Inactivating mutations of the caspase-10 gene in gastric cancer

Abstract

We have analysed the genetic alteration of the entire coding region and all splice sites of caspase-8 and -10 genes in 99 gastric cancers by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and sequencing. We found LOH of the caspase-8 and -10 in nine (28%) of 32 and in four (15%) of 26 informative cases, respectively. Overall, three of 99 gastric cancers (3%) were found to have the caspase-10 mutations, which were identi®ed in the coding regions of the death eector domain (codon 147) and the p17 large protease domain (codons 257 and 410), whereas no mutation was detected in caspase-8. In vitro expression studies, the M147T and Q257stop mutants severely impaired caspase-10-mediated apoptosis, whereas the V410I which was the same mutation detected in ALPS patient had a signi®cant, albeit less severe, eect on apoptosis. The data presented here suggest that somatic alterations of the caspase-10 gene might contribute to the pathogenesis in a subset of gastric cancers through the loss of their apoptotic function.

E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients

“…The possibility of SMAD4 involvement in genetic predisposition to diffuse gastric cancer was raised by the observation of foci of adenocarcinoma with signet-ring cells in the stomach of heterozygous knock-out SMAD4 mice [15]. Caspase-10 is another candidate gene for familial gastric cancer, possibly through loss of apoptotic function, as suggested by reports of loss of heterozygosity (LOH) and mutations in coding regions of this gene in 15% and 3%, respectively, of sporadic gastric cancer cases [16]. From all of the probands screened in this study, we identified sequence variants in SMAD4 and Caspase-10.…”

“…CA, USA) following the manufacturer's instructions. Caspase-10 genomic sequences were amplified using primer sequences and conditions previously described in [16]. Genomic DNA (25-100 ng) was amplified by PCR using the following cycling conditions: 30 s at 94°C, 30 s at the appropriate annealing temperature, and 45 s at 72°C for 35 cycles.…”

Caspase function in programmed cell death

“…92 Recently, caspase-10, along with caspase-8, was shown to be essential for mediating NF-kB-dependent inflammatory responses in antiviral signalling. 93 Missense and inactivating mutations in casp10 gene have been reported to be associated with some cases of the autoimmune lymphoproliferative syndrome II (ALPS II), 94 non-Hodgkin lymphoma 95 and gastric cancer, 96 however it is unclear whether these mutations directly contribute to the disease phenotype.…”

Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells

“…Acquired inactivating mutations of caspase-10 have been identified in tumor cells from patients with nonHodgkin's lymphomas (Shin et al, 2002a) and solid tumors (Harada et al, 2002;Park et al, 2002;Shin et al, 2002b). Chemotherapeutic agents such as etoposide and doxorubicin induce casp-10 gene transcription in a p53-dependent manner (Rikhof et al, 2003) and arsenic trioxide stimulates casp-10 gene transcription by promoting histone H3 phosphoacetylation in acute promyelocytic leukemia cells (Li et al, 2002).…”