Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers.

We previously demonstrated that mutational inactivation of transforming growth factor beta type II receptors (RIIs) is very common among the 13% of human colon cancers with microsatellite instability. These mutations principally cluster in the BAT-RII polyadenine sequence repeat. Among microsatellite stable (MSS) colon cancers, we now find that non-BAT-RII point mutations inactivate RII in another 15% of cases, thus doubling the known number of colon cancers in which RII mutations are pathogenetic. Functional analysis confirms that these mutations inactivate RII signaling. Moreover, another 55% of MSS colon cancers demonstrate a transforming growth factor beta signaling blockade distal to RII. The transforming growth factor beta pathway and RII in particular are major targets for inactivation in MSS colon cancers as well as in colon cancers with microsatellite instability.

[1]  J. Eshleman,et al.  Microsatellite instability in inherited and sporadic neoplasms. , 1995, Current opinion in oncology.

[2]  Scott E. Kern,et al.  Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers , 1996, Nature Genetics.

[3]  Anita B. Roberts,et al.  Tumor suppressor activity of the TGF-β pathway in human cancers , 1996 .

[4]  Jeffrey L. Wrana,et al.  TGFβ signals through a heteromeric protein kinase receptor complex , 1992, Cell.

[5]  H. Lodish,et al.  A dominant inhibitory mutant of the type II transforming growth factor beta receptor in the malignant progression of a cutaneous T-cell lymphoma , 1996, Molecular and cellular biology.

[6]  K. Kinzler,et al.  Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. , 1995, Science.

[7]  J. Graff,et al.  Smad3 Mutant Mice Develop Metastatic Colorectal Cancer , 1998, Cell.

[8]  Keunchil Park,et al.  Expression of Transforming Growth Factor β Type II Receptor Reduces Tumorigenicity in Human Gastric Cancer Cells , 1997 .

[9]  Irene L Andrulis,et al.  MADR2 Maps to 18q21 and Encodes a TGFβ–Regulated MAD–Related Protein That Is Functionally Mutated in Colorectal Carcinoma , 1996, Cell.

[10]  Luzhe Sun,et al.  Demonstration That Mutation of the Type II Transforming Growth Factor β Receptor Inactivates Its Tumor Suppressor Activity in Replication Error-positive Colon Carcinoma Cells (*) , 1995, The Journal of Biological Chemistry.

[11]  K. Kinzler,et al.  Frequency of Smad gene mutations in human cancers. , 1997, Cancer research.

[12]  Kathleen R. Cho,et al.  DPC4 gene in various tumor types. , 1996, Cancer research.

[13]  R. Derynck,et al.  TGF- receptor signaling , 1997 .

[14]  J. Yokota,et al.  Mutation analysis of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human colon cancer using genomic DNA and Intron primers , 1997, Oncogene.

[15]  J. Willson,et al.  Cell culture of human colon adenomas and carcinomas. , 1987, Cancer research.

[16]  J. Massagué,et al.  The TGF-β family and its composite receptors , 1994 .

[17]  Hiroyuki Miyoshi,et al.  Intestinal Tumorigenesis in Compound Mutant Mice of both Dpc4(Smad4) and Apc Genes , 1998, Cell.

[18]  K. Kinzler,et al.  Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. , 1995, Cancer research.

[19]  L. Myeroff,et al.  Mutation of the type II transforming growth factor-beta receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. , 1998, Cancer research.

[20]  L. Myeroff,et al.  A benign cultured colon adenoma bears three genetically altered colon cancer oncogenes, but progresses to tumorigenicity and transforming growth factor-beta independence without inactivating the p53 tumor suppressor gene. , 1994, The Journal of clinical investigation.

[21]  J. Massagué.  TGFβ Signaling: Receptors, Transducers, and Mad Proteins , 1996, Cell.

[22]  R. Weinberg,et al.  Expression cloning of the TGF-β type II receptor, a functional transmembrane serine/threonine kinase , 1992, Cell.

[23]  J. Eshleman,et al.  Both transforming growth factor-beta and substrate release are inducers of apoptosis in a human colon adenoma cell line. , 1995, Cancer research.

[24]  P. Hoodless,et al.  MADR2 Is a Substrate of the TGFβ Receptor and Its Phosphorylation Is Required for Nuclear Accumulation and Signaling , 1996, Cell.

[25]  Harold L. Moses,et al.  TGF-β stimulation and inhibition of cell proliferation: New mechanistic insights , 1990, Cell.

[26]  J. Eshleman,et al.  Mismatch repair defects in human carcinogenesis. , 1996, Human molecular genetics.

[27]  Kathleen R. Cho,et al.  A transforming growth factor beta receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. , 1995, Cancer research.