Among 5 HNPCC families without microsatellite instability, Lu et al. (1998) found a germline missense mutation in the TGFBR2 gene in 1 family. The proband and her 2 brothers had colorectal cancers complying with the clinical criteria A ... Among 5 HNPCC families without microsatellite instability, Lu et al. (1998) found a germline missense mutation in the TGFBR2 gene in 1 family. The proband and her 2 brothers had colorectal cancers complying with the clinical criteria A of HNPCC, but the onset of cancer was beyond 50 years of age in all cases (80 in the case of the proband and 65 and 60 in her 2 brothers, respectively), which did not satisfy the Amsterdam criteria. Unlike patients with typical HNPCC, affected members of this family lacked multiple synchronous, metachronous colorectal cancers and extracolonic cancers.
In the family of Lu et al. (1998) in which HNPCC was associated with germline mutation of the TGFBR2 gene (T315M; 190182.0002), loss of wildtype fragments was observed in the tumor of the proband. It was unknown whether ... In the family of Lu et al. (1998) in which HNPCC was associated with germline mutation of the TGFBR2 gene (T315M; 190182.0002), loss of wildtype fragments was observed in the tumor of the proband. It was unknown whether the affected brothers of the proband also carried the variant because tumor tissue samples from them were unavailable. The variant was present in 2 of the proband's 6 children, but they had not developed cancer. Functional assays demonstrated that the mutant TGFBR2 protein could not restore growth inhibition in response to TGF-beta (190180). The tumor of the proband exhibited loss of heterozygosity in chromosomes 5q, 17p, and 18q without alteration in 10 microsatellite loci, MLH1 (120436), MSH2 (609309), MSH3 (600887), or at the TGFBR2 (A)10 repeat sequence. Coupled with the lack of multiple synchronous, metachronous colorectal cancers or extracolonic cancers in this family, these data showed that the tumorigenic pathway in this kindred is different from the mutator pathway in typical HNPCC tumorigenesis. Somatic mutation in the TGFBR2 gene has been found in HNPCC (e.g., Markowitz et al. (1995), 190182.0001; Grady et al. (1999), 190182.0011).