Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members  SMAD4. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. Somatic SMAD4 mutations have been reported to be more common in advanced stages of CRCs and LOH at the SMAD4 locus has been associated with poor prognosis. SMAD4 mutations were associated with mucinous histology.

SMAD4 is a tumor suppressor gene that is mutated in one third of colorectal cancer and half of pancreatic tumors. SMAD4 inactivation by allelic deletion or mutation mainly occurs in late stage pancreatic ductal adenocarcinoma and is associated with poorer prognosis. SMAD4 loss increased resistance to the chemotherapeutic agent 5'-fluorouracil.

Homozygous mutations causing SMAD4 loss are found in approximately 3% of lung adenocarcinomas and squamous cell carcinomas cases. SMAD4 loss tends to act synergistically with TP53 and KRAS mutations to increase lymphatic metastasis and tumor size. Experimental work in a mouse model has demonstrated increased susceptibility to DNA topoisomerase inhibitors with homozygous SMAD4 loss of function mutation coupled with KRAS G12D activating mutations.

Smad4 is tumor suppressor gene and is crucial for thyroid development and function. It is key component of the transforming growth factor beta (TGFB) pathway which regulates the expression of thyroid-specific genes. The role of SMAD4 in thyroid tumorigenesis remains unclear. However, mutations affecting the coding region of the SMAD4 gene have been detected in some sporadic thyroid neoplasms. Studies that analyzed expression of SMAD4 in thyroid tumors gave contradictory results. Some studies showed that the expression of SMAD4 was reduced in thyroid cancer cells. Other studies indicated that it was expressed and present in the nucleus in all thyroid cell lines and controls analyzed, indicating propagation of TGFB signaling in thyroid tumors. Of note, a SMAD4 mutation C324Y, recently isolated from nodal metastases of papillary thyroid carcinoma (PTC), was confirmed to cause an increase in TGFB signaling and lead to the acquisition of transformed phenotype and invasive behavior in thyroid cells, enabling them to proliferate independently from thyroid-stimulating hormone.

SMAD4 is tumor suppressor gene and it encodes an intracellular mediator in the transforming growth factor β (TGF β) signal transduction pathway. Somatic mutations affecting the SMAD4 gene are rare in breast neoplasms and their role in breast tumorigenesis remains unclear. However, it has been demonstrated that SMAD4 protein expression is markedly downregulated or lost in breast ductal carcinoma when compared with that in the normal breast epithelium. Loss of SMAD4 protein expression may play a role in disease progression and overall prognosis in breast cancer patients but this need to be fully elucidated.

SMAD4 is a tumor suppressor gene and it encodes an intracellular mediator in the transforming growth factor β (TGF β) signal transduction pathway. The gene is inactivated in 40% of human gastric cancers by loss of heterozygosity, promoter hypermethylation, and somatic mutation. Prior sequencing studies have shown that SMAD4 is mutated in up to 8% of gastric cancers. SMAD4 p.R361H mutation occurs within the MH2 domain which is the SMAD-SMAD interaction and transcription activation domain of the protein. The loss of SMAD4, especially loss of nuclear SMAD4 expression, is involved in gastric cancer progression. Mutations at codon 361 have been previously reported in various tumor types. The exact clinical significance of this mutation in gastric cancers needs to be fully elucidated.

SMAD4 is a tumor suppressor gene encoding an intracellular mediator in the transforming growth factor β (TGF β) signal transduction pathway. SMAD4 mutations have been observed in ~3% of cervical cancers. Functional inactivation of SMAD4 was found in 4 of 13 cervical squamous cancer cell lines, mostly due to homozygous loss. Loss of protein expression did not correlate with loss of heterozygosity and mutations in cervical squamous carcinomas; however, it was associated with poor disease-free and overall 5-year survival in one study. The predictive and prognostic significance of SMAD4 mutations in cervical cancers needs further elucidation. Results should be interpreted in conjunction with other laboratory and clinical findings.

SMAD4 is a tumor suppressor gene encoding an intracellular mediator in the transforming growth factor β (TGF β) signal transduction pathway. SMAD4 mutations have been reported in up to 2% of urothelial carcinomas. The predictive and prognostic significance of SMAD4 mutations in urothelial carcinoma needs further elucidation. Results should be interpreted in conjunction with other laboratory and clinical findings.

This gene is a known cancer gene.

This gene is a known cancer gene.

SMAD4 is tumor suppressor gene and it encodes an intracellular mediator in the transforming growth factor b (TGF b) signal transduction pathway. Somatic mutations in SMAD4 are exceedingly rare in glial neoplasms. SMAD4 I525V has been reported as a likely benign germline variant in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/41788/). These results should be interpreted in the clinical context.

Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members SMAD4. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. SMAD4 R361C lies at a hotspot residue within MH2 domain and has displayed reduced SMAD4 transactivating activity in cell assays. Somatic SMAD4 mutations have been reported to be more common in advanced stages of CRCs. Studies of loss of function somatic mutations and studies of loss of heterozygosity (LOH) at the SMAD4 locus have shown an association with poor prognosis. SMAD4 mutations were also associated with mucinous histology. There are ongoing clinical trials for colorectal tumors harboring SMAD4 alterations.

SMAD4 is a tumor suppressor gene and it encodes an intracellular mediator in the transforming growth factor b (TGF b) signal transduction pathway. SMAD4 mutations are very rare in glioblastoma and are present in less than 1% of cases and the significance of these mutations are unclear in this tumor type. The effect on protein function of SMAD4 P472T remains to be further elucidated. These results should be interpreted in the clinicopathologic context.

SMAD4 encodes a tumor suppressor and transcription factor that is a downstream effector in the TGF-ss signal transduction pathway. Germline mutations in SMAD4 have been associated with juvenile polyposis syndrome. SMAD4 is mutated in one third of colorectal cancer and half of pancreatic tumors. Genetic alterations in SMAD4 have been identified in 33% of pancreatic adenocarcinomas. SMAD4 inactivation by allelic deletion or mutation mainly occurs in late stage pancreatic ductal adenocarcinoma and is associated with poorer prognosis. SMAD4 D351G lies at a hotspot residue within the MH2 domain of the Smad4 protein (UniProt.org). D351G has been identified in sequencing studies, but has not been biochemically characterized and therefore, its effect on Smad4 protein function is unknown. The SMAD4 D351H variant has been described in human colorectal cancer cell lines and reported as likely oncogenic, suggesting that the D351G variant is also likely to be oncogenic. SMAD4 loss has been found to increase resistance to the chemotherapeutic agent 5'-fluorouracil.

SMAD4 encodes a tumor suppressor and transcription factor that is a downstream effector in the TGF-ss signal transduction pathway. Germline mutations in SMAD4 have been associated with juvenile polyposis syndrome (JPS). Loss of SMAD4 expression or somatic mutations in SMAD4 are found in pancreatic cancer and are associated with tumor grade. Somatic alterations in SMAD4 are observed at lower frequencies in multiple tumor types, including colon and lung adenocarcinoma. SMAD4 R361C lies at a hotspot residue within MH2 domain of the Smad4 protein (UniProt.org). R361C confers a loss of function to the Smad4 protein as demonstrated by reduced Smad4 transactivating activity in cell assays. The SMAD4 R361C mutation is likely oncogenic. Studies of loss of function somatic mutations and studies of loss of heterozygosity (LOH) at the SMAD4 locus have shown an association with poor prognosis. There are ongoing clinical trials for colorectal tumors harboring SMAD4 alterations.

SMAD4 is a transcription factor that functions as a critical effector in the transforming growth factor beta (TGFss) signal pathway that controls cellular proliferation, differentiation and tissue homeostasis. The TGFss pathway suppresses tumorigenesis in premalignant states and promotes invasiveness and metastasis during cancer progression. Germline mutations in SMAD4 have been associated with juvenile polyposis syndrome (JPS). Somatic alterations in SMAD4 are in multiple tumor types, including colon and lung adenocarcinoma. SMAD4 inactivation by allelic deletion or mutation mainly occurs in late stage pancreatic ductal adenocarcinoma and is associated with poorer prognosis. SMAD4 loss increased resistance to the chemotherapeutic agent 5'-fluorouracil. The identified deletion is not characterized but is present at a site of frequent mutations and is potentially oncogenic. The role of SMAD4 variants in small intestinal adenocarcinomas need further characterization. Clinical correlation is recommended.

Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members SMAD4. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. Somatic SMAD4 mutations have been reported to be more common in advanced stages of CRCs and LOH at the SMAD4 locus has been associated with poor prognosis. SMAD4 mutations were associated with mucinous histology. SMAD4 P356L has been identified in tumors. Although it has not been biochemically characterized, it is a statistically significant hotspot and is predicted to be oncogenic.