Gene

SMAD4

SMAD family member 4

Explore in graph →CI-GENE-00031381HGNC:6770 ENSG00000141646 NCBI 4089 CIViC Cancer geneApproved

Curated evidence

Clinical evidence (31)

CIViC items involving this gene, grouped by molecular profile and therapy, with native levels and directions. 50 items per page.

civicCuratedShowing 1–31 of 31 evidence items · levels, directions and significance as curated at the source; each row links to its CIViC record.

Therapy	Cancer	Type	Level	Direction · significance	Rating (1–5)	Status	Evidence	Source
BRAF V600E + ERBB2 Amplification + SMAD4 LOSS + TP53 V218EERBB2 TP53 BRAF SMAD41
Bevacizumab + Lapatinib +

Cohorts

Alteration frequency by cohort (146)

Frequency = cases affected / cases profiled within one cohort. Cohorts are never pooled.

cbioportalObserved146 cohort rows (showing 50, sorted by frequency) · frequency = affected / profiled, as published by each cohort; cohorts are not pooled. Hover a row badge for its release.

Cohort	Mapped cancer	Alteration	Affected (n)	Profiled (n)	Frequency (%)	Rank in cohort	Source
Cutaneous Squamous Cell Carcinoma (DFCI, Clin Cancer Res 2015) cscc_dfarber_2015	Skin Squamous Cell Carcinoma	Ssm

Literature

Linked publications (7)

25 per page, newest first.

pubmedPublishedShowing 1–7 of 7 publications · bibliographic data as recorded by PubMed; abstracts are not reproduced.

SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer.
· Clin Cancer Res · 2009 · PMID 19584151 · validated civic_curation pubmed
The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma.
· Clin Cancer Res · 2001 · PMID 11751510 · validated civic_curation pubmed
DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer.
· J Clin Oncol · 2009 · PMID 19273710 · validated civic_curation pubmed
SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer.
· Br J Cancer · 2002 · PMID 12237773 · validated civic_curation pubmed

CDKN2A Loss + CDKN2B Loss + KRAS G12D + KRAS G12R + SMAD4 Deletion + TP53 R267WKRAS TP53 CDKN2A CDKN2B SMAD41
Bevacizumab + Palbociclib + TrametinibCombination	Malignant Pancreatic Neoplasm	Predictive	C	Supports Sensitivity Response	3	submitted	EID11711 In this clinical trial, 18 patients with pancreatic cancer were recruited. In this case, the patient (63 y/F) with pancreatic cancer harboring, CDKN2A exons 1-2 loss, CDKN2B loss, KRAS G12D, KRAS G12R… (full text at CIViC) PMID 36670111 · Shaya et al., 2023 · Open in CIViC	civic

CDKN2A Loss + CDKN2B Loss + KRAS G12D + KRAS G12R + SMAD4 Deletion + TP53 R267WKRAS TP53 CDKN2A CDKN2B SMAD41

Bevacizumab + Palbociclib + TrametinibCombination

Malignant Pancreatic Neoplasm

Predictive

Supports Sensitivity Response

submitted

EID11711

In this clinical trial, 18 patients with pancreatic cancer were recruited. In this case, the patient (63 y/F) with pancreatic cancer harboring, CDKN2A exons 1-2 loss, CDKN2B loss, KRAS G12D, KRAS G12R… (full text at CIViC)

PMID 36670111 · Shaya et al., 2023 · Open in CIViC

SMAD4 Expression2
(prognostic)	Pancreatic Ductal Adenocarcinoma	Prognostic	B	Supports Better Outcome	3	accepted	EID1306 In 249 patients that have undergone a pancreaticoduodenectomy (Whipple) for the resection of pancreatic ductal adenocarcinoma, expression of SMAD4 is associated with favorable prognosis. SMAD4 was ass… (full text at CIViC) PMID 11751510 · Tascilar et al., 2001 · Open in CIViC	civic
〃	Malignant Pancreatic Neoplasm	Prognostic	C	Supports N/A	3	submitted	EID7179 One of the goals in this study was to examine the correlation between Smad4 expression, detected by immunostaining, and the pattern of disease progression in pancreatic adenocarcinoma. Eleven of 15 (7… (full text at CIViC) PMID 21709185 · Crane et al., 2011 · Open in CIViC	civic

SMAD4 LOSS2
(prognostic)	Malignant Prostate Neoplasm	Prognostic	B	Supports Poor Outcome	4	submitted	EID6452 One of the goals of this study was to find the local failure rates in tumors for patients with Prostate Cancer. The failure rates for the first and second year for patients who lost SMAD4 expression w… (full text at CIViC) PMID 29329157 · Herman et al., 2018 · Open in CIViC	civic
〃	Malignant Pancreatic Neoplasm	Prognostic	B	Supports Poor Outcome	3	accepted	EID1412 Study employed a rapid autopsy technique on a cohort of 76 patients with pancreatic cancer and explored the status of several genes. 63% (41/65) of carcinomas analyzed showed inactivation of SMAD4 (DP… (full text at CIViC) PMID 19273710 · Iacobuzio-Donahue et al., 2009 · Open in CIViC	civic

SMAD4 Mutation4
(prognostic)	Pancreatic Adenocarcinoma	Prognostic	B	Supports Poor Outcome	3	accepted	EID511 In a study of 89 patients with adenocarcinoma of the pancreas who underwent a pancreaticoduodenectomy, those with mutations in SMAD4 had shorter overall survival than wild-type patients. PMID 19584151 · Blackford et al., 2009 · Open in CIViC	civic
〃	Malignant Colorectal NeoplasmCURATED_BROADER	Prognostic	B	Supports Poor Outcome	3	submitted	EID6451 Sequence analysis between normal vs. tumor samples showed the presence of 4 missense mutations and a somatic 12–base pair deletion in 16% of the 31 colorectal cancer (CRC) patients. The results of thi… (full text at CIViC) PMID 8898652 · Takagi et al., 1996 · Open in CIViC	civic
Cetuximab + PanitumumabSubstitutes	Malignant Colorectal NeoplasmCURATED_BROADER	Predictive	B	Supports Resistance	2	accepted	EID719 In a retrospective analysis of 65 patients with metastatic colorectal cancer, SMAD4 mutations were more common among patients with no benefit from EGFR-inhibition (cetuximab or panitumumab) (4 patient… (full text at CIViC) PMID 26508446 · Lupini et al., 2015 · Open in CIViC	civic
Regorafenib	Malignant Colorectal NeoplasmCURATED_BROADER	Predictive	B	Supports Reduced Sensitivity	2	submitted	EID13265 In a retrospective cohort of 76 patients with metastatic colorectal cancer treated with regorafenib monotherapy, SMAD4 mutations were identified in ~14% of the 76 patients. Patients with SMAD4-mutant … (full text at CIViC) PMID 33224274 · Lee et al., 2020 · Open in CIViC	civic

SMAD4 R361C3
(predisposing)	Juvenile Polyposis SyndromeUNRESOLVED	Predisposing	C	Supports Predisposition	1	accepted	EID6446 The goal of this study was to find out if there was a link between the mutation of SMAD4 and Juvenile polyposis syndrome (JPS). Eight families of JPS were analyzed and there was no evidence of linkage… (full text at CIViC) PMID 9811934 · Houlston et al., 1998 · Open in CIViC	civic
(functional)	—UNRESOLVED	Functional	D	Supports Loss Of Function	3	submitted	EID7680 Constructs containing SMAD4 mutations were introduced into MDA-MB468, a breast adenocarcinoma cell line with homozygous loss of SMAD4 and insensitivity to TGF-beta. A TGF-beta responsive luciferase re… (full text at CIViC) PMID 14647410 · Kuang et al., 2004 · Open in CIViC	civic
〃	—UNRESOLVED	Functional	D	Supports Loss Of Function	3	submitted	EID9713 A luciferase reporter gene with SMAD binding elements was transfected into the HT-29 cell line, which lacks a functional SMAD4 gene due to a nonsense mutation. HT-29 cells expressing R361C mutated SMA… (full text at CIViC) PMID 26488212 · Yoshioka et al., 2015 · Open in CIViC	civic