Tissue Antigens (1975), 6, 101-104
Short Communication
Published by Munksgaard, Copenhagen, Denmark No part may be reproduced by any process without written permission from the author(s)
The Association of W17 with Familial Renal Cell Carcinoma W. E. BRAUN,C. V. STRIMLAN, A. G. NEGRON, R. A. STRAFFON, A. A. ZACHARY, S. L. BARTEE AND D. R. GRECEK Departments of Hypertension and Nephrology, Medicine, Urology, and the Histocompatibility Laboratory, Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.
Despite several strong associations between HL-A antigens and disease states, for example, W27 and ankylosing spondylitis (Schlosstein et al. 1973), HL-A8 and chronic active hepatitis (Mackay & Morris 1972) and celiac disease (Stokes et al. 1972), and W17 and HL-A13 and psoriasis (Russell et al. 1972), no clear correlation has been found with any neoplastic disease in large studies by Dick et al. (1972), Takasugi et al. (1973), Miller (1974), and Lamm et al. (1974),although
early studies were suggestive (Amiel 1967, Rogentine et al. 1972). Using the standard microcytotoxicity technique (Mittal et al. 1968), our studies of three unrelated Caucasian families (F, W, and B) (Figs. 1, 2, and 3) each with renal cell carcinoma (RCC) in two generations disclose a remarkably high frequency of W17 both in the patients (5/6, 83 %) and in apparently unaffected family members (10J13, 77 %). I n Family W the deceased grandfather with RCC had
FAMILY F
I
II 24 16
3 16
m
1p
Figure 1 . Family F ; propositus +
24 16
102
B M U N ET AL,
FAMILY W
I
II 2 50 2 8
31 17 2 13
m
31 17
2 8
31 17 2 12
31 17 31 16
Figure 2. Family W; propositus +
his antigens and haplotypes constructed by virtue of his three children and his
FAMILY B
I 3 12
2 17
wife. The W17 haplotypes of those with RCC are: 1-17 ( 2 ) , 31-17 ( 2 ) , and 2-17 (1). Consanguinity occurs in only one family (F). Five of the six patients with RCC are male. The four males who were tested all are red cell type A, and the single female patient is an 0. The age of onset of RCC ranges from 32 to 77 years. Places of birth of the grandparents include the Ukraine and Lithuania ( F ) , England and the Netherlands ( W ) , and Czechoslovakia
(B).
2171 32 15
m
2 17 3 12
6
2 17
I I 50 Figure 3. Family B; propositus +
The antigen frequency of W17 has been reported as 8 % in 906 controls (Schlosstein et al. 1973) and is 10 "/o in the 485 controls in this study. Since the occurrence of RCC is examined in families, only one member (the propositus) from each family can be considered as a random inheritor of W17. Using the control group of 485, the uncorrected P value is 0.0011. When
103
W17 AND RENAL CELL CARCINOMA
corrected for one-sidedness and the number of antigens tested (30), the P value is of borderline significance (0.066). If a larger, published control group of 906 is used (Schlosstein et al. 1973), the corrected P value is 0.032. Somewhat surprising is the failure to find W17 in any of 13 other random cases of renal cell carcinoma. This apparent discrepancy suggests that W17 might be a “marker” antigen only in families and that other antigens, possibly of LD origin, may be better markers in a random population because they are gene products of a locus that may be positioned closer to the I r locus. Because of the tendency for RCC to occur in an older age group, the risk and/ or incidence of RCC in other family members is uncertain at present. The strength of W17 as a possible marker for familial RCC, then, may require urography, angiography, and years of observation to determine the true incidence of RCC among W17-bearing family members without current evidence of the disease. Familial carcinomas such as renal cell carcinoma may be the best starting place to find such disease-linked LD antigens detectable with homozygote typing cells. However, the possibility exists that there are multiple gene products marking or determining susceptibility to neoplasia that include not only SD, LD, and I r antigens, but also those for race, sex, and red cell type that would provide the necessary substrate for the properly timed intervention of an oncogenic agent.
Acknowledgments We appreciate the cooperation of Dr. Leonard Horn in the study of Family F, the assistance of Prof. J. N. Berrettoni for performing the statistical analysis, and the constructive comments of Drs. A. Svejgaard and L. Lamm.
References Amiel, J. L. (1967) Study of the leucocyte phenotypes in Hodgkin’s disease. Histocompatibility Testing 1967, p. 79. Munksgaard, Copenhagen. Dick, F. R., Fortuny, I., Theologides, A., Greally, J., Wood, N. & Yunis, E. J. (1972) HLA and lymphoid tumors. Cancer Res. 32, 2608-261 1. Lamm, L. U., Kissmeyer-Nielsen, F., Kjerbye, K. E., Mortensen, B. & Petersen, N. C. ( 1974) HL-A and ABO antigens and malignant melanoma. A study of 212 cases. Cancer 33, 1458-1461.
Mackay, I. R. & Morris, P. J. (1972) Association of autoimmune active chronic hepatitis with HL-A1, 8. Lancet ii, 793-795. Miller, W. V. (1974) HL-A antigens and hematologic malignancy. Arch. intern. M e d . 133, 397-399. Mittal, K. K., Mickey, M. R., Singal, D. P. & Terasaki, P. I. (1968) Serotyping for homotransplantation XVIII. Refinement of microdroplet lymphocyte cytotoxicity test. Transplantation 6, 913-927. Rogentine, G. N., Jr., Yankee, R. A., Gart, J. J., Nam, J. & Tripani, R. J. (1972) HL-A antigens and disease: Acute lymphocytic leukemia. J. clin. Invest. 51, 2420-2428. Russell, T. J., Schultes, L. M. & Kuban, D. J. ( 1972) Histocompatibility (HL-A) antigens associated with psoriasis. N e w Engl. J. M e d . 287, 738-740. Schlosstein, L., Terasaki, P. I., Bluestone, R. & Pearson, C. M. (1973) High association of an HL-A antigen, W27, with ankylosing spondylitis. N e w Engl. J. M e d . 288, 704-706. Stokes, P. L., Asquith, P., Holmes, G. K. T., Mackintosh, P. & Cooke, W. T. (1972) Histocompatibility antigens associated with adult coeliac disease. Lancet ii, 162-164. Takasugi, M., Terasaki, P. I., Henderson, B., Mickey, M. R., Menck, H. & Thompson, R. W. (1973) HL-A antigens in solid tumors. Cancer Res. 33, 648-650.
N o t e added in Proof Since the time of submission of this article, we have encountered a fourth family with renal cell carcinoma occurring in two brothers, both of whom had W17 as second segregant series antigens. The W 17
104
BRAUN ET AI..
haplotypes in which they occurred were both A3-Wl7. A second point in proof is based on the mixed lymphocyte cultures carried out between the propositus in Family B (Cell A ) , the father of the propositus in Family B (Cell B), and the propositus in Family W (Cell C) . Mixed lymphocyte cultures among these three individuals yielded relative responses of .04 (AB,), .10 (BAm), .37 (AC,), .28 (CA,) and .06 (BC,) ; the CB, combination was technically unsatisfactory. These results suggest that indi-
viduals with RCC respond among themselves in mixed lymphocyte cultures essentially in the same way as MLC typing cells which have been found to have relative responses up to .35 to .38 (Dupont, Fersonal communication; Stastny, personal communication). Address: William E. Braun, M.D. Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, Ohio 44106 U.S.A.
Short Communication
Published by Munksgaard, Copenhagen, Denmark No part may be reproduced by any process without written permission from the author(s)
The Association of W17 with Familial Renal Cell Carcinoma W. E. BRAUN,C. V. STRIMLAN, A. G. NEGRON, R. A. STRAFFON, A. A. ZACHARY, S. L. BARTEE AND D. R. GRECEK Departments of Hypertension and Nephrology, Medicine, Urology, and the Histocompatibility Laboratory, Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.
Despite several strong associations between HL-A antigens and disease states, for example, W27 and ankylosing spondylitis (Schlosstein et al. 1973), HL-A8 and chronic active hepatitis (Mackay & Morris 1972) and celiac disease (Stokes et al. 1972), and W17 and HL-A13 and psoriasis (Russell et al. 1972), no clear correlation has been found with any neoplastic disease in large studies by Dick et al. (1972), Takasugi et al. (1973), Miller (1974), and Lamm et al. (1974),although
early studies were suggestive (Amiel 1967, Rogentine et al. 1972). Using the standard microcytotoxicity technique (Mittal et al. 1968), our studies of three unrelated Caucasian families (F, W, and B) (Figs. 1, 2, and 3) each with renal cell carcinoma (RCC) in two generations disclose a remarkably high frequency of W17 both in the patients (5/6, 83 %) and in apparently unaffected family members (10J13, 77 %). I n Family W the deceased grandfather with RCC had
FAMILY F
I
II 24 16
3 16
m
1p
Figure 1 . Family F ; propositus +
24 16
102
B M U N ET AL,
FAMILY W
I
II 2 50 2 8
31 17 2 13
m
31 17
2 8
31 17 2 12
31 17 31 16
Figure 2. Family W; propositus +
his antigens and haplotypes constructed by virtue of his three children and his
FAMILY B
I 3 12
2 17
wife. The W17 haplotypes of those with RCC are: 1-17 ( 2 ) , 31-17 ( 2 ) , and 2-17 (1). Consanguinity occurs in only one family (F). Five of the six patients with RCC are male. The four males who were tested all are red cell type A, and the single female patient is an 0. The age of onset of RCC ranges from 32 to 77 years. Places of birth of the grandparents include the Ukraine and Lithuania ( F ) , England and the Netherlands ( W ) , and Czechoslovakia
(B).
2171 32 15
m
2 17 3 12
6
2 17
I I 50 Figure 3. Family B; propositus +
The antigen frequency of W17 has been reported as 8 % in 906 controls (Schlosstein et al. 1973) and is 10 "/o in the 485 controls in this study. Since the occurrence of RCC is examined in families, only one member (the propositus) from each family can be considered as a random inheritor of W17. Using the control group of 485, the uncorrected P value is 0.0011. When
103
W17 AND RENAL CELL CARCINOMA
corrected for one-sidedness and the number of antigens tested (30), the P value is of borderline significance (0.066). If a larger, published control group of 906 is used (Schlosstein et al. 1973), the corrected P value is 0.032. Somewhat surprising is the failure to find W17 in any of 13 other random cases of renal cell carcinoma. This apparent discrepancy suggests that W17 might be a “marker” antigen only in families and that other antigens, possibly of LD origin, may be better markers in a random population because they are gene products of a locus that may be positioned closer to the I r locus. Because of the tendency for RCC to occur in an older age group, the risk and/ or incidence of RCC in other family members is uncertain at present. The strength of W17 as a possible marker for familial RCC, then, may require urography, angiography, and years of observation to determine the true incidence of RCC among W17-bearing family members without current evidence of the disease. Familial carcinomas such as renal cell carcinoma may be the best starting place to find such disease-linked LD antigens detectable with homozygote typing cells. However, the possibility exists that there are multiple gene products marking or determining susceptibility to neoplasia that include not only SD, LD, and I r antigens, but also those for race, sex, and red cell type that would provide the necessary substrate for the properly timed intervention of an oncogenic agent.
Acknowledgments We appreciate the cooperation of Dr. Leonard Horn in the study of Family F, the assistance of Prof. J. N. Berrettoni for performing the statistical analysis, and the constructive comments of Drs. A. Svejgaard and L. Lamm.
References Amiel, J. L. (1967) Study of the leucocyte phenotypes in Hodgkin’s disease. Histocompatibility Testing 1967, p. 79. Munksgaard, Copenhagen. Dick, F. R., Fortuny, I., Theologides, A., Greally, J., Wood, N. & Yunis, E. J. (1972) HLA and lymphoid tumors. Cancer Res. 32, 2608-261 1. Lamm, L. U., Kissmeyer-Nielsen, F., Kjerbye, K. E., Mortensen, B. & Petersen, N. C. ( 1974) HL-A and ABO antigens and malignant melanoma. A study of 212 cases. Cancer 33, 1458-1461.
Mackay, I. R. & Morris, P. J. (1972) Association of autoimmune active chronic hepatitis with HL-A1, 8. Lancet ii, 793-795. Miller, W. V. (1974) HL-A antigens and hematologic malignancy. Arch. intern. M e d . 133, 397-399. Mittal, K. K., Mickey, M. R., Singal, D. P. & Terasaki, P. I. (1968) Serotyping for homotransplantation XVIII. Refinement of microdroplet lymphocyte cytotoxicity test. Transplantation 6, 913-927. Rogentine, G. N., Jr., Yankee, R. A., Gart, J. J., Nam, J. & Tripani, R. J. (1972) HL-A antigens and disease: Acute lymphocytic leukemia. J. clin. Invest. 51, 2420-2428. Russell, T. J., Schultes, L. M. & Kuban, D. J. ( 1972) Histocompatibility (HL-A) antigens associated with psoriasis. N e w Engl. J. M e d . 287, 738-740. Schlosstein, L., Terasaki, P. I., Bluestone, R. & Pearson, C. M. (1973) High association of an HL-A antigen, W27, with ankylosing spondylitis. N e w Engl. J. M e d . 288, 704-706. Stokes, P. L., Asquith, P., Holmes, G. K. T., Mackintosh, P. & Cooke, W. T. (1972) Histocompatibility antigens associated with adult coeliac disease. Lancet ii, 162-164. Takasugi, M., Terasaki, P. I., Henderson, B., Mickey, M. R., Menck, H. & Thompson, R. W. (1973) HL-A antigens in solid tumors. Cancer Res. 33, 648-650.
N o t e added in Proof Since the time of submission of this article, we have encountered a fourth family with renal cell carcinoma occurring in two brothers, both of whom had W17 as second segregant series antigens. The W 17
104
BRAUN ET AI..
haplotypes in which they occurred were both A3-Wl7. A second point in proof is based on the mixed lymphocyte cultures carried out between the propositus in Family B (Cell A ) , the father of the propositus in Family B (Cell B), and the propositus in Family W (Cell C) . Mixed lymphocyte cultures among these three individuals yielded relative responses of .04 (AB,), .10 (BAm), .37 (AC,), .28 (CA,) and .06 (BC,) ; the CB, combination was technically unsatisfactory. These results suggest that indi-
viduals with RCC respond among themselves in mixed lymphocyte cultures essentially in the same way as MLC typing cells which have been found to have relative responses up to .35 to .38 (Dupont, Fersonal communication; Stastny, personal communication). Address: William E. Braun, M.D. Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, Ohio 44106 U.S.A.
