Structural alterations of transforming growth factor-? receptor genes in human cervical carcinoma

Abstract

The development and progression of invasive uterine cervical carcinomas appear to be associated with the progressive loss of sensitivity to transforming growth factor‐β (TGFβ)‐mediated cell cycle arrest. In order to identify possible molecular mechanisms responsible for TGFβ resistance, we screened the 7 exons of the type II (TβR‐II) TGFβ receptor and the 9 exons of the type I (TβR‐I) TGFβ receptor genes for mutations in 16 paraffin‐embedded primary invasive cervical carcinoma specimens. In one of these carcinomas, we found a novel G→T transversion in exon 3 of TβR‐II that introduces a premature stop codon (E142Stop) and presumably results in the synthesis of a truncated soluble exoreceptor. In one tumor, a silent A→C transversion mutation that may affect mRNA splicing was present in exon 6 of TβR‐I. In addition, 7 of 16 cases were heterozygous for a G→A polymorphism in intron 7 of TβR‐I. Finally, we identified a 9 base pair in‐frame germline deletion in exon 1 of TβR‐I resulting in loss of 3 of 9 sequential alanine residues at the N‐terminus in 6 of 16 cases. Analysis of specimens from case‐control studies indicated that carriers of this del(GGC)3 TβR‐I variant allele may be at a increased risk for the development of cervical carcinoma (p=0.22). Furthermore, the response of cells expressing the variant receptor to TGFβ was diminished. Our results support the notion that diverse alterations in the TGFβ signaling pathway may play a role in the development of cervical cancer. Int. J. Cancer 82:43–51, 1999. © 1999 Wiley‐Liss, Inc.

An intronic variant of the TGFBR1 gene is associated with carcinomas of the kidney and bladder

“…16 Previously, we identified several novel mutations and genetic variants in the TGFBR1 gene among cancers of the breast, cervix, head/neck and ovary. [17][18][19][20] Taken together, these studies provide strong support for the indispensable role played by the molecular inactivation of TGF-␤ signaling in malignant transformation and implicate TGF-␤ signaling perturbation in human malignancies.…”

“…16 Previously, we identified several novel mutations and genetic variants in the TGFBR1 gene among cancers of the breast, cervix, head/neck and ovary. [17][18][19][20] Taken together, these studies provide strong support for the indispensable role played by the molecular inactivation of TGF-␤ signaling in malignant transformation and implicate TGF-␤ signaling perturbation in human malignancies.To determine whether genetic alterations of TGFBR1 are linked to carcinomas of the human kidney and bladder, we evaluated 151 cases of urinary system carcinoma for somatic or germline mutations of the TGFBR1 gene. We show that somatic mutations of TGFBR1 in patients with cancers of the urinary system were rare, with only one somatic mutation identified in a patient with upper urinary tract TCC.…”

“…18 This genetic variant is located in intron 7 of the TGFBR1 gene, 24 bp downstream of the boundary of exon/intron 7 (Fig. 1a).…”

“…17,18,20 It is important to determine whether genetic alterations of TGFBR1 are involved in carcinogenesis of the human kidney and bladder as well. Though somatic mutation of the coding region was infrequent, our data revealed a significant association linking the presence of the Int7G24A variant with RCC and TCC.…”

Expression of Smad2 and Smad4 in cervical cancer: absent nuclear Smad4 expression correlates with poor survival

“…1 Although a number of studies have investigated the expression status and alterations in the canonical TGF-b signaling (Smad) pathway, the role of Smad signaling in the progression of cervical cancer remains unclear. 3,10,11,24 In this study, we investigated whether decreased Smad2 and Smad4 protein expression in primary cervical cancers was associated with molecular alterations at 18q21.1, mutations in the functional domains of Smad2 and Smad4 or hypermethylation, and we assessed the biological relevance of decreased Smad2 and Smad4 expression.…”