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© 2003 American Society for Clinical Oncology TGFBR1*6A and Cancer Risk: A Meta-Analysis of Seven Case-Control StudiesFrom the Cancer Genetics Program, Division of Hematology/Oncology; the Center for Medical Genetics, Evanston Northwestern Healthcare; and the Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; and Clinical Genetics Service and the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Boris Pasche, MD, PhD, FACP, Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 676 N. St Clair St, Suite 880, Chicago, IL 60611; e-mail: b-pasche{at}northwestern.edu.
Purpose: TGFBR1*6A is a hypomorphic polymorphic allele of the type I transforming growth factor beta receptor (TGFBR1). TGFBR1*6A is a candidate tumor susceptibility allele that has been associated with an increased incidence of various types of cancer. This study was undertaken to analyze all published case-control studies on TGFBR1*6A and cancer and determine whether TGFBR1*6A is associated with cancer. Patients and Methods: All published case-control studies assessing the germline frequency of TGFBR1*6A were included. Studies assessing TGFBR1*6A in tumors were excluded. The results of seven studies comprising 2,438 cases and 1,846 controls were pooled and analyzed. Results: Overall, TGFBR1*6A carriers have a 26% increased risk of cancer (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.07 to 1.49). Cancer risk for TGFBR1*6A homozygotes (OR, 2.53; 95% CI, 1.39 to 4.61) is twice that of TGFBR1*6A heterozygotes (OR, 1.26; 95% CI, 1.04 to 1.51). Analysis of various types of tumors shows that TGFBR1*6A carriers are at increased risk of developing breast cancer (OR, 1.48; 95% CI, 1.11 to 1.96), hematological malignancies (OR, 1.70; 95% CI, 1.13 to 2.54), and ovarian cancer (OR, 1.53; 95% CI, 1.07 to 2.17). Carriers of TGFBR1*6A who are from the United States are at increased risk of colorectal cancer (OR, 1.38; 95% CI, 1.02 to 1.86). However, Southern European TGFBR1*6A carriers have no increased colorectal cancer risk. There is no association between TGFBR1*6A and bladder cancer. Conclusion: TGFBR1*6A is emerging as a highfrequency, low-penetrance tumor susceptibility allele that predisposes to the development of breast, ovarian, and colorectal cancer, as well as hematologic malignancies.
RECENT ANALYSES of cohorts of twins show a relatively large effect of heritability for several forms of cancer, suggesting that our current knowledge of cancer genetics is limited.1 This effect is likely due to a combination of low-penetrance tumor susceptibility genes. Such variants are relatively common in the population and may confer a much higher attributable risk in the general population than rare mutations in high-penetrance cancer susceptibility genes, such as BRCA1, BRCA2, and APC. Candidate low-penetrance genes are usually chosen on the basis of biologic plausibility. Alterations in their protein sequence, and therefore its function, could affect pathways involved in cell-growth control, detoxification, and carcinogenesis. Several polymorphisms of genes involved in these pathways have been identified during the past few years. Transforming growth factor beta (TGF-ß) fulfills the requirements for designation as a cancer-related pathway. TGF-ß is the most potent naturally occurring inhibitor of cell growth. It exerts its action by binding to type I (TGFBR1) and type II (TGFBR2) transmembrane receptors located on the cell membrane.2 Intracellular signaling is activated once TGF-ß has induced the formation of a TGFBR1/TGFBR2 heteromeric complex. TGFBR2 phosphorylates TGFBR1, resulting in activation of TGFBR1 kinase. Unrestricted cell growth due to a lack of growth inhibitory activity appears to be the most important of the possible consequences of a defect in TGF-ß function. This hypothesis was confirmed by the discovery that Tgfb1+/- and Tgfbr2+/- haploinsufficient mice resulting in decreased TGF-ß signaling have an increased susceptibility to develop cancer than their wild-type counterparts.3,4 Specific targeting of the TGF-ß receptors in human cancer has been demonstrated by the identification of inactivating mutations in TGFBR2 in colon cancers and head and neck cancers, homozygous deletion of TGFBR1 in pancreatic and biliary carcinomas and in lymphoma, and a TGFBR1 tumor-specific mutation in breast cancer.5–7 Additionally, restoration of functional receptor expression reverses the transformed phenotype of several human cancer cell lines that inherently lack functional TGF-ß receptors.8,9 Clinical evidence that decreased TGF-ß signaling increases cancer susceptibility stems from studies showing that germline mutations of TGFBR2 and SMAD4 may predispose to the development of hereditary nonpolyposis colorectal cancer and juvenile polyposis, respectively.10,11 Similarly, a polymorphism of TGF-ß1 resulting in increased TGF-ß signaling has been associated with a decreased risk of breast cancer.12 TGFBR1*6A is a polymorphic allele of the type I TGF-ß receptor (TGFBR1) that has a deletion of three alanines within a 9-alanine stretch of exon 1 coding sequence.13 Several epidemiological studies show an overrepresentation of both TGFBR1*6A heterozygotes and homozygotes among patients with a diagnosis of cancer.14–18 Using mink lung epithelial cell lines devoid of endogenous TGFBR1, two groups of investigators have shown that TGFBR1*6A, compared to TGFBR1, is impaired as a mediator of TGF-ß antiproliferative signals.14,15 Several recent studies have assessed the frequency of TGFBR1*6A among patients with a diagnosis of cancer and controls, with mixed results. Some studies confirmed this association; some did not.18–21 The aim of this meta-analysis was to determine whether current epidemiological data support the hypothesis that TGFBR1*6A is a tumor susceptibility allele.
Selection and Review of Studies We performed a MEDLINE and CANCERLIT search from the database from January 1966 to April 2002. The search headings used were "Type I TGF-beta receptor," "TßR-I," "genetic polymorphism," "mutation analysis," "transforming growth factor-ß receptor," "mutation," "tumor susceptibility allele," "transforming growth factor," "TbR-I(6A)," "TbetaR-I(6A)," "TGFBR1*6A." The search was limited to human studies. A manual search of the bibliographies of all retrieved articles was performed by two independent investigators. All studies had to clearly describe the study population, including its ethnicity; if this was not clear, the corresponding authors were contacted and asked to provide the missing data. We excluded reviews, case series, and editorials, as well as studies assessing TGFBR1*6A in tumors. Overall, we identified seven studies investigating the TGFBR1*6A polymorphism in relation to cancer susceptibility. These studies are presented below. We were able to contact the senior author of each study except for one, and we received additional information that has been included in this report.
The study by Pasche et al,15 published in 1999, was the first case-control study to show an association of TGFBR1*6A {*6A} with cancer susceptibility.15 Subjects were from New York City and comprised 851 cases and 735 controls (Table 1
The study by Chen et al,14 published in 1999, reported two separate case-control studies. All cases were patients with a diagnosis of cancer of the cervix. In the first case-control study patients were randomly selected from a multicenter study on cervical cancer conducted in six centers in the East coast of the US. Controls and cases were similar by age, ethnic status, and location. In the second case-control study, cases and controls were enrolled through institutional affiliates of the University of West Indies Hospital in Kingston, Jamaica. All subjects were black. Overall, the two studies included 66 cases and 68 controls (Table 1  ). In the study, 89.7% of the controls carried the *9A/*9A genotype, compared with 83.3% of the cases. The *6A/*9A genotype was present in 10.3% of controls and 15.2% of the cases and the *6A/*6A genotype was present in 1.5% of cases versus none in the controls. A positive association of *6A with cervical cancer was found in the US patient population. Frequency of *6A was identical among cases and controls of the Jamaican population. Another case-control study by Pasche et al,15 performed on a Northern Italian population, consisted of 347 cancer patients and 50 controls. This case-control study, although a separate study, was presented in addition to the New York study in the Pasche et al article.15 The results showed a *9A/*9A frequency of 76% among controls and 84.7% among patients with a diagnosis of cancer. Furthermore, the *6A/*9A polymorphism was present in 24% of the controls and 14.7% of the cases. One patient with a diagnosis of breast cancer was homozygous for *6A.
In the study by Samowitz et al,19 published in 2001, 252 cases of colon cancer and 362 controls were studied in relation to the TGFBR1 polymorphism. Patients and controls from the state of Utah were similar by age, ethnicity, and sex (Table 1 The letter published by Stefanovska et al20 in 2001 included 117 colon cancer patients and 200 controls. One hundred controls were newborn infants, and one hundred were elderly individuals. The study populations were from the Former Yugoslav Republic of Macedonia (FYROM) and were of similar ethnic status and the same sex. The frequency of the *9A/*9A genotype was 89.5% in the control population and 92.3% in the cancer cases. The *6A/*9A genotype was present in 10% of the controls and 6.8% of cases, and the *6A/*6A polymorphism was found in 1.0% of controls and 0.9% of cases. These results were not significant for any of the polymorphisms.
The study by van Tilborg et al22 published in 2001 was a case-control study, which included 183 normal blood donors and 146 patients with transitional carcinoma of the bladder, from the Netherlands. Patients were from similar ethnic groups but were not matched for age, sex, or ethnic status (Table 1
The final study included in our meta-analysis is from Baxter et al.18 This was a case-control study, which consisted of patients with breast (n = 355) and ovarian cancer (n = 304), endometriosis (n = 98), and 248 controls (Table 1
Statistical Methods
Study Characteristics
Cases differed with regard to cancer diagnosis in the different studies. For this reason we have analyzed our data according to specific cancer types. The frequency of the *9A/*9A genotype in the controls ranges from 76% to 90% (median, 83.5%). The frequency of the *6A/*9A genotype ranges from 10% to 24% (median, 15.7%). The frequency of the *6A/*6A genotype ranged from 0 to 1.6% (median, 0.8%). The frequency of the *9A/*9A genotype in cases ranges from 76.4% to 92.3% (median, 83.3%). The frequency of the *6A/*9A genotype ranges from 6.8% to 18.3% (median, 15.1%). The frequency of the *6A/*6A genotype ranges from 0% to 1.5% (median, 0.8%).
Overall Data Combined analysis of the seven studies showed that *6A allelic frequency was 28.8% higher among all cancer cases (0.0935) combined than among controls (0.0726; P < .001). *6A carriers had increased overall cancer risk (OR, 1.26; 95% CI, 1.07 to 1.49; Fig 1 ). Having demonstrated that *6A is associated with an overall increased risk of cancer, we proceeded with the analysis of each tumor group including at least 200 cases.
Breast Cancer
Ovarian Cancer Ovarian cancer cases were present in two studies, with a total of 352 patients.15,18 The OR for *6A carriers was 1.53 (95% CI, 1.07 to 2.17) (Fig 3  ). The *6A/*6A genotype was associated with a high OR of 3.35 (95% CI, 1.16 to 9.69). Hence, *6A homozygous females appear to have a particularly high risk of developing ovarian cancer. Histology information was only available for one study.
Colorectal Cancer Three studies included 546 patients with colorectal cancer15,19–21(Tables 1 and 2B, Fig 4). The OR for *6A homozygotes was 2.19 (95% CI, 1.08 to 4.45) and 1.05 (95% CI, 0.78 to 1.40) for *6A heterozygotes. The meta-analysis restricted to the 364 patients from US studies showed that *6A carriers from the US were at increased risk of developing colorectal cancer (OR, 1.38; 95% CI, 1.02 to 1.86). The lack of overall significance for *6A heterozygotes was mainly due to an opposite effect noted among European *6A heterozygous patients with colon cancer. Indeed, as recently discussed, there was a trend toward lower colorectal cancer risk associated with *6A heterozygosity, which may be attributable to different environmental factors between Southern Europe and the US21 Information on tumor histology, microsatellite instability status, and location of the tumor was not available for these patients.
Bladder Cancer In contrast to breast, colon, and ovarian cancer, we did not find any evidence of an association between bladder cancer and *6A. None of the 457 patients with bladder cancer from three different studies carried the *6A/*6A genotype. Furthermore, the *6A/*9A genotype was not associated with bladder cancer.
Hematologic Malignancies
Analysis Excluding Bladder Cancer Cases
Age Distribution
Sex Distribution
Ethnic Distribution Two BRCA1, one BRCA2, and one APC mutations are found predominantly among Ashkenazi (Eastern European) Jews and only rarely in the remainder of the white population. For this reason, we analyzed our subjects according to whether they were or not of Jewish decent. For some studies, we did not have any available information. In the US study by Pasche et al (1999), data were available for both cases and controls. From the 617 cases for which data were available, 166 were Jews. There were 146 *9A/*9A (88.0%), 17 *6A/*9A (10.2%), and 2 *6A/*6A (1.2%). Of the 605 non-Jews, 503 were genotyped as *9A/*9A (83.1%), 98 *6A/*9A (16.2%), and 4 *6A/*6A (0.03%). An analysis of these data did not show any difference in the frequency of *6A between Jews and non-Jews (P = .09).
This meta-analysis of seven case-control studies shows that *6A correlates significantly with breast and ovarian cancer as well as with colon cancer in the US only (Table 4 ). Individually, only two of the seven studies included in our meta-analysis concluded that there was an association between *6A and cancer. Although this argues against a publication bias of positive studies only, we conducted a comprehensive search to identify unpublished studies. Publication bias is unlikely in the current meta-analysis since all studies that have assessed the relation of *6A with cancer were included. A funnel plot of any *6A mutation for all cancers (Fig 5) supports the lack of publication bias in that studies are evenly distributed in each half of the plot. Small negative studies with OR that are relatively small in magnitude are included in this analysis.
Our meta-analysis has several limitations. The quality and usefulness of any meta-analysis is dependent on the quality of the component studies. A drawback of our meta-analysis is the heterogeneity of the different studies as far as the populations studied. The distribution of cancers in this meta-analysis does not match that of the general population and is almost certainly not representative of all forms of cancer. Cases and controls in individual studies were mostly hospital-based, which could potentially prevent the inference of our results to the general population. No quantitative assessment of confounders could be made given the lack of specific data on these confounders. We have included the available information on sex and ethnic background of our cases and controls, although a statistical analysis on the pooled data could not be performed. The geographic location of the different studies included varies considerably and we are therefore presenting our data according to the geographic location of individual studies. The quality of individual studies does not seem to bias the results of our meta-analysis. Despite its limitations, our meta-analysis has some important benefits. It provides pooled data on a substantial number of cases and controls and has the power to evaluate the role of the highly prevalent *6A allele in cancer susceptibility. All studies are case-control studies that are internally controlled for sex and ethnic background. Furthermore, the genotyping methods used in individual studies are similar and confer good internal and external validity. We found a significant association of *6A with cancer. After exclusion of all patients with bladder cancer, a tumor type unequivocally not associated with *6A, we were able to better estimate the OR for cancer associated with *6A carrier status. The OR for *6A homozygotes was twice that of *6A heterozygotes suggesting an allelic dosing effect. The data indicate that *6A results in a low-penetrance syndrome for heterozygotes and a low-frequency, low-to-moderate penetrance syndrome for homozygotes. Our combined results reveal that more than one in eight healthy individuals and one in six patients with cancer is a *6A carrier. This sets a new paradigm and establishes *6A as the first high-frequency, low-penetrance tumor susceptibility allele affecting a variety of ethnic groups. Our US results suggest that 8,099 (5.5%) of 148,300 new colon cancer cases per year may be attributable to *6A. Our combined results indicate that 14,555 (7.1%) of 205,000 and 2,515 (10.8%) of 23,200 new US cases of breast and ovarian cancer per year may be attributable to *6A. Our findings support the growing evidence that alterations in TGF-ß signaling as a result of polymorphisms or variants may affect risk for certain forms of cancer.10–12,25 This study warrants additional large case-control studies as well as studies among families with increased incidence of breast, ovarian and colon cancer.
This work was supported by grants CA76156–04, CA082516–01A2, and CA89018 from the National Cancer Institute (B.P.), an Avon Breast Cancer Career Development Award (B.P.), a grant from the Mander Foundation to the Cancer Genetics Program, and a grant from the Lymphoma Foundation (K.O.).
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ABSTRACT
INTRODUCTION
C polymorphism in the transforming growth factor beta1 gene and breast cancer among elderly white women: The study of osteoporotic fractures. JAMA 285:2859–2863, 2001
