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Pasche B , Knobloch TJ , Bian Y , Liu J , Phukan S , Rosman D , Kaklamani V , Baddi L , Siddiqui FS , Frankel W , Prior TW , Schuller DE , Agrawal A , Lang J , Dolan ME , Vokes EE , Lane WS , Huang CC , Caldes T , Di Cristofano A , Hampel H , Nilsson I , Von Heijne G , Fodde R , Murty VVVS , De La Chapelle A , Weghorst CM
Somatic acquisition and signaling of TGFBR1*6A in cancer
Journal of the American Medical Association. 2005 ;294(13) :1634-1646
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Abstract
Context: TGFBR1*6A is a common polymorphis of the type I transforming growth factor ? receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown. Objectives: To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3-amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells. Design, Setting, and Patients: Tumor and germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A. Main Outcome Measures: TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-?-dependent cell proliferation. Results: TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-? growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells. Conclusions: TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-?. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-? signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer. ©2005 American Medical Association. All rights reserved.
Notes
00987484 (ISSN) Cited By: 3; Export Date: 25 May 2006; Source: Scopus CODEN: JAMAA Language of Original Document: English Correspondence Address: Pasche, B.; Department of Medicine; Robert H. Lurie Comprehensive Cancer Center; Northwestern University Feinberg School of Medicine; 676 N St Clair St Chicago, IL 60611, United States; email: b-pasche@northwestern.edu References: Siegel, P.M., Massague, J., Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer (2003) Nat Rev Cancer, 3, pp. 807-820; Derynck, R., Zhang, Y.E., Smad-dependent and Smad-independent pathways in TGF-beta family signalling (2003) Nature, 425, pp. 577-584; Lo, R.S., Wotton, D., Massague, J., Epidermal growth factor signaling Ras controls the Smad transcriptional co-repressor TGIF (2001) EMBO J, 20, pp. 128-136; Ulloa, L., Doody, J., Massague, J., Inhibition of transforming growth factor-beta/Smad signalling by the interferon-gamma/STAT pathway (1999) Nature, 397, pp. 710-713; Bitzer, M., Von Gersdorff, G., Liang, D., A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA (2000) Genes Dev, 14, pp. 187-197; Kretzschmar, M., Doody, J., Timokhina, I., Massague, J., A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras (1999) Genes Dev, 13, pp. 804-816; Hannon, G.J., Beach, D., p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest (1994) Nature, 371, pp. 257-261; Reynisdottir, I., Polyak, K., Iavarone, A., Massague, J., Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta (1995) Genes Dev, 9, pp. 1831-1845; Datto, M.B., Li, Y., Panus, J.F., Howe, D.J., Xiong, Y., Wang, X.F., Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism (1995) Proc Natl Acad Sci U S A, 92, pp. 5545-5549; Massague, J., G1 cell-cycle control and cancer (2004) Nature, 432, pp. 298-306; Rotello, R.J., Lieberman, R.C., Purchio, A.F., Gerschenson, L.E., Coordinated regulation of apoptosis and cell proliferation by transforming growth factor beta 1 in cultured uterine epithelial cells (1991) Proc Natl Acad Sci U S A, 88, pp. 3412-3415; Oberhammer, F.A., Pavelka, M., Sharma, S., Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor beta 1 (1992) Proc Natl Acad Sci U S A, 89, pp. 5408-5412; Chaouchi, N., Arvanitakis, L., Auffredou, M.T., Blanchard, D.A., Vazquez, A., Sharma, S., Characterization of transforming growth factor-beta 1 induced apoptosis in normal human B cells and lymphoma B cell lines (1995) Oncogene, 11, pp. 1615-1622; Landstrom, M., Heldin, N.E., Bu, S., Smad7 mediates apoptosis induced by transforming growth factor beta in prostatic carcinoma cells (2000) Curr Biol, 10, pp. 535-538; Larisch, S., Yi, Y., Lotan, R., A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif (2000) Nat Cell Biol, 2, pp. 915-921; Patil, S., Wildey, G.M., Brown, T.L., Choy, L., Derynck, R., Howe, P.H., Smad7 is induced by CD40 and protects WEHI 231 B-lymphocytes from transforming growth factor-beta-induced growth inhibition and apoptosis (2000) J Biol Chem, 275, pp. 38363-38370; Tang, B., Bottinger, E.P., Jakowlew, S.B., Transforming growth factor-?1 is a new form of tumor suppressor with true haploid insufficiency (1998) Nat Med, 4, pp. 802-807; Im, Y.H., Kim, H.T., Kim, I.Y., Heterozygous mice for the transforming growth factor-beta type II receptor gene have increased susceptibility to hepatocellular carcinogenesis (2001) Cancer Res, 61, pp. 6665-6668; Markowitz, S., Wang, J., Myeroff, L., Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability (1995) Science, 268, pp. 1336-1338; Garrigue-Antar, L., Munoz-Antonia, T., Antonia, S.J., Gesmonde, J., Vellucci, V.F., Reiss, M., Missense mutations of the transforming growth factor beta type II receptor in human head and neck squamous carcinoma cells (1995) Cancer Res, 55, pp. 3982-3987; Wang, D., Song, H.J., Evans, J.A., Lang, J.C., Schuller, D.E., Weghorst, C.M., Mutation and downregulation of the transforming growth factor beta type II receptor gene in primary squamous cell carcinomas of the head and neck (1997) Carcinogenesis, 18, pp. 2285-2290; Chen, T., Triplett, J., Dehner, B., Transforming growth factor-beta receptor type I gene is frequently mutated in ovarian carcinomas (2001) Cancer Res, 61, pp. 4679-4682; Wang, D., Kanuma, T., Mizunuma, H., Analysis of specific gene mutations in the transforming growth factor-beta signal transduction pathway in human ovarian cancer (2000) Cancer Res, 60, pp. 4507-4512; Wang, J., Sun, L., Myeroff, L., Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells (1995) J Biol Chem, 270, pp. 22044-22049; Sun, L., Wu, G., Willson, J.K., Expression of transforming growth factor beta type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells (1994) J Biol Chem, 269, pp. 26449-26455; Pierce Jr., D.F., Gorska, A.E., Chytil, A., Mammary tumor suppression by transforming growth factor beta 1 transgene expression (1995) Proc Natl Acad Sci U S A, 92, pp. 4254-4258; Cui, W., Fowlis, D.J., Bryson, S., TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice (1996) Cell, 86, pp. 531-542; Siegel, P.M., Shu, W., Cardiff, R.D., Muller, W.J., Massague, J., Transforming growth factor ? signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis (2003) Proc Natl Acad Sci U S A, 100, pp. 8430-8535; Pasche, B., Luo, Y., Rao, P.H., Type I transforming growth factor beta receptor maps to 9q22 and exhibits a polymorphism and a rare variant within a polyalanine tract (1998) Cancer Res, 58, pp. 2727-2732; Pasche, B., Kolachana, P., Nafa, K., T beta R-I (6A) is a candidate tumor susceptibility allele (1999) Cancer Res, 59, pp. 5678-5682; Baxter, S.W., Choong, D.Y., Eccles, D.M., Campbell, I.G., Transforming growth factor beta receptor 1 polyalanine polymorphism and exon 5 mutation analysis in breast and ovarian cancer (2002) Cancer Epidemiol Biomarkers Prev, 11, pp. 211-214; Kaklamani, V.G., Baddi, L., Liu, J., Combined genetic assessment of transforming growth factor-? signaling pathway variants may predict breast cancer risk (2005) Cancer Res, 65, pp. 3454-3461; Bian, Y., Caldes, T., Wijnen, J., TGFBR1*6A may contribute to hereditary colorectal cancer (2005) J Clin Oncol, 23, pp. 3074-3078; Kaklamani, V.G., Hou, N., Bian, Y., TGFBR1*6A and cancer risk: A meta-analysis of seven casecontrol studies (2003) J Clin Oncol, 21, pp. 3236-3243; Pasche, B., Kaklamani, V.G., Hou, N., TGFBR1*6A and Cancer: A Meta-Analysis of 12 Case-Control Studies (2004) J Clin Oncol, 22, pp. 756-758; Chen, T., De Vries, E.G., Hollema, H., Structural alterations of transforming growth factor-beta receptor genes in human cervical carcinoma (1999) Int J Cancer, 82, pp. 43-51; Knobloch, T.J., Lynch, M.A., Song, H., Analysis of TGF-beta type I receptor for mutations and polymorphisms in head and neck cancers (2001) Mutat Res, 479, pp. 131-139; Pasche, B., Bian, Y., Reich, J., Rademaker, A., Kolachana, P., Offit, K., T beta R-I(6A) association with colorectal cancer: A new twist? (2001) Cancer Res, 61, pp. 8351-8352, reply; Boland, C.R., Thibodeau, S.N., Hamilton, S.R., A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial pre-disposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer (1998) Cancer Res, 58, pp. 5248-5257; Umar, A., Boland, C.R., Terdiman, J.P., Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability (2004) J Natl Cancer Inst, 96, pp. 261-268; Edmonston, T.B., Cuesta, K.H., Burkholder, S., Colorectal carcinomas with high microsatellite instability: Defining a distinct immunologic and molecular entity with respect to prognostic markers (2000) Hum Pathol, 31, pp. 1506-1514; Ionov, Y., Peinado, M.A., Malkhosyan, S., Shibata, D., Perucho, M., Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis (1993) Nature, 363, pp. 558-561; Pasche, B., Mulcahy, M., Benson III, A.B., Molecular markers in prognosis of colorectal cancer and prediction of response to treatment (2002) Best Pract Res Clin Gastroenterol, 16, pp. 331-345; Kaklamani, V., Baddi, L., Rosman, D., No major association between TGFBR1*6A and prostate cancer (2004) BMC Genet, 5, p. 28; Kielman, M.F., Rindapaa, M., Gaspar, C., Apc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signaling (2002) Nat Genet, 32, pp. 594-605; Pihan, G., Doxsey, S.J., Mutations and aneuploidy. Co-conspirators in cancer? (2003) Cancer Cell, 4, pp. 89-94; Sonoda, G., Palazzo, J., Du Manoir, S., Comparative genomic hybridization detects frequent over-representation of chromosomal material from 3q26, 8q24, and 20q13 in human ovarian carcinomas (1997) Genes Chromosomes Cancer, 20, pp. 320-328; Canzian, F., Salovaara, R., Hemminki, A., Semi-automated assessment of loss of heterozygosity and replication error in tumors (1996) Cancer Res, 56, pp. 3331-3337; Altschul, S.F., Gish, W., Miller, W., Myers, E.W., Lipman, D.J., Basic local alignment search tool (1990) J Mol Biol, 215, pp. 403-410; Kozak, M., Regulation of translation in eukaryotic systems (1992) Annu Rev Cell Biol, 8, pp. 197-225; Wrana, J.L., Attisano, L., Wieser, R., Ventura, F., Massague, J., Mechanism of activation of the TGF-beta receptor (1994) Nature, 370, pp. 341-347; Nilsson, I., Johnson, A.E., Von Heijne, G., How hydrophobic is alanine? (2003) J Biol Chem., 278, pp. 29389-29393; Zhou, X.P., Hoang, J.M., Cottu, P., Thomas, G., Hamelin, R., Allelic profiles of mononucleotide repeat microsatellites in control individuals and in colorectal tumors with and without replication errors (1997) Oncogene, 15, pp. 1713-1718; Gierasch, L.M., Signal sequences (1989) Biochemistry, 28, pp. 923-930; Walter, P., Johnson, A.E., Signal sequence recognition and protein targeting to the endoplasmic reticulum membrane (1994) Annu Rev Cell Biol, 10, pp. 87-119; Franze?n, P., Ten Dijke, P., Ichijo, H., Yamashita, H., Schulz, P., Heldin, C.-H., Cloning of a TGF? type I receptor that forms a heteromeric complex with the TGF? type II receptor (1993) Cell, 75, pp. 681-692; Nielsen, H., Engelbrecht, J., Brunak, S., Von Heijne, G., Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites (1997) Protein Eng, 10, pp. 1-6; Von Heijne, G., Patterns of amino acids near signal-sequence cleavage sites (1983) Eur J Biochem, 133, pp. 17-21; Streisinger, G., Okada, Y., Emrich, J., Frame-shift mutations and the genetic code (1966) Cold Spring Harb Symp Quant Biol, 31, pp. 77-84; Bebenek, K., Kunkel, T.A., Streisinger revisited: DNA synthesis errors mediated by substrate misalignments (2000) Cold Spring Harb Symp Quant Biol, 65, pp. 81-91; Warren, S.T., Polyalanine expansion in synpolydactyly might result from unequal crossing-over of HOXD13 (1997) Science, 275, pp. 408-409; Friedman, E., Gold, L.I., Klimstra, D., Zeng, Z.S., Winawer, S., Cohen, A., High levels of transforming growth factor beta 1 correlate with disease progression in human colon cancer (1995) Cancer Epidemiol Biomarkers Prev, 4, pp. 549-554; Bellone, G., Carbone, A., Tibaudi, D., Differential expression of transforming growth factors-beta1, -beta2 and -beta3 in human colon carcinoma (2001) Eur J Cancer, 37, pp. 224-233; Iavarone, A., Massague, J., Repression of the CDK activator Cdc25a and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15 (1997) Nature, 387, pp. 417-422; Ko, Y., Banerji, S.S., Liu, Y., Expression of transforming growth factor-beta receptor type II and tumorigenicity in human breast adenocarcinoma MCF-7 cells (1998) J Cell Physiol, 176, pp. 424-434; Goggins, M., Shekher, M., Turnacioglu, K., Yeo, C.J., Hruban, R.H., Kern, S.E., Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas (1998) Cancer Res, 58, pp. 5329-5332; Wolfraim, L.A., Fernandez, T.M., Mamura, M., Loss of Smad3 in acute t-cell lymphoblastic leukemia (2004) N Engl J Med, 351, pp. 552-559.