The prevalence of recurrent spontaneous abortions, cancer, and congenital anomalies in the families of couples with recurrent spontaneous abortions or gestational trophoblastic tumors Hong-Nerng Ho, MD, Thomas J. Gill III, MD, Chang-Yao Hsieh, MD, Yu-Shih Yang, MD, and Tzu·Yao Lee, MD
Taipei, Taiwan, and Pittsburgh, Pennsylvania This study extends our previous work on the genetics of recurrent spontaneous abortion and of gestational trophoblastic tumors in an ethnically homogeneous population of Chinese in Taiwan by comparing the prevalence of recurrent spontaneous abortions, cancer, and congenital anomalies in the first-, secondo, and third-degree relatives of the index couples to that of normally fertile couples from the same population. The rationale for this study was to provide another test for our hypothesis that genes linked to the major histocompatibility complex are responsible for the diseases in the index couples. If they are, these genes should segregate with a higher frequency in the relatives of the index couples than in the relatives of normally fertile couples and lead to a higher prevalence of these diseases in the extended families. Such a difference was found and adds support to our hypothesis that major histocompatibility complex-linked genes affect growth, development, and susceptibility to cancer. (AM J OBSTET GVNECOL 1991 ;165:461-6.)
Key words: Genetics of reproduction, genetics of cancer, human leukocyte antigen sharing, recurrent spontaneous abortion, congenital anomalies
Experimental studies in rats and observations in the clinical literature led us to develop the hypothesis that recessive genes linked to the major histocompatibility complex influence growth, development, reproduction, and susceptibility to cancer. l . 5 We tested this hypothesis in a series of clinical studies in an ethnically homogeneous Chinese population in Taiwan (originally emigrated from the southeastern part of mainland China) to minimize the genetic variation in the population. The basic assumptions of the studies were that sharing of major histocompatibility complex antigens [human leukocyte antigens (HLA) in human beings] indicates the sharing of the major histocompatibility complex-linked region as well and that this region contains recessive genes that affect the growth and reproductive processes. We examined couples for HLA antigen sharing and the prevelance of gestational trophoblastic tumors and of recurrent spontaneous abortions and compared the results with those in normally fertile couples from the same population. From the Department of Obstetrics and Gynecology, National Taiwan University Hospital, and the Department of Pathology, University of Pittsburgh School of Medicine. Supported by grants from the National Science Council of the Republic of China (NSC-79-0412-B002-111 and 112), the Tim Camcio Memorial Cancer Fund, the Beaver County Cancer Society, and the Pathology Education and Research Foundation. Received for publication November 30, 1990; revised March 5, 1991; accepted March 22,1991. Reprint requests: Thomas]. Gill 111, MD, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
6/1/29786
Couples in whom the woman had a gestational trophoblastic tumor 6 and couples with primary or secondary recurrent spontaneous abortions 7 shared HLA antigens more frequently than did normally fertile couples. No specific HLA antigen was uniquely shared, and the strongest correlation was sharing of three or more of the HLA-A, B, DR, and DQ antigens. This observation strengthens our hypothesis that the HLA genes themselves are only passenger genes and that the genes responsible for these defects are on the same segment of chromosome 6 and linked to the genes encoding the HLA antigens. Two collateral observations are consistent with this genetic interpretation. First, gestational trophoblastic tumors have a high prevalance in the Taiwan Chinese population and a very low prevalence in whites, and the genetic association was observed only in the Chinese population in Taiwan: thus the disease is genetically determined (familial) in Taiwan Chinese and sporadic in whites. Retinoblastoma also has familial and sporadic forms.B,g Second, immunotherapy for recurrent spontaneous abortion was not effective in this Taiwanese population, as would be expected for a genetically determined disease. lo This study extends our work in this Taiwan Chinese population to examine the prevalence of recurrent spontaneous abortions, cancer, and congenital anomalies in the first-, second- and third-degree relatives of the index couples (i,e., those couples with gestational trophoblastic tumors or recurrent spontaneous abortions in our previous studies).6, 7 The rationale for this
461
462
He et al.
August 1991 Am J Obstet Gynecol
Table I. The prevalence of recurrent spontaneous abortions, cancer, and congenital anomalies in the first-degree relatives of couples who are normally fertile, have recurrent spontaneous abortions, or have gestational trophoblastic tumors Reproductive histories of the index couples
Population
No. of index couples whose families were studied First-degree relatives Number Recurrent spontaneous abortions Cancer Total
Normally fertile (controls)
Congenital anomalies
Primary
406
158
2519 4
632 9 P < 0.0001
95
Taipei, Taiwan, and Pittsburgh, Pennsylvania This study extends our previous work on the genetics of recurrent spontaneous abortion and of gestational trophoblastic tumors in an ethnically homogeneous population of Chinese in Taiwan by comparing the prevalence of recurrent spontaneous abortions, cancer, and congenital anomalies in the first-, secondo, and third-degree relatives of the index couples to that of normally fertile couples from the same population. The rationale for this study was to provide another test for our hypothesis that genes linked to the major histocompatibility complex are responsible for the diseases in the index couples. If they are, these genes should segregate with a higher frequency in the relatives of the index couples than in the relatives of normally fertile couples and lead to a higher prevalence of these diseases in the extended families. Such a difference was found and adds support to our hypothesis that major histocompatibility complex-linked genes affect growth, development, and susceptibility to cancer. (AM J OBSTET GVNECOL 1991 ;165:461-6.)
Key words: Genetics of reproduction, genetics of cancer, human leukocyte antigen sharing, recurrent spontaneous abortion, congenital anomalies
Experimental studies in rats and observations in the clinical literature led us to develop the hypothesis that recessive genes linked to the major histocompatibility complex influence growth, development, reproduction, and susceptibility to cancer. l . 5 We tested this hypothesis in a series of clinical studies in an ethnically homogeneous Chinese population in Taiwan (originally emigrated from the southeastern part of mainland China) to minimize the genetic variation in the population. The basic assumptions of the studies were that sharing of major histocompatibility complex antigens [human leukocyte antigens (HLA) in human beings] indicates the sharing of the major histocompatibility complex-linked region as well and that this region contains recessive genes that affect the growth and reproductive processes. We examined couples for HLA antigen sharing and the prevelance of gestational trophoblastic tumors and of recurrent spontaneous abortions and compared the results with those in normally fertile couples from the same population. From the Department of Obstetrics and Gynecology, National Taiwan University Hospital, and the Department of Pathology, University of Pittsburgh School of Medicine. Supported by grants from the National Science Council of the Republic of China (NSC-79-0412-B002-111 and 112), the Tim Camcio Memorial Cancer Fund, the Beaver County Cancer Society, and the Pathology Education and Research Foundation. Received for publication November 30, 1990; revised March 5, 1991; accepted March 22,1991. Reprint requests: Thomas]. Gill 111, MD, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
6/1/29786
Couples in whom the woman had a gestational trophoblastic tumor 6 and couples with primary or secondary recurrent spontaneous abortions 7 shared HLA antigens more frequently than did normally fertile couples. No specific HLA antigen was uniquely shared, and the strongest correlation was sharing of three or more of the HLA-A, B, DR, and DQ antigens. This observation strengthens our hypothesis that the HLA genes themselves are only passenger genes and that the genes responsible for these defects are on the same segment of chromosome 6 and linked to the genes encoding the HLA antigens. Two collateral observations are consistent with this genetic interpretation. First, gestational trophoblastic tumors have a high prevalance in the Taiwan Chinese population and a very low prevalence in whites, and the genetic association was observed only in the Chinese population in Taiwan: thus the disease is genetically determined (familial) in Taiwan Chinese and sporadic in whites. Retinoblastoma also has familial and sporadic forms.B,g Second, immunotherapy for recurrent spontaneous abortion was not effective in this Taiwanese population, as would be expected for a genetically determined disease. lo This study extends our work in this Taiwan Chinese population to examine the prevalence of recurrent spontaneous abortions, cancer, and congenital anomalies in the first-, second- and third-degree relatives of the index couples (i,e., those couples with gestational trophoblastic tumors or recurrent spontaneous abortions in our previous studies).6, 7 The rationale for this
461
462
He et al.
August 1991 Am J Obstet Gynecol
Table I. The prevalence of recurrent spontaneous abortions, cancer, and congenital anomalies in the first-degree relatives of couples who are normally fertile, have recurrent spontaneous abortions, or have gestational trophoblastic tumors Reproductive histories of the index couples
Population
No. of index couples whose families were studied First-degree relatives Number Recurrent spontaneous abortions Cancer Total
Normally fertile (controls)
Congenital anomalies
Primary
406
158
2519 4
632 9 P < 0.0001
95
