Overexpression of SAMD9 suppresses tumorigenesis and progression during non small cell lung cancer

Ma, Qing; Yu, Tao; Ren, Yaoyao; Gong, Ting; Zhong, Diansheng

doi:10.1016/j.bbrc.2014.10.054

Cited by 24 publications

(22 citation statements)

References 10 publications

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“…Here, we present two additional patients with de novo heterozygous, activating variants in SAMD9 that result in overlapping phenotypes best described by MIRAGE syndrome. SAMD9 is known to be a widely‐expressed and potent growth suppressor (Ma, Yu, Ren, Gong, & Zhong, ; Topaz et al, ) and we have shown that the novel p.R824Q variant significantly restricts growth in vitro. As noted by Buonocore et al, there is a preponderance of mutations altering arginine residues in reported patients.…”

Section: Discussionmentioning

confidence: 54%

A novel SAMD9 mutation causing MIRAGE syndrome: An expansion and review of phenotype, dysmorphology, and natural history

Jeffries

Shima

et al. 2017

American J of Med Genetics Pt A

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Germline gain-of-function variants in SAMD9 have been associated with a high risk of mortality and a newly recognized constellation of symptoms described by the acronym MIRAGE: Myelodysplasia, Infection, Restriction of growth, Adrenal insufficiency, Genital phenotypes, and Enteropathy. Here, we describe two additional patients currently living with the syndrome, including one patient with a novel de novo variant for which we provide functional data supporting its pathogenicity. We discuss features of dysmorphology, contrasting with previously described patients as well as drawing attention to additional clinical features, dysautonomia and hearing loss that have not previously been reported. We detail both patients' courses following diagnosis, with attention to treatment plans and recommended specialist care. Our patients are the oldest known with arginine-substituting amino acid variants, and we conclude that early diagnosis and multidisciplinary management may positively impact outcomes for this vulnerable group of patients.

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Section: Discussionmentioning

confidence: 54%

A novel SAMD9 mutation causing MIRAGE syndrome: An expansion and review of phenotype, dysmorphology, and natural history

Jeffries

Shima

et al. 2017

American J of Med Genetics Pt A

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“…SAMD9 has little homology to other proteins except for SAMD9L, also on 7q21.2, with which it shares 58% identity (1–3). SAMD9 and SAMD9L are likely to act as growth suppressors, and overexpression of SAMD9 suppresses tumor progression in non–small cell lung cancer cells (4). In contrast, reduced SAMD9 expression has been reported in several tumor tissues, cisplatin chemoresistance, and normophosphatemic familial tumoral calcinosis (5–7).…”

Section: Introductionmentioning

confidence: 99%

Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans

Buonocore¹,

Kühnen²,

Suntharalingham³

et al. 2017

Journal of Clinical Investigation

144

210

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It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain–containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (–7), deletions of 7q (7q–), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with –7 and 7q– developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.

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“…SAMD9 and SAMD9L are significantly down-regulated in various neoplasms including aggressive fibromatosis, breast and colon cancers [8]. Overexpression of SAMD9 protein in tissue culture results in reduction of cell proliferation rate and invasion index, and increasing activity of caspase 3 [8, 9]. In addition, SAMD9 is an innate antiviral host factor and is the target of poxvirus host range factors of the C7L family [10–12] that have been shown to bind SAMD9 via a distinct “molecular claw” [13].…”

Section: Resultsmentioning

confidence: 99%

The complex domain architecture of SAMD9 family proteins, predicted STAND-like NTPases, suggests new links to inflammation and apoptosis

2017

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We report a comprehensive computational dissection of the domain architecture of the SAMD9 family proteins that are involved in antivirus and antitumor response in humans. We show that the SAMD9 protein family is represented in most animals and also, unexpectedly, in bacteria, in particular actinomycetes. From the N to C terminus, the core SAMD9 family architecture includes DNA/RNA-binding AlbA domain, a variant Sir2-like domain, a STAND-like P-loop NTPase, an array of TPR repeats and an OB-fold domain with predicted RNA-binding properties. Vertebrate SAMD9 family proteins contain the eponymous SAM domain capable of polymerization, whereas some family members from other animals instead contain homotypic adaptor domains of the DEATH superfamily, known as dedicated components of apoptosis networks. Such complex domain architecture is reminiscent of the STAND superfamily NTPases that are involved in various signaling processes, including programmed cell death, in both eukaryotes and prokaryotes. These findings suggest that SAMD9 is a hub of a novel, evolutionarily conserved defense network that remains to be characterized.ReviewersThis article was reviewed by Igor B. Zhulin and Mensur Dlakic.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-017-0185-2) contains supplementary material, which is available to authorized users.

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Overexpression of SAMD9 suppresses tumorigenesis and progression during non small cell lung cancer

Cited by 24 publications

References 10 publications

A novel SAMD9 mutation causing MIRAGE syndrome: An expansion and review of phenotype, dysmorphology, and natural history

A novel SAMD9 mutation causing MIRAGE syndrome: An expansion and review of phenotype, dysmorphology, and natural history

Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans

The complex domain architecture of SAMD9 family proteins, predicted STAND-like NTPases, suggests new links to inflammation and apoptosis

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