Smad4 inactivation predicts for worse prognosis and response to fluorouracil-based treatment in colorectal cancer

Kozak, Margaret M.; Eyben, Rie von; Pai, Jonathan; Vossler, S.R.; Limaye, Maneesha; Jayachandran, Priya; Anderson, Eric M.; Shaffer, J.; Longacre, Teri A.; Pai, Reetesh K.; Koong, Albert C.; Chang, Daniel T.

doi:10.1136/jclinpath-2014-202660

Cited by 39 publications

(42 citation statements)

References 19 publications

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“…Loss of SMAD4 in CRC tumors appears to induce resistance to 5FU-based therapy through regulation of a downstream apoptotic pathway and upregulation of PI3K/Akt and VEGF [14, 79, 81]. These findings were validated in other retrospective studies [81]. Thus, tumors with SMAD4 LOH may benefit from adjuvant treatment with non-5FU based regimens.…”

Section: Discussionmentioning

confidence: 89%

Prognostic value of loss of heterozygosity and sub-cellular localization of SMAD4 varies with tumor stage in colorectal cancer

et al. 2017

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BackgroundAlthough loss of heterozygosity (LOH) at chromosome location 18q21 and decreased expression of SMAD4 in invasive colorectal cancers (CRCs) correlate with poor patient survival, the prognostic value of LOH at 18q21 and sub-cellular localization of SMAD4 have not been evaluated in relation to tumor stage.MethodsGenomic DNA samples from 209 formalin-fixed, paraffin-embedded sporadic CRC tissues and their matching controls were analyzed for 18q21 LOH, and corresponding tissue sections were evaluated by immunohistochemistry for expression of SMAD4 and assessed for its sub-cellular localization (nuclear vs. cytoplasmic). In addition, 53 frozen CRCs and their matching control tissues were analyzed for their mutational status and mRNA expression of SMAD4. The phenotypic expression pattern and LOH status were evaluated for correlation with patient survival by the use of Kaplan-Meier and Cox regression models.ResultsLOH of 18q21 was detected in 61% of the informative cases. In 8% of the cases, missense point mutations were detected in Smad4. In CRCs, relative to controls, there was increased SMAD4 staining in the cytoplasm (74%) and decreased staining in the nuclei (37%). LOH of 18q21 and high cytoplasmic localization of SMAD4 were associated with shortened overall survival of Stage II patients, whereas low nuclear expression of SMAD4 was associated with worse survival, but only for patients with Stage III CRCs.ConclusionsLOH of 18q21 and high cytoplasmic localization of SMAD4 in Stage II CRCs and low nuclear SMAD4 in Stage III CRCs are predictors of shortened patient survival.

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Section: Discussionmentioning

confidence: 89%

Prognostic value of loss of heterozygosity and sub-cellular localization of SMAD4 varies with tumor stage in colorectal cancer

et al. 2017

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“…Clinically, the genetic alterations associated with mucinous histology bear practical relevance: BRAF V600E is associated with a poor prognosis(23) and may also predict cetuximab resistance(24); PIK3CA mutations appear to be predictive of a benefit from aspirin;(25, 26) SMAD4 mutations have been shown to be an adverse prognostic marker. (27) As such, the mucinous histology may serve as a readily identifiable feature that can facilitate the efficient recognition of these molecularly important tumor subsets.…”

Section: Discussionmentioning

confidence: 99%

Morphological characterization of colorectal cancers in The Cancer Genome Atlas reveals distinct morphology–molecular associations: clinical and biological implications

et al. 2017

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The-Cancer-Genome-Atlas data on colorectal carcinoma have provided a comprehensive view of the tumor’s genomic alterations and their tumorigenic roles. Tumor morphology, however, has not been fully integrated into the analysis. The aim of this study was to explore relevant associations between tumor morphology and the newly characterized genomic alterations in colorectal carcinoma. Two-hundred-and-seven colorectal carcinomas that had undergone whole exome sequencing as part of The-Cancer-Genome-Atlas project and had adequate virtual images in the cBioPortal for Cancer Genomics http://www.cbioportal.org/ constituted our study population. Upon analysis, a tight association between “microsatellite instability-high histology” and microsatellite instability-high (p<.001) was readily detected and helped validate our image-based histology evaluation. Further, we showed: 1) among all histologies, the not-otherwise-specified type had the lowest overall mutation count (p<.001 for entire cohort, p<.03 for the microsatellite instable group), and among the microsatellite instable tumors, this type also correlated with fewer frameshift mutations in coding mononucleotide repeats of a defined set of relevant genes (p<.01); 2) cytosine-phosphate-guanine-island-methylator-phenotype-high colorectal cancers with or without microsatellite instability tended to have different histological patterns: the former more often mucinous and the latter more often not-otherwise-specified; 3) mucinous histology was associated with more frequent alterations in BRAF, PIK3CA, and the transforming-growth-factor-beta pathway when compared to non-mucinous histologies (p<.001, p=.01, and p<0.001, respectively); and 4) few colorectal cancers (<9%) exhibited upregulation of immune inhibitory genes including major immune checkpoints; these tumors were primarily microsatellite instable (up to 43%, versus <3% in microsatellite-stable group) and had distinctly non-mucinous histologies with a solid growth. These morphology-molecular associations are interesting and propose important clinical implications. The morphological patterns associated with alterations of immune checkpoint genes bear the potential to guide patient selection for clinical trials that target immune checkpoints in colorectal cancer, and provide directions for future studies.

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“…The region carrying the deleted in colorectal cancer gene (a dependence factor) is more frequently lost in advanced cancers 70 . The mutations in similar to mothers against decapentaplegic (SMAD) homologproteins, namely SMAD2, SMAD3, SMAD4 and SMAD7, which are regulators of TGF β signaling, have been associated with CRC [71][72][73] . SMAD 4 loss predicts worse prognosis for fluorouracil-based therapies 74 .…”

Section: Mutational Landscape In Chromosomal Instabilitymentioning

confidence: 99%

Colorectal cancer carcinogenesis: a review of mechanisms

Tariq¹,

Ghias²

2016

Cancer Biology &Amp; Medicine

228

138

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Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men globally. CRC arises from one or a combination of chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Genetic instability is usually caused by aneuploidy and loss of heterozygosity. Mutations in the tumor suppressor or cell cycle genes may also lead to cellular transformation. Similarly, epigenetic and/or genetic alterations resulting in impaired cellular pathways, such as DNA repair mechanism, may lead to microsatellite instability and mutator phenotype. Non-coding RNAs, more importantly microRNAs and long non-coding RNAs have also been implicated at various CRC stages. Understanding the specific mechanisms of tumorigenesis and the underlying genetic and epigenetic traits is critical in comprehending the disease phenotype. This paper reviews these mechanisms along with the roles of various non-coding RNAs in CRCs.

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Smad4 inactivation predicts for worse prognosis and response to fluorouracil-based treatment in colorectal cancer

Abstract: Loss of Smad4 expression is associated with worse DFS and OS in multiple subsets of patients with CRC. Further studies are required to validate our findings and ascertain the role of Smad4 status in the management of this disease.

Cited by 39 publications

References 19 publications

Prognostic value of loss of heterozygosity and sub-cellular localization of SMAD4 varies with tumor stage in colorectal cancer

Prognostic value of loss of heterozygosity and sub-cellular localization of SMAD4 varies with tumor stage in colorectal cancer

Morphological characterization of colorectal cancers in The Cancer Genome Atlas reveals distinct morphology–molecular associations: clinical and biological implications

Colorectal cancer carcinogenesis: a review of mechanisms

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