Phenotype variability of two FAP families with an identical <i>APC</i> germline mutation at codon 1465: a potential modifier effect?

Martin-Denavit, Tanguy; Duthel, S.; Giraud, Sophie; Olschwang, Sylviane; Saurin, JC; Plauchu, H

doi:10.1034/j.1399-0004.2001.600206.x

Cited by 5 publications

(1 citation statement)

References 30 publications

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“…Mutations in these genes have been shown to drive Wnt signaling in other tumors (17)(18)(19); however, the effect of these specific mutations on Wnt signaling in MM remains to be established. In addition, in analyzing the data of Mulligan et al (44) involving targeted sequencing of established oncogenes, we identified a T41I mutation in β-catenin (CTNNB1) and a frameshift mutation in APC (S1465fs*3), both of which have been shown to drive oncogenic Wnt signaling (45,46). Thus, these mutations might represent alternative mechanisms driving Wnt signaling in a subset of MMs.…”

Section: Discussionmentioning

confidence: 99%

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Andel

Ren

Koopmans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche. Here, we report a pivotal role for the R-spondin/leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis in driving aberrant Wnt/ β-catenin signaling in MM. We show that LGR4 is expressed by MM plasma cells, but not by normal plasma cells or B cells. This aberrant LGR4 expression is driven by IL-6/STAT3 signaling and allows MM cells to hijack R-spondins produced by (pre)osteoblasts in the BM niche, resulting in Wnt (co)receptor stabilization and a dramatically increased sensitivity to auto-and paracrine Wnts. Our study identifies aberrant R-spondin/LGR4 signaling with consequent deregulation of Wnt (co)receptor turnover as a driver of oncogenic Wnt/ β-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM.M ultiple myeloma (MM) in most patients is an incurable hematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow (BM). Despite the wide variety of underlying structural and numerical genomic abnormalities (1-3), virtually all MMs are highly dependent on a protective BM microenvironment, or "niche," for growth and survival (4). Understanding the complex reciprocal interaction between MM cells and the BM microenvironment is critical for the development of new targeted therapies.In MM, aberrant activation of the canonical Wnt pathway drives proliferation and is associated with disease progression, dissemination, and drug resistance (5-9). Because MMs with hallmarks of active Wnt signaling do not harbor mutations that typically underlie constitutive Wnt pathway activation, this oncogenic Wnt pathway activity was proposed to involve autocrine and/or paracrine Wnt ligands (6,8,10). Wnts are lipid-modified glycoproteins that function as typical niche factors because they are relatively unstable and insoluble due to their hydrophobic nature, which constrains long-range signaling (11). Binding of a Wnt ligand to its receptor Frizzled (Fzd) initiates a signaling cascade that ultimately results in stabilization and nuclear translocation of the Wnt effector β-catenin. In cooperation with TCF/LEF family transcription factors this orchestrates a transcriptional program (12, 13), comprising targets such as MYC and CCND1 (Cyclin D1) that play crucial roles in the pathogenesis of MM (14-16). Aberrant Wnt signaling in cancer typically results from mutations in APC, β-catenin (CTNNB1), or AXIN that drive constitutive, ligand-independent pathway ac...

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Section: Discussionmentioning

confidence: 99%

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Andel

Ren

Koopmans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Something not quite right: Gardner syndrome diagnosed by multiple cutaneous lesions and genetic testing

Tan¹,

Wilson²,

O’Neill³

et al. 2005

The Surgeon

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Aggressive mutation in a familial adenomatous polyposis syndrome family: when phenotype guides clinical surveillance

Neffa

García

Valle

et al. 2018

J. Gastrointest. Oncol.

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Familial adenomatous polyposis (FAP) is an autosomal dominant genetic condition, caused by mutations in the adenomatous polyposis coli APC tumor suppressor gene. Desmoid tumors (DTs) are seen in 15% to 20% of FAP patients. Specific location of mutation serves as a guide to predict colonic and extra colonic manifestations and their aggressiveness. A severe FAP-phenotypic family was registered in a genetic counselling high-risk Uruguayan hereditary cancer clinic. Proband's DNA was analysed by NGS, detecting a pathogenic mutation in APC gene. All willing family members were counselled and encouraged to be tested. Here we report a kindred formed by 16 individuals with a very severe FAP phenotype. A two-base deletion mutation: c.4393_4394delAG in APC gene and a consequent premature stop codon was detected. DTs were diagnosed in 6 individuals, ranging from 2 to 25 years of age. The causes of death were diverse: gastric cancer, rectal cancer and desmoid tumor. The already described genotype-phenotype correlation has proved its worth in this family, as clinical features reflect the mutation location at 3' end of gene. The inheritable and lethal nature of the disease needs a tailored follow up approach in order to reduce mortality, optimize local tumor control, and preserve patients' quality of life.

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Phenotype variability of two FAP families with an identical APC germline mutation at codon 1465: a potential modifier effect?

Cited by 5 publications

References 30 publications

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Something not quite right: Gardner syndrome diagnosed by multiple cutaneous lesions and genetic testing

Aggressive mutation in a familial adenomatous polyposis syndrome family: when phenotype guides clinical surveillance

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