SMAD4, SMAD family member 4, is one of eight SMAD proteins in the human genome (Massague 1998). SMAD4 is sometimes referred to as DPC4 (Hahn et al. 1996). SMAD4 is a signal transduction protein that is the central mediator for downstream transcriptional output in the TGF-β family signaling pathways via its interaction with upstream receptors and fellow SMAD transcription factors (Goustin et al. 1986; Tucker et al. 1984a; Tucker et al. 1984b). The TGF-β pathway plays a complex role in cancer development, progression, and metastasis (Bierie and Moses 2006; Elliott and Blobe 2005; Massague 2008; Miyaki and Kuroki 2003).
SMAD4 consists of two domains connected by a linker region (Shi and Massague 2003). MAD homology domain 1 (MH1) is the N-terminal, DNA-binding domain (NCBI Gene Database). MAD homology domain 2 (MH2) is the C-terminal domain that interacts with upstream receptors and mediates oligomerization and transactivation to provide specificity and selectivity (NCBI Gene Database). Smad4 is made up of 11 coding exons.
Mutations in SMAD4 are involved in several hereditary syndromes with cancer predisposition, including juvenile polyposis syndrome and hemorrhagic hereditary telangiectasia (HHT) syndrome. SMAD4 loss or mutation is also seen in approximately 50% of pancreatic tumors and in 10–35% of invasive CRC (Elliott and Blobe 2005; Hahn et al. 1996; Miyaki et al. 1999). The MH2, C-terminal domain of SMAD4 is the target of tumorigenic inactivation, and mutations in this region disrupt RSMAD oligomerization, which interrupts normal signaling pathways (Shi et al. 1997; Shi and Massague 2003).
Last Updated: June 1, 2012
In CRC, loss of SMAD4 has been historically thought to be a late event in tumor development with rates of SMAD4 loss of 0%, 8%, 6%, and 22% in stages I-IV CRC, respectively (Maitra et al. 2000). However, downregulation of SMAD4 is associated with worse survival in stages I–II colon cancer patients (Mesker et al. 2009). Loss of SMAD4 protein expression evaluated by immunohistochemistry in stage III (lymph node positive disease) is associated with worse overall and disease-free survival (Alazzouzi et al. 2005). Low SMAD4 expression may also identify a subset of patients with early recurrence after curative therapy (Ahn et al. 2011).
SMAD4 mutations or loss of expression may portend a worse prognosis in patients with resected colorectal cancer. In a retrospective analysis of molecular markers in tumors from patients treated on two adjuvant trials (E2284 and INT 0035) for resected stage III or high risk stage II colon cancer, patients with tumors containing 18q LOH (SMAD4 resides on 18q) had significantly worse disease-free survival than patients with tumors retaining both 18q alleles (Watanabe et al. 2001). However, a retrospective analysis of 2 other adjuvant colon trials (CALGB 9581 and CALGB 89803) for stage II and III resected colon cancer did not show that 18q LOH was prognostic for survival (Bertagnolli et al. 2011). E5202 was designed to prospectively investigate the impact of several molecular markers, including loss of heterozygosity (LOH) of chromosome 18q on recurrence in stage II CRC (NCT00217737). This trial was terminated early, and results from the trial have not yet been reported.
Last Updated: June 1, 2012
|Location of mutation||MH2 domain|
|Frequency of SMAD4 mutations in colorectal cancer||~10–35% (COSMIC; De Bosscher, Hill, and Nicolas 2004; Koyama et al. 1999; Miyaki and Kuroki 2003; Takagi et al. 1996)|
|Frequency of D351H mutations among SMAD4 mutant colorectal cancers||~3% (COSMIC)|
|Implications for Targeted Therapeutics|
|Response to EGFR TKIs||Unknown at this time|
|Response to anti-EGFR antibodies||Unknown at this time|
|Response to BRAF inhibitors||Unknown at this time|
|Response to MEK inhibitors||Unknown at this time|
H351 in SMAD4 occurs in the loop-helix region, and disruption prevents formation of a homotrimer and is required for complex formation of activated SMADs 2 and 3 (De Bosscher, Hill, and Nicolas 2004). The D351H mutation results in an amino acid substitution at position 351 in SMAD4, from an aspartic acid (D) to a histidine (H) yielding a non-functional SMAD4. This mutation occurs within the MH2 domain (Figure 1).
Figure 1. Schematic of SMAD4 D351H mutation. Functional domains of SMAD4 are depicted. MH1: MAD homology 1, a DNA-binding domain of the protein. Linker: a flexible, proline-rich section of the protein linking MH1 with MH2. MH2: MAD homology 2, the SMAD-SMAD interaction and transcription activation domain of the protein. (De Bosscher, Hill, and Nicolas 2004; Massague and Wotton 2000)
Last Updated: July 19, 2012
Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.
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