Reduced Expression of SMAD4 Is Associated with Poor Survival in Colon Cancer

Yan, Ping; Klingbiel, Dirk; Saridaki, Zenia; Ceppa, Paola; Curto, Monica; Mckee, Thomas Alexander; Roth, Arnaud; Tejpar, Sabine; Delorenzi, Mauro; Bosman, F.; Fiocca, Roberto

doi:10.1158/1078-0432.ccr-15-0939

Cited by 61 publications

(76 citation statements)

References 56 publications

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“…When SMAD4 function is lost, due to either inactivating mutations or homozygous deletion of SMAD4 (DPC4) , the subsequent abrogation of signalling in the TGF‐β pathway leads to disruption of the transcription of genes involved in cell cycle control and apoptosis . Mutations and deletions of SMAD4 have been most commonly documented in pancreatic, biliary and colonic adenocarcinomas, with corresponding loss of SMAD4 protein expression reported in approximately 50% of pancreatic adenocarcinomas and 25% of biliary and colonic adenocarcinomas . SMAD4 dysfunction is relatively infrequent in other adenocarcinomas .…”

Section: Introductionmentioning

confidence: 99%

Loss of SMAD4 protein expression in gastrointestinal and extra‐gastrointestinal carcinomas

Ritterhouse

Kim

et al. 2019

Histopathology

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Aims SMAD4 (DPC4) is a tumour suppressor gene that is dysregulated in various tumour types, particularly pancreaticobiliary and gastrointestinal carcinomas. Corresponding loss of protein expression has been reported in approximately 50% of pancreatic and 25% of colonic adenocarcinomas. In the evaluation of carcinoma of unknown primary site, immunohistochemical loss of SMAD4 expression is often used to suggest pancreaticobiliary origin, but there are limited data on the spectrum of SMAD4 expression in carcinomas of other sites. This study evaluates the frequency of SMAD4 loss in a large cohort of carcinomas from diverse anatomical sites. Methods and results Immunohistochemistry for SMAD4 was performed on tissue microarrays or whole tissue sections of 1210 carcinomas from various organs: gastrointestinal tract, liver, pancreas/biliary tract, lung, breast, thyroid, kidney, ovary and uterus. Expression was considered lost when there was complete absence of staining in tumour cell nuclei, in the presence of intact staining in non‐neoplastic cells. SMAD4 loss was seen in 58% of pancreatic adenocarcinomas, 27% of appendiceal adenocarcinomas, 19% of colorectal adenocarcinomas, 16% of cholangiocarcinomas, 10% of lung adenocarcinomas and <5% of oesophageal, breast, gastric and mucinous ovarian adenocarcinomas. All papillary thyroid, hepatocellular, non‐mucinous ovarian, endometrial and renal cell carcinomas showed intact SMAD4 nuclear expression. Conclusion In addition to pancreaticobiliary, appendiceal and colonic tumours, SMAD4 loss is also seen in a small subset of other carcinomas, specifically breast, lung, oesophageal and gastric adenocarcinomas, all of which are typically CK7‐positive, similar to pancreaticobiliary carcinoma. Awareness of SMAD4 loss in these other carcinoma types is helpful in the evaluation of carcinomas of unknown or uncertain primary site.

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Section: Introductionmentioning

confidence: 99%

Loss of SMAD4 protein expression in gastrointestinal and extra‐gastrointestinal carcinomas

Ritterhouse

Kim

et al. 2019

Histopathology

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“…Supporting this concept, the formation and subsequent progression of various solid malignancies was strongly associated with loss of SMAD4 activity via inactivating mutations or loss of heterozygosity within the 18q21 locus, containing SMAD4 (19–22). For example, loss of SMAD4 promotes pancreatic and colorectal tumor progression and is strongly associated with increased metastatic potential, lower overall survival and poor chemotherapeutic responses (23–25). Likewise, loss of SMAD4 activity was reported to cause spontaneous HNSCC formation, to induce epithelial-to-mesenchymal transition (EMT) and cetuximab resistance, and to result in genomic instability through the downregulation of DNA repair-related genes (18, 26, 27).…”

Section: Introductionmentioning

confidence: 99%

SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells

Ozawa

Ranaweera

Izumchenko

et al. 2017

Clinical Cancer Research

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Purpose We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC. Experimental Design SMAD4 expression was assessed by immunohistochemistry in 130 newly diagnosed and 43 recurrent HNSCC patients. Correlative statistical analysis with clinicopathological data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivo. Results Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of pro-survival and anti-apoptotic pathways that were commonly dysregulated in SMAD4-low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in a HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo. We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss. Conclusions Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors.

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“…The association between survival and SMAD4 loss in CLM patients has been described in patients undergoing resection, but its importance in patients undergoing liver‐directed chemotherapy (eg, HAI) and systemic therapy has not been previously reported. SMAD4 is a central mediator of TGF‐β signaling whose alteration is observed in 15%‐20% of sporadic CRC cases and correlates with poor overall and disease‐free survival, regardless of tumor stage . SMAD4 is an important transcription factor that regulates cell proliferation, differentiation, migration, and apoptosis .…”

Section: Discussionmentioning

confidence: 99%

Genomic stratification beyond Ras/B‐Raf in colorectal liver metastasis patients treated with hepatic arterial infusion

Smith¹,

Chatila²,

Sánchez-Vega³

et al. 2019

Cancer Medicine

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BackgroundResection of colorectal liver metastases (CLM) can cure disease, but many patients with extensive disease cannot be fully resected and others recur following surgery. Hepatic arterial infusion (HAI) chemotherapy can convert extensive liver disease to a resectable state or decrease recurrence risk, but response varies and no biomarkers currently exist to identify patients most likely to benefit.MethodsWe performed a retrospective cohort study of CLM patients receiving HAI chemotherapy whose tumors underwent MSK‐IMPACT sequencing. The frequency of oncogenic alterations and their association with overall survival (OS) and objective response rate were analyzed at the individual gene and signaling pathway levels.ResultsThree hundred and seventy patients met inclusion criteria: 189 (51.1%) who underwent colorectal liver metastasectomy followed by HAI + systemic therapy (Adjuvant cohort), and 181 (48.9%) with unresectable CLM (Metastatic cohort) who received HAI + systemic therapy, consisting of 63 (34.8%) with extrahepatic disease and 118 (65.2%) with liver‐restricted disease. Genomic alterations were similar in each cohort, and no individual gene or pathway was significantly associated with objective response. Patients in the adjuvant cohort with concurrent Ras/B‐Raf alteration and SMAD4 inactivation had worse prognosis while in the metastatic cohort patients with co‐alteration of Ras/B‐Raf and TP53 had worse OS. Similar findings were observed in a validation cohort.ConclusionsConcurrently altered Ras/B‐Raf and SMAD4 mutations were associated with worse survival in resectable patients, while concurrent Ras/B‐Raf and TP53 alterations were associated with worse survival in unresectable patients. The mutual exclusivity of Ras/B‐Raf, SMAD4, and TP53 may have prognostic value for CLM patients receiving HAI.

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Reduced Expression of SMAD4 Is Associated with Poor Survival in Colon Cancer

Cited by 61 publications

References 56 publications

Loss of SMAD4 protein expression in gastrointestinal and extra‐gastrointestinal carcinomas

Loss of SMAD4 protein expression in gastrointestinal and extra‐gastrointestinal carcinomas

SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells

Genomic stratification beyond Ras/B‐Raf in colorectal liver metastasis patients treated with hepatic arterial infusion

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