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Journal of Clinical Oncology, Vol 23, No 13 (May 1), 2005: pp. 3074-3078 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.00.281
TGFBR1
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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6A is a tumor susceptibility gene that increases breast, colon, and ovarian cancer risk. Fourteen percent of the general population carries TGFBR16A, and TGFBR16A homozygotes have a greater than 100% increased colon cancer risk compared with noncarriers. Low-penetrance genes such as TGFBR16A may account for a sizable proportion of familial colorectal cancer occurrences. To test this hypothesis, we determined whether TGFBR16A contributes to a proportion of mismatch repair (MMR) gene mutation–negative hereditary nonpolyposis colorectal cancer (HNPCC) patients.
PATIENTS AND METHODS: A case-case study was performed of 208 index patients with HNPCC meeting the Amsterdam criteria. Patients were examined for mutations and genomic rearrangements in the MLH1, MSH2, and MSH6 genes and genotyped for TGFBR16A. Tumor microsatellite instability status was available for 95 patients.
RESULTS: A total of 144 patients (69.2%) carried a deleterious mutation and were classified as positive for MMR gene mutation; 64 patients (30.8%) had no evidence of mutations and were classified as MMR negative. TGFBR16A allelic frequency was significantly higher among MMR-negative patients (0.195) than among MMR-positive patients (0.104; P = .011). The proportion of TGFBR16A homozygotes was nine-fold higher among MMR-negative (6.3%) than among MMR-positive patients (0.7%; P = .032). The highest TGFBR16A allelic frequency was found among MMR-negative patients with tumors exhibiting no microsatellite instability (0.211), and the lowest frequency was found among MMR-positive patients with tumors exhibiting microsatellite instability (0.121); the difference was not statistically significant (P = .17).
CONCLUSION: TGFBR16A may be causally responsible for a proportion of HNPCC occurrences.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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The newer Amsterdam II criteria recognize additional clinical features such as cancer of the endometrium, small bowel, ureter, or renal pelvis that are suggestive of HNPCC. The sensitivity of the Amsterdam criteria ranges between 54% to 91%, and specificity ranges between 62% to 84%.4 In the largest single study to date, comprising 184 high-risk families from Europe, the sensitivity and specificity of the Amsterdam criteria for genetically defined HNPCC were 87% and 63%, respectively.5 The use of the revised Amsterdam II criteria increases sensitivity and decreases specificity to a lesser degree. In one study of 70 high-risk families, sensitivity increased from 61% to 78% and specificity decreased from 67% to 61%.6 HNPCC defined by these criteria accounts for 1% to 6% of all CRC patients,1 but only 1% to 3% of all CRC patients have a known mutation in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS1, and PMS2.1,7 The molecular cause of most of the remaining patients belonging to HNPCC-like families and familial colon cancer is still unexplained. Some occurrences may be due to occult mutations in MMR genes or their promoters, but others are presumably caused by mutations in tumor suppressor genes other than MMR, and by low-penetrance polymorphisms in modifying genes.1
We have previously identified TGFBR16A, a relatively common variant of the TGFBR1 gene.8 It has a deletion of three GCG triplets coding for alanine within a nine alanine (9A) repeat sequence of TGFBR1 exon 1, forming a variant that transmits TGF-ß growth-inhibitory signals less effectively than TGFBR1.9 Epidemiologically, the TGFBR16A allele is a tumor-susceptibility allele that has been associated with an increased incidence of several types of cancer.9-11 A meta-analysis of 12 case-control studies, which included 4,399 patients with a diagnosis of cancer and 3,451 healthy controls, suggests that TGFBR16A carriers have an increased risk of colon, breast, and ovarian cancer compared with noncarriers. Overall, cancer risk is increased by 19% among TGFBR16A heterozygotes and 70% among TGFBR16A homozygotes—a pattern indicative of an allelic dosing effect. A combined analysis of the six studies assessing colon cancer in 1,585 patients and 2,470 healthy controls indicates that TGFBR16A carriers are at increased risk of developing CRC (odds ratio [OR], 1.20; 95% CI, 1.01 to 1.43). CRC risk is especially high for TGFBR16A homozygotes (OR, 2.02; 95% CI, 1.18 to 3.48).12 The fact that 14% of the general population carries at least one copy of TGFBR16A provides a strong rationale to study the role of TGFBR16A in familial CRC.
We hypothesized that TGFBR16A might explain a proportion of CRC patients with family histories meeting Amsterdam criteria, but without an identifiable mutation in an MMR gene. Using a case-only design, we investigated the TGFBR16A allele prevalence and MMR gene mutation status in CRC patients with family histories meeting the Amsterdam criteria. We also assessed the potential for the allele to affect one aspect of the disease phenotype: age at disease onset. Finally, we investigated the association between the TGFBR16A allele and tumor microsatellite instability (MSI).
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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TGFBR1 Exon 1 Genotyping
To test the study hypotheses, we used DNA samples from 208 HNPCC index patients meeting the Amsterdam I or II criteria enrolled onto research protocols approved by institutional review boards. TGFBR1 exon 1 genotyping was performed as described previously.8,9
MSI Determination
MSI testing was performed at some centers (Germany, Spain, and New York, NY) according to a defined protocol involving testing paired normal and tumor DNA for MSI with the five original microsatellite sequences on the National Cancer Institute panel: BAT25, BAT26, D2S123, D5S346, and D17S250.15 If two or more of the five microsatellite sequences in the tumor DNA were mutated, the tumor was termed MSI high (MSI-H). If only one of the five microsatellite sequences in the tumor DNA was mutated, the tumor was termed MSI low (MSI-L). If none of the five microsatellite sequences in the tumor DNA was mutated, the tumor was termed microsatellite stable (MSS).16
Data Analysis
The frequency of the TGFBR16A allele and proportion of TGFBR16A homozygous carriers were contrasted between MMR gene mutation–negative and MMR gene mutation–positive patients in contingency table analyses using a 
2 test or Fisher’s exact test. TGFBR16A allelic frequency was calculated as the ratio of TGFBR16A alleles divided by the total number of alleles in a group. Ninety-five percent exact CIs for the allele frequency in each group were estimated using a method recommended for small proportions.17 Age at first CRC diagnosis was dichotomized (above v below the overall median). The association between age at CRC onset and TGFBR1 allele frequency was evaluated with the Mantel-Haenszel test in an analysis stratified by MMR gene mutation status. We also conducted 2 tests to compare TGFBR16A allelic frequency and proportion of TGFBR16A homozygotes in MMR-negative patients with the estimates in 4,399 patients and 3,451 controls from data previously used for a meta-analysis by our group.12 Although several subgroup analyses were conducted and multiple comparisons were made, because most of these comparisons are based on a priori defined hypotheses, we did not perform any formal adjustments of the reported P values in this report.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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6A allele, respectively (TGFBR16A allelic frequency, 0.104; 95% CI, 0.129 to 0.271). Sixty-four index patients (30.8%) were MMR gene mutation negative; 17 and four were TGFBR16A hetero- and homozygotes, respectively (6A allelic frequency, 0.195; 95% CI, 0.071 to 0.145). The 2 test of independence indicated that the TGFBR16A allelic frequencies differed significantly between the two groups (P = .011; Table 2). The TGFBR16A allelic frequency among MMR gene mutation–negative patients was more than twice as high as that among 4,399 patients (0.090) with a diagnosis of cancer (P < .01) and almost three-fold higher than that among 3,451 healthy controls (0.071; P < .01).12 The proportion of TGFBR16A homozygotes was significantly higher in the MMR gene mutation–negative (6.3%) than in the MMR gene mutation–positive group (0.7%; P = .032, Fisher’s exact test). It was eight-fold higher than among patients with a diagnosis of cancer (0.8%; P < .01) and 13-fold higher than among healthy controls (0.46%; P < .01).
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6A in the overall study population (P = .51), among MMR gene mutation–positive patients (P = .54), or among MMR gene mutation–negative patients (P = .22). Test results were based on 2 tests with 1 degree of freedom.
Age at diagnosis was available for 207 of the 208 index patients. The median age at diagnosis was 42 years. All patients were classified according to their age at first CRC diagnosis: 
42 versus older than 42 years. There was no overall association between age at CRC onset and TGFBR1 allele frequency. The average age at cancer diagnosis for TGFBR16A carriers (n = 49) and noncarriers (n = 158) was 43.2 and 43.5 years (P = .88), respectively. Among MMR gene mutation–negative patients, the average age at first cancer diagnosis was similar for TGFBR16A carriers (n = 21; mean, 47.5 years) and for noncarriers (n = 43; mean, 49.1 years; P = .61).
Tumor-derived DNA samples were available for 95 of the 208 patients included in this study for MSI analysis. In this subset of patients, TGFBR16A allelic frequency was 0.194 among MMR gene mutation–negative and 0.119 among MMR gene mutation–positive patients (P = .149). The tumors from 75 patients exhibited MSI-H and 20 patients exhibited either MSI-L or MSS. Although not statistically significant, TGFBR16A allelic frequency was higher among patients with MSI-L/MSS tumors (0.200) than among patients with MSI-H tumors (0.133; P = .28). MMR gene mutation–negative patients with MSI-L/MSS tumors had the highest TGFBR16A allelic frequency (0.211), and MMR gene mutation–positive patients with MSI-H cancers had the lowest TGFBR16A allelic frequency (0.121), but the difference was not statistically significant (P = .17; Table 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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The TGFBR16A allelic frequency among patients with germline MMR gene mutations in our study (0.104) is almost identical to that found among patients from the United States and Europe with sporadic CRC (0.095),9,25,26 and is 42% higher than among healthy controls from the same geographic areas.12 In contrast, the TGFBR16A allelic frequency among MMR gene mutation–negative HNPCC patients (0.195) is significantly higher (> two-fold) than among MMR gene mutation–positive HNPCC patients. This is by far the highest TGFBR16A allelic frequency ever reported in any group of individuals. It is two and two and one half times higher than among patients from the United States and Europe with a diagnosis of cancer (0.090) and healthy controls (0.071), respectively12 (P < .01).
MSI is found in approximately 15% to 20% of sporadic CRCs, and in approximately 90% of CRCs in patients with HNPCC.1 MSI testing was performed routinely at some but not all centers. The absence of a significant difference in allelic frequency between patients with MSI-L/MSS and MSI-H tumors may be due to the limited numbers of MSI data. The high TGFBR16A allelic frequency found among MMR gene mutation–negative patients with MSI-L/MSS tumors (0.211) suggests that the TGFBR16A contribution to CRC development is particularly marked in this subgroup. Additional studies that include larger numbers of patients with tumor tissue available for MSI testing will be needed to test this hypothesis.
Of the MMR gene mutation–negative patients, 6.3% were TGFBR16A homozygotes, which is 13-fold higher than in the general population (0.46%; P < .01).12 This is additional evidence that TGFBR16A homozygosity may confer a particularly high risk of CRC. Given that the overwhelming majority of patients with familial CRC are MMR gene mutation negative, we predict that TGFBR16A may contribute to a significant proportion of familial cancer occurrences as well. The data warrant studies of individuals belonging to MMR gene mutation–negative families with a history of hereditary or familial colon cancer to validate our findings of an increased risk incurred by TGFBR16A carriers.
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Authors' Disclosures of Potential Conflicts of Interest |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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NOTES |
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Yansong Bian, Trinidad Caldes, and Juul Wijnen contributed equally to this work.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors' Disclosures of...REFERENCES |
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2. Vasen HF, Mecklin JP, Khan PM, et al: The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34:424-425, 1991[CrossRef][Medline]
3. Vasen HF, Watson P, Mecklin JP, et al: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 116:1453-1456, 1999[CrossRef][Medline]
4. Kievit W, de Bruin JH, Adang EM, et al: Current clinical selection strategies for identification of hereditary non-polyposis colorectal cancer families are inadequate: A meta-analysis. Clin Genet 65:308-316, 2004[CrossRef][Medline]
5. Wijnen JT, Vasen HFA, Khan PM, et al: Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 339:511-518, 1998
6. Syngal S, Fox EA, Eng C, et al: Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1. J Med Genet 37:641-645, 2000
7. Samowitz WS, Curtin K, Lin HH, et al: The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer. Gastroenterology 121:830-838, 2001[CrossRef][Medline]
8. Pasche B, Luo Y, Rao PH, et al: Type I transforming growth factor beta receptor maps to 9q22 and exhibits a polymorphism and a rare variant within a polyalanine tract. Cancer Res 58:2727-2732, 1998
9. Pasche B, Kolachana P, Nafa K, et al: T beta R-I(6A) is a candidate tumor susceptibility allele. Cancer Res 59:5678-5682, 1999
10. Chen T, Triplett J, Dehner B, et al: Transforming growth factor-beta receptor type I gene is frequently mutated in ovarian carcinomas. Cancer Res 61:4679-4682, 2001
11. Baxter SW, Choong DY, Eccles DM, et al: Transforming growth factor beta receptor 1 polyalanine polymorphism and exon 5 mutation analysis in breast and ovarian cancer. Cancer Epidemiol Biomarkers Prev 11:211-214, 2002
12. Pasche B, Kaklamani VG, Hou N, et al: TGFBR16A and cancer: A meta-analysis of 12 case-control studies. J Clin Oncol 22:756-758, 2004
13. Wijnen J, van der Klift H, Vasen H, et al: MSH2 genomic deletions are a frequent cause of HNPCC. Nat Genet 20:326-328, 1998[CrossRef][Medline]
14. Charbonnier F, Olschwang S, Wang Q, et al: MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer. Cancer Res 62:848-853, 2002
15. Boland CR, Thibodeau SN, Hamilton SR, et al: A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248-5257, 1998
16. Umar A, Boland CR, Terdiman JP, et al: Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability. J Natl Cancer Inst 96:261-268, 2004
17. Fleiss JL: Statistical Methods for Rates and Proportions (ed 2). New York, NY, Wiley and Sons, 1981
18. Hoosein NM, McKnight MK, Levine AE, et al: Differential sensitivity of subclasses of human colon carcinoma cell lines to the growth inhibitory effects of transforming growth factor-beta 1. Exp Cell Res 181:442-453, 1989[CrossRef][Medline]
19. Howe JR, Roth S, Ringold JC, et al: Mutations in the smad4/dpc4 gene in juvenile polyposis. Science 280:1086-1088, 1998
20. Roth S, Sistonen P, Salovaara R, et al: SMAD genes in juvenile polyposis. Genes Chromosomes Cancer 26:54-61, 1999[CrossRef][Medline]
21. Friedl W, Kruse R, Uhlhaas S, et al: Frequent 4-bp deletion in exon 9 of the SMAD4/MADH4 gene in familial juvenile polyposis patients. Genes Chromosomes Cancer 25:403-406, 1999[CrossRef][Medline]
22. Howe JR, Sayed MG, Ahmed AF, et al: The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet 41:484-491, 2004
23. Lu SL, Kawabata M, Imamura T, et al: HNPCC associated with germline mutation in the TGF-beta type II receptor gene. Nat Genet 19:17-18, 1998[Medline]
24. Lu SL, Kawabata M, Imamura T, et al: Two divergent signaling pathways for TGF-beta separated by a mutation of its type II receptor gene. Biochem Biophys Res Commun 259:385-390, 1999[CrossRef][Medline]
25. Samowitz WS, Curtin K, Leppert MF, et al: Uncommon TGFBR1 allele is not associated with increased susceptibility to colon cancer. Genes Chromosomes Cancer 32:381-383, 2001[CrossRef][Medline]
26. Stefanovska AM, Efremov GD, Dimovski AJ, et al: TbetaR-I(6A) polymorphism is not a tumor susceptibility allele in Macedonian colorectal cancer patients. Cancer Res 61:8351-8352, 2001
Submitted December 14, 2004; accepted February 1, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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6A May Contribute to Hereditary Colorectal Cancer
