Dataset Information

Variants in the netrin-1 receptor UNC5C prevent apoptosis and increase risk of familial colorectal cancer.

ABSTRACT: Expression of the netrin-1 dependence receptor UNC5C is reduced in many colorectal tumors; mice with the UNC5C mutations have increased progression of intestinal tumors. We investigated whether specific variants in UNC5C increase risk of colorectal cancer (CRC).We analyzed the sequence of UNC5C in blood samples from 1801 patients with CRC and 4152 controls from 3 cohorts (France, United States, and Finland). Almost all cases from France and the United States had familial CRC; of the Finnish cases, 92 of 984 were familial. We analyzed whether CRC segregates with the UNC5C variant A628K in 3 families with histories of CRC. We also performed haplotype analysis to determine the origin of this variant.Of 817 patients with familial CRC, 14 had 1 of 4 different, unreported missense variants in UNC5C. The variants p.Asp353Asn (encodes D353N), p.Arg603Cys (encodes R603C), and p.Gln630Glu (encodes Q630E) did not occur significantly more often in cases than controls. The variant p.Ala628Lys (A628K) was detected in 3 families in the French cohort (odds ratio, 8.8; Wald's 95% confidence interval, 1.47-52.93; P = .03) and in 2 families in the US cohort (odds ratio, 1.9; P = .6) but was not detected in the Finnish cohort; UNC5C A628K segregated with CRC in families. Three families with A628K had a 109-kilobase identical haplotype that spanned most of UNC5C, indicating recent origin of this variant in white subjects (14 generations; 95% confidence interval, 6-36 generations). Transfection of HEK293T cells with UNC5C-A628K significantly reduced apoptosis compared with wild-type UNC5C, measured in an assay of active caspase-3.Inherited mutations in UNC5C prevent apoptosis and increase risk of CRC.

SUBMITTER: Coissieux MM

PROVIDER: S-EPMC3221775 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Variants in the netrin-1 receptor UNC5C prevent apoptosis and increase risk of familial colorectal cancer.

Coissieux Marie-May MM Tomsic Jerneja J Castets Marie M Hampel Heather H Tuupanen Sari S Andrieu Nadine N Comeras Ilene I Drouet Youenn Y Lasset Christine C Liyanarachchi Sandya S Mazelin Laetitia L Puisieux Alain A Saurin Jean-Christophe JC Scoazec Jean-Yves JY Wang Qing Q Aaltonen Lauri L Tanner Stephan M SM de la Chapelle Albert A Bernet Agnès A Mehlen Patrick P

Gastroenterology 20110903 6

<h4>Background & aims</h4>Expression of the netrin-1 dependence receptor UNC5C is reduced in many colorectal tumors; mice with the UNC5C mutations have increased progression of intestinal tumors. We investigated whether specific variants in UNC5C increase risk of colorectal cancer (CRC).<h4>Methods</h4>We analyzed the sequence of UNC5C in blood samples from 1801 patients with CRC and 4152 controls from 3 cohorts (France, United States, and Finland). Almost all cases from France and the United St ...[more]

PMID: 21893118

Similar Datasets

Project description:Modulation of microtubule (MT) dynamics is a key event of cytoskeleton remodeling in the growth cone (GC) during axon outgrowth and pathfinding. Our previous studies have shown that the direct interaction of netrin receptor DCC and DSCAM with polymerized TUBB3, a neuron-specific MT subunit in the brain, is required for netrin-1-mediated axon outgrowth, branching, and attraction. Here, we show that uncoupling of polymerized TUBB3 with netrin-1-repulsive receptor UNC5C is involved in netrin-1-mediated axonal repulsion. TUBB3 directly interacted with UNC5C and partially colocalized with UNC5C in the peripheral area of the GC of primary neurons from the cerebellar external granule layer of P2 mouse pups of both sexes. Netrin-1 reduced this interaction as well as the colocalization of UNC5C and TUBB3 in the GC. Results from the in vitro cosedimentation assay indicated that UNC5C interacted with polymerized TUBB3 in MTs and netrin-1 decreased this interaction. Knockdown of either TUBB3 or UNC5C blocked netrin-1-promoted axon repulsion in vitro and caused defects in axon projection of DRG toward the spinal cord in vivo Furthermore, live-cell imaging of end-binding protein 3 tagged with EGFP (EB3-GFP) in primary external granule layer cells showed that netrin-1 differentially increased MT dynamics in the GC with more MT growth in the distal than the proximal region of the GC during repulsion, and knockdown of either UNC5C or TUBB3 abolished the netrin-1 effect. Together, these data indicate that the disengagement of UNC5C with polymerized TUBB3 plays an essential role in netrin-1/UNC5C-mediated axon repulsion.SIGNIFICANCE STATEMENT Proper regulation of microtubule (MT) dynamics in the growth cone plays an important role in axon guidance. However, whether guidance cues modulate MT dynamics directly or indirectly is unclear. Here, we report that dissociation of UNC5C and polymerized TUBB3, the highly dynamic β-tubulin isoform in neurons, is essential for netrin-1/UNC5C-promoted axon repulsion. These results not only provide a working model of direct modulation of MTs by guidance cues in growth cone navigation but also help us to understand molecular mechanisms underlying developmental brain disorders associated with TUBB3 mutations.

Project description:BackgroundPolymorphisms in the gene encoding the vitamin D receptor (VDR) affect the protective role of vitamin D against many types of cancers, including colorectal cancer (CRC).ObjectiveThe objective of this study was to assess the effect of four major polymorphisms of the VDR gene (ApaI, TaqI, BsmI and FokI) on the risk of CRC in a Saudi population.Materials and methodsThis case-control study recruited 132 CRC patients from the oncology clinics at King Abdulaziz University Hospital and 124 healthy controls from the blood bank at King Fahad General Hospital, Jeddah, Saudi Arabia, between September 2017 and August 2018. All participants were Saudis and aged 20-80 years. Genomic DNA samples were extracted from the peripheral blood cells and amplified with polymerase chain reaction. The resulting fragments were digested with different endonucleases to reveal the genotypes using the restriction fragment length polymorphism technique. The genotype distribution and allele frequency, odds ratio (OR), risk ratio (RR) and P values were determined with contingency table analysis following Hardy-Weinberg equilibrium equation.ResultsFor the ApaI single-nucleotide polymorphism (SNP) (rs7975232), only the heterozygous (Aa) genotype increased the risk of CRC (OR = 3.4, RR = 2.3, and P < 0.0001), whereas the TaqI SNP (rs731236) carriers with either the heterozygous (Tt) or homozygous (tt) genotype displayed an increased risk for the disease (OR = 6.18, RR = 4, P < 0.0001; OR = 3, RR = 2.4, P = 0.02, respectively). In contrast, heterozygous (Bb) and homozygous (bb) carriers of the BsmI SNP (rs1544410) had significantly lower risk for CRC (P < 0.0001). Finally, for the FokI SNP (rs2228570), there was no association with CRC risk.ConclusionThis study found that VDR SNPs ApaI and TaqI increase the risk of CRC, whereas BsmI reduces the risk of CRC in the selected Saudi population. Therefore, ApaI and TaqI SNPs could potentially be used as a diagnostic biomarker for CRC. However, the molecular mechanisms by which these variants increase or decrease the risk of CRC need to be investigated.

Dataset Information

Variants in the netrin-1 receptor UNC5C prevent apoptosis and increase risk of familial colorectal cancer.

Publications

Variants in the netrin-1 receptor UNC5C prevent apoptosis and increase risk of familial colorectal cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets