.4 6.9
9 28 17 26 6 9 9 8 10
$23.0
24 t t 1 2 . 3
-
HLAAl 2 3 9 10 I1
29 52 30 18 16 7
28.7 51.5 29.7 17.8
HLAB5 7 8 12 13 14 27 W15 W17
19 28 20 35 6 7 7 15 9
**HLACW4
23
*
15.8
37.1
T Sample of 95, q sample of 100, t $sample of 195. * xz 5.37 with I d.f. and P=O.O2-0.05. +* x* 5.52 with I d.f. and P=O.OI-0.02. The numbers and percentages are those who respond positively to the appropriate antisera out of the total number tested with that particular specificity.
Type A
T Y PB~
Type C
43.9 46.3 7.3
37.9 44.8
45.5 47.5
16.1 30.7 19.4 11.3 12.9 6.5
21.7 28.3 21.7 15.2 8.7 4.4
24.2 39.4 18.2 9. I
11.4
8
14. I 12.5 12.5
12
12.5
25.0 18.2 22.7
w15 w17
14. I 10.9
13.3 26.7 10.0 30.0 3.3
4.6
-
cw4
21.9
32. I
22.7
41
29
22
ABO phenotypes 0 A, + A2 B HLA phenotypes A! 2 3 9 10
I1
B5 7
Totals
10.3
9.1
-
9.1
-
The results arc given as percentagcs of thc number of cascu: positive to the appropriatc antisera.
76 history of TCC and gene frequency occurrence in patients acquiring the disease, having contrasted these patients with a matched control population. For such studies the control population is important in its composition and great care has been exercised in grouping the controls for age, social class and geographical location. The reason for this is partly because ABO and possibly HLA gene frequencies vary for these factors in this country and partly because the study is a small one. This is compensated to some degree by the fact that the study includes nearly all the cases known in the area. The results of the control population contrast favourably with existing gene frequency data from the North of England (Kopkc, 1970; Murray et al., 1976) in that chisquared comparisons show no statistical differences between the samples. The ABO results presented here show that the TCC group has an increased frequency of the A gene contrasted with the control population. This is not a new finding; Vogel and Kruger (1968) and others have reported a general bias to the A gene in many types of cancer including TCC. They showed for TCC that the A : O ratio for several combined studies was 1.26, although there was significant heterogeneity amongst the various series. The A:O ratio for the present study is 1.20. The largest comparable European series is by Dick et al. (1962) with a sample of 558; this series had an A : O ratio of 1.38. This was a German series, however, where the A gene is naturally more common. The HLA series shows 2 genetic associations with TCC. At the B locus there is an excess of the B5 antigen and at the C locus there is an excess of the CW4 factor. There is only one major series of HLA types in cancer reported by Terasaki et al. (1977) and among other data this paper gives the results of 264 bladder cancer patients. The data are given in Table 5 . These Californian results are difficult to contrast with the present study because of the biological diversity of the American population and the lack of detail on the techniques of sample and control collection. The study showed a weak association between HLA BW35 and TCC and no association with HLA B5, while HLA CW4 was not tested for. The associations found in this report are thus unreported hitherto. The link with HLA CW4 might be due to the fact that this gene is in linkage disequilibrium with HLA I3W35, a specificity not tested for in our study.
BRITISH JOURNAL OF UROLOGY
The relative incidence for the HLA associations are 2.23 and 2.13 for HLA B5 and HLA CW4 respectively. The combined risks for HLA B5, HLA CW4 and the ABO A gene together are much greater; for example, the risk of getting TCC in a person who is ABO A, HLA €35 and HLA CW4 is over 15 times the mean population risk. The mechanistic basis for these genetic associations is still obscure, in particular for the ABO system. There are some pointers for the HLA system, however. A reduced T-lymphocyte response in patients with TCC has been reported by Catalona et al. (1974). Such responses may be controlled by the immune response genes located very close to the HLA loci on chromosome 6, as suggested by Nerup et al. (1976). It is necessary to perform many chi-squared tests to assess the results and one might expect some tests to be significant by chance. However, 3 significant tests out of 17 are greater than one might expect fortuitously and the results are likely to be statistically valid. The classification of the natural history of the disease is manifestly an artificial aggregation of an infinitely varying disease. Inevitably, some types classed as A or B will, in time, become B or C and so the dynamic nature of the disease is still partially obscured. The overall picture gained from this exercise is useful. It points to the fact that there appear to be different genes involved with the more and the less severe forms of the disease. It might be significant in this respect that the genes which appear to differ with respect to disease course are not the ones which are associated with acquiring the disease in the first instance. Perhaps 2 mechanisms are involved here: those genes which determine susceptibility to TCC and those genes that influence the natural response to the neoplastic process. This is a preliminary study designed along the lines suggested by Emery (1976) to see if further work is justified. Now it would seem appropriate to find corroboration using larger series and a prospective study designed to monitor the natural history of the disease.
Acknowledgement We are grateful to M r Petticrew and M r G . Dunstone for allowing us to interview their patients. The work was partly supported by the Department of Anthropology, University of Durham and a grant from the Durham University Staff Fund.
GENETIC ASSOCIATIONS OF TRANSITIONAL CELL CARCINOMA
References Case, R. A. M. (1966). Tumours of the urinary tract as an occupational disease in several industries. Annals of the Royal College of Surgeons of England, 39, 213-235. Case, R. A. M. (1969). Some environmental carcinogens. Proceedings of the Royal Society of Medicine, 62, 106 I - 1066. Case. R. A. M., Hosker, M. E., MacDonald, D. B. and Pearson, 1. T. (1954). Tumours of the urinary bladder in workmen engaged in the manufacture and use of certain dyestuff intermediates in the British chemical industry. Part 1. British Journal of Industrial Medicine, I 1, 75- 104. Catalona. W. J., Potvin. C. and Chretien, P. B. (1974). T-lymphocytes in bladder and prostatic cancer patients. Journal of Urology. 112. 378-382. Dick, W., Schneider, W. and Brockmiiller, K. (1962) u b e r das gegenstitzliche Verhalten der Blutgruppen A , und A,. Deutsche Medizinische Wochenschrgt, 87, 2567-2573.
Emery, A. E. H. (1976). Methodology in Human Genetics. pp. 98-106. London: Churchill Livingstone. Fraumeni, J. F. and Thomas, L. B. (1967). Malignant bladder tumors in a man and his three sons. Journal of the American Medical Association, 201. 507-509.
Hoover, R. and Cole, P. (1971). Population trends in cigarette smoking and bladder cancer. American Journal of Epidemiology, 94, 409-419.
KopCc, A. C. (1970). The Distribution of the Blood Groups in the United Kingdom. London: Oxford University Press. McCullough, D. L., Lamm, D. L., McLaughlin, A. P. and Gittes, R. F. (1975). Familial transitional cell carcinoma of the bladder. Journal of Urology, 113, 629-635. Mourant, A. E. (1976). Blood groups and diseases. Biotesf Bulletin, 1, 1-14.
77
Murray, S., Dewar, P., Lee, F., McNay, L. and Collins, F. (1976). A study of the HLA types in rhesus haemolytic disease of the newborn. Vox Sanguinis, 30. 91-98. Nerup, J., Platz, P., Ortved Anderson, O., Christy, M.. Egeberg, J., Lyngsge, J., Poulsen, J. E., Ryder, L. P.. Thomsen, N. and Svejgaard, A. (1976). HLA autoimmunity and insulin dependent diabetes mellitus. In Genetics of Diabetes Mellitus, ed. Creutzfelt, W., Koberling, J. and Neel, J. V. pp. 106-1 12. Berlin: Springer-Verlag. Sharma, S. K., Bapna, B. C. and Singh. S. M. (1976). Familial profile of transitional cell carcinoma. British Journal of Urology. 48, 442. Terasaki. P. I., Perdue, S. T. and Mickey, M. R. (1977). HLA frequencies in cancer. A second study. In The Geneticsof Human Cancer, ed. Mulvihill, J . J . pp. 321-327. New York: Raven Press. Vogel, F. and Kriiger, 1. (1968). Statistische Beziehungen zwischen den ABO-Blutgruppen und Krankheiten mil Ausnahme des lnfektionskrankheiten. Blur, 16. 351-376.
The Authors D. W. Herring, MB, BS, FRCS, Consultant Surgeon, Dryburn Hospital, Durham. R. A. Cartwright, MA, MB, BChir, PhD, Epidemiologist, Yorkshire Regional Cancer Organisation, Cookridge Hospital, Leeds. D. D. R. Williams, MB, BS, Research Fellow, Department of Anthropology, University of Durham. Requests for reprints to: R. A. Cartwright, Yorkshire Regional Cancer Organisation. Cookridge Hospital, Leeds LS16 6QB.
Genetic Associations of Transitional Cell Carcinoma D. W. HERRING, R. A. CARTWRIGHT and D. D. R. WILLIAMS Department of Surgery, Dr yburn Hospital, Durham; Yorkshire Regional Cancer Organisation, Cookridge Hospital, Leeds; Department of Anthropolog y, University of Durham, Durham
Summary-A series of 1 0 1 cases of transitional cell carcinoma (TCC) w a s contrasted with a control series for several genetic parameters. Three genetic associations were demonstrated with the TCC patients having A gene frequencies, HLA 85 and HLA CW4 genes all higher than might be expected by chance. A classification of the natural history of the disease is used t o show that the HLA frequencies vary with the more or t h e less severe forms of the disease.
Transitional cell carcinoma of the urothelium has well-described environmental causes related to the dyeing and rubber industries (Case et a/., 1954; Case, 1966; Case, 1969) and to smoking cigarettes (Hoover and Cole, 1971). However, not all people subjected to these environmental stimuli develop the disease, while a few who do develop TCC have never smoked or had industrial contact with the appropriate carcinogens. This paper is concerned with the possibility that individual genetic variability influences the appearance of the disease and contributes to the differing natural histories seen in TCC. The best understood attributes of individual variability are inherited factors such as blood groups. The general relationships between such factors and disease have been reviewed by Mourant (1976). lndividual variability is particularly relevant in cancer studies in that immune competence, in the recognition of cell surfaces, is suppressed in such diseases. Human cell surface variability is measured, to a certain degree, by red and white cell groups. The results do not depend on the use of genetics in the classical sense and although there have been 3 reports showing familial transmission of TCC (Fraumeni and Thomas, 1967; McCullough el a/., 1975; Sharma el a/., 1976), it is unlikely that the disease is commonly a unifactorially inherited attribute. This paper attempts to indicate how improved identification of those at risk in the community might take place.
Received 10 August 1977. Accepted for publication 2 August 1978.
73
Patients and Methods
All patients treated by surgeons in the Durham Hospital Area over the last 5 years were identified and contact was attempted with all living patients when they presented to the hospital for routine review, or they were asked by letter to attend an out-patient session. Each patient was asked for his address and occupation and for details of any change in each. A record was also made of sex, age, smoking habits and family history of bladder disease and other diseases. This was supplemented in each case by information from the notes on the site of the tumour, its histology and staging and the action taken at the first and each subsequent cystoscopies. Finally a blood sample was taken for analysis. The red blood cells were grouped for a variety of antigens including the ABO system, whilst the white cells were typed for a range of HLA specificities using the NIH method. A control group was assembled having about 2 controls for each case matched for social class, within 3 years of the age of the propositi and from the same village. The controls were not matched for sex. The control group comprised either trauma patients with no other known pathology or the neighbours of diabetics used originally in another study. Blood from the controls was analysed in the same way as that from the disease group. The characteristics of the TCC were defined by cystoscopy and on a broad histopathological basis. The grading of the tumour was recorded using the standard TNM classification. An important aspect of this study was to see
74
BRITISH JOURNAL OF UROLOGY
if the natural history of the disease (incorporating interventional treatments), as measured by repeated cystoscopies, is influenced by individual genetic variation. An attempt has been made to measure this by devising an artificial classification reflecting the varying invasiveness and aggressiveness of TCC. Patients who had at least 3 cystoscopies and who had been under review for at least 6 months were incorporated into this part of the study. Each patient was grouped into one of the following types:
These patients had 1 to 3 well differentiated carcinomas with no recurrence or few recurrences over at least 6 months. The carcinomas were either sessile or papillary in configuration. These were mainly TI grade at first cystoscopy. These patients had more than 3 carcinomas and/or more than 3 recurrences. The disease took longer to settle down. These tumours were either T1 or T2 at first cystoscopy. These patients had tumours which started off as type A or B but which became more aggressive over the first year of follow-up. More commonly these were patients who presented with deeply invasive tumours or spread beyond the urothelium. All data were computerised and the analyses performed using the Northern Universities Multiple Access Computer, an IBM 370/137.
Results One hundred and five patients were eligible for the study in that they were alive between September and December 1976. Four refused to participate, leaving a sample of 101 which was contrasted with 207 controls (Table 1). The mean Table 1 The Contrast between the Control and Patient Samples which shows no Statistical Difference between the Groups
Table 2 The TNM Staging Based on the Biopsy Results from the First Cystoscopy Showing Absolute Numbers and the Percentages for each Sex in Brackets Males
Females
TI
39 (56.6)
I S (62.5)
T2
18 (26.1)
3 (12.5)
T3
9 (13.0)
5 (20.8)
T4
3 14.4)
I
14.2)
age at presentation was 52.25 years, with a standard deviation of 12.10. The tumours were mainly sited in the bladder except for 2 from the ureter and 3 in the urethra. The staging at first cystoscopy is shown in Table 2. There was no significant sex difference (x2 0.23 for males v. females, T1 v. rest, P > 0 . 5 ) . The duration of the disease from the occasion of the first cystoscopy until January 1977 is given in Table 3. The range in this cross-sectional sample is considerable, being from 1 month to 16 years, the mean duration being 3.3 years. Table 3 also contrasts spread with the duration of the disease. Consideration was given to the ABO blood groups in patients presenting with TCC, contrasting the findings with the matched control group. Detailed results are given in Table 4 and these indicate a statistically significant increase in blood group A in TCC patients. HLA typing of the sample group with TCC and the control group was undertaken. The results are given in Table 5 where they are also contrasted with the results of Terasaki et al. (1977). These results, together with the results given in Table 4, are statistically homogenous for sex. Contrasting the disease and control groups in Table 5 by a series of chi-squared tests (2 x 2) showed 2 significant results which are asterisked. No corr6ction was made for the number of chi-square tests perTable 3 Tumour Spread and the Duration of Disease from First Cystoscopy until January 1977; the Numbers of Cases are given Under Each Heading
TCC
Control
Under 1 year
Mean age (years)
63.83
63.55
1-2 years
Standard deviation
11.09
1 1.45
Range (years)
37-86
35-89
2-3 years 3-4 years
Males (To)
73.50
42.50
Over 4 years
TI
T2
10 5 8, 4
23
T3
T4
4
3
2
4
4
2
3 3 5
1 2
-
2
-
75
GENETIC ASSOCIATIONS OF TRANSITIONAL CELL CARCINOMA
ABO Blood Groups in TCC Patients and Controls: Total Numbers and their Percentage Frequencies are given in Brackets
Table 4
~
TCC Control
37 (36.6)
12 (11.9)
49 (48.5)
6 (5.9)
5 (5.0)
41 (40.6)
101
64 (31.1)
13 (6.3)
71 (37.4)
20 (9.7)
6 (2.9)
103 (50.0)
206
The chi-squared test contrasting the aggregated groups A and Ab with 0 and B gives a significant value of 4.84, P=O.O2-0.05 for I d.f.
formed. The chi-square value for the significantly increased frequency of HLA-I35 amongst TCC patients is 4.46 and that for HLA-CW4 is 4.70. The sample sizes in Table 5 are 101 for the TCC group, and as some were not HLA tested, 202 for the controls and 264 for the Californian series of Terasaki et al. (1977), unless otherwise stated. The natural histories of the diseased group, incorporating interventional treatment, in ABO and HLA types were then classified into types A, B or C as previously defined. The results are shown in Table 6. Some specificities have been omitted because of small subsample sizes. The table gives the percentage frequencies of the phenotypes. It was not possible t o classify all the TCC sample into these types. The sex ratio of the
3 natural history subgroups is of interest in that type A, the least aggressive group, incorporates 36 males (87.8%) while the other 2 types have more females (55.2 and 72.7% males respectively in types B and C). It is impossible to establish if these are significant differences because of small samples. However, there are apparently considerable genetic differences between the 3 groups.
Discussion Transitional cell carcinoma is a complex disease. The role of environmental carcinogens has been extensively studied but clearly the host response plays an important part not only in the acquisition of the disease but also in the progress of the Table 5 HLA Types in TCC Patients and Controls disease once acquired. This paper deals in the and TCC Patients from California main with the relationship between the natural Control
TCC
N ~~
N
(%) ~
Terasaki
et al. (1977)
(%I
~~
(%I
The Natural History Typology Contrasted with the ABO and HLA Blood Groupings Table 6
~
HLA antigens
6.9
75 82 61 24 28 18
40.6 30.2 11.9 13.9 8.9
25 45 30 22 14 11
18.8 27.7 19.8 34.7 5.9 6.9 6.9 t14.9 8.9
19 53 62 74 8 18 16 19 14
9.4 26.2 30.7 36.6 3.9 13.9 7.9 9.4 6.9
9 28 17 26 6 9 9 8 10
$23.0
24 t t 1 2 . 3
-
HLAAl 2 3 9 10 I1
29 52 30 18 16 7
28.7 51.5 29.7 17.8
HLAB5 7 8 12 13 14 27 W15 W17
19 28 20 35 6 7 7 15 9
**HLACW4
23
*
15.8
37.1
T Sample of 95, q sample of 100, t $sample of 195. * xz 5.37 with I d.f. and P=O.O2-0.05. +* x* 5.52 with I d.f. and P=O.OI-0.02. The numbers and percentages are those who respond positively to the appropriate antisera out of the total number tested with that particular specificity.
Type A
T Y PB~
Type C
43.9 46.3 7.3
37.9 44.8
45.5 47.5
16.1 30.7 19.4 11.3 12.9 6.5
21.7 28.3 21.7 15.2 8.7 4.4
24.2 39.4 18.2 9. I
11.4
8
14. I 12.5 12.5
12
12.5
25.0 18.2 22.7
w15 w17
14. I 10.9
13.3 26.7 10.0 30.0 3.3
4.6
-
cw4
21.9
32. I
22.7
41
29
22
ABO phenotypes 0 A, + A2 B HLA phenotypes A! 2 3 9 10
I1
B5 7
Totals
10.3
9.1
-
9.1
-
The results arc given as percentagcs of thc number of cascu: positive to the appropriatc antisera.
76 history of TCC and gene frequency occurrence in patients acquiring the disease, having contrasted these patients with a matched control population. For such studies the control population is important in its composition and great care has been exercised in grouping the controls for age, social class and geographical location. The reason for this is partly because ABO and possibly HLA gene frequencies vary for these factors in this country and partly because the study is a small one. This is compensated to some degree by the fact that the study includes nearly all the cases known in the area. The results of the control population contrast favourably with existing gene frequency data from the North of England (Kopkc, 1970; Murray et al., 1976) in that chisquared comparisons show no statistical differences between the samples. The ABO results presented here show that the TCC group has an increased frequency of the A gene contrasted with the control population. This is not a new finding; Vogel and Kruger (1968) and others have reported a general bias to the A gene in many types of cancer including TCC. They showed for TCC that the A : O ratio for several combined studies was 1.26, although there was significant heterogeneity amongst the various series. The A:O ratio for the present study is 1.20. The largest comparable European series is by Dick et al. (1962) with a sample of 558; this series had an A : O ratio of 1.38. This was a German series, however, where the A gene is naturally more common. The HLA series shows 2 genetic associations with TCC. At the B locus there is an excess of the B5 antigen and at the C locus there is an excess of the CW4 factor. There is only one major series of HLA types in cancer reported by Terasaki et al. (1977) and among other data this paper gives the results of 264 bladder cancer patients. The data are given in Table 5 . These Californian results are difficult to contrast with the present study because of the biological diversity of the American population and the lack of detail on the techniques of sample and control collection. The study showed a weak association between HLA BW35 and TCC and no association with HLA B5, while HLA CW4 was not tested for. The associations found in this report are thus unreported hitherto. The link with HLA CW4 might be due to the fact that this gene is in linkage disequilibrium with HLA I3W35, a specificity not tested for in our study.
BRITISH JOURNAL OF UROLOGY
The relative incidence for the HLA associations are 2.23 and 2.13 for HLA B5 and HLA CW4 respectively. The combined risks for HLA B5, HLA CW4 and the ABO A gene together are much greater; for example, the risk of getting TCC in a person who is ABO A, HLA €35 and HLA CW4 is over 15 times the mean population risk. The mechanistic basis for these genetic associations is still obscure, in particular for the ABO system. There are some pointers for the HLA system, however. A reduced T-lymphocyte response in patients with TCC has been reported by Catalona et al. (1974). Such responses may be controlled by the immune response genes located very close to the HLA loci on chromosome 6, as suggested by Nerup et al. (1976). It is necessary to perform many chi-squared tests to assess the results and one might expect some tests to be significant by chance. However, 3 significant tests out of 17 are greater than one might expect fortuitously and the results are likely to be statistically valid. The classification of the natural history of the disease is manifestly an artificial aggregation of an infinitely varying disease. Inevitably, some types classed as A or B will, in time, become B or C and so the dynamic nature of the disease is still partially obscured. The overall picture gained from this exercise is useful. It points to the fact that there appear to be different genes involved with the more and the less severe forms of the disease. It might be significant in this respect that the genes which appear to differ with respect to disease course are not the ones which are associated with acquiring the disease in the first instance. Perhaps 2 mechanisms are involved here: those genes which determine susceptibility to TCC and those genes that influence the natural response to the neoplastic process. This is a preliminary study designed along the lines suggested by Emery (1976) to see if further work is justified. Now it would seem appropriate to find corroboration using larger series and a prospective study designed to monitor the natural history of the disease.
Acknowledgement We are grateful to M r Petticrew and M r G . Dunstone for allowing us to interview their patients. The work was partly supported by the Department of Anthropology, University of Durham and a grant from the Durham University Staff Fund.
GENETIC ASSOCIATIONS OF TRANSITIONAL CELL CARCINOMA
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Murray, S., Dewar, P., Lee, F., McNay, L. and Collins, F. (1976). A study of the HLA types in rhesus haemolytic disease of the newborn. Vox Sanguinis, 30. 91-98. Nerup, J., Platz, P., Ortved Anderson, O., Christy, M.. Egeberg, J., Lyngsge, J., Poulsen, J. E., Ryder, L. P.. Thomsen, N. and Svejgaard, A. (1976). HLA autoimmunity and insulin dependent diabetes mellitus. In Genetics of Diabetes Mellitus, ed. Creutzfelt, W., Koberling, J. and Neel, J. V. pp. 106-1 12. Berlin: Springer-Verlag. Sharma, S. K., Bapna, B. C. and Singh. S. M. (1976). Familial profile of transitional cell carcinoma. British Journal of Urology. 48, 442. Terasaki. P. I., Perdue, S. T. and Mickey, M. R. (1977). HLA frequencies in cancer. A second study. In The Geneticsof Human Cancer, ed. Mulvihill, J . J . pp. 321-327. New York: Raven Press. Vogel, F. and Kriiger, 1. (1968). Statistische Beziehungen zwischen den ABO-Blutgruppen und Krankheiten mil Ausnahme des lnfektionskrankheiten. Blur, 16. 351-376.
The Authors D. W. Herring, MB, BS, FRCS, Consultant Surgeon, Dryburn Hospital, Durham. R. A. Cartwright, MA, MB, BChir, PhD, Epidemiologist, Yorkshire Regional Cancer Organisation, Cookridge Hospital, Leeds. D. D. R. Williams, MB, BS, Research Fellow, Department of Anthropology, University of Durham. Requests for reprints to: R. A. Cartwright, Yorkshire Regional Cancer Organisation. Cookridge Hospital, Leeds LS16 6QB.
