The apoptotic regulatory gene, BCL10, is mutated in sporadic mismatch repair deficient colorectal cancers

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BCL10, a novel apoptotic regulatory gene, was recently cloned from a low-grade MALT lymphoma and is mutated in 45% primary lymphoid cancers and in cell lines derived from cancers of the colon, mesothelium and testicular germ cells.¹ BCL10, also described in the literature as mE10, CIPER and CLAP contains an amino terminal caspase recruitment domain, or CARD, similar to other proteins involved in the control of apoptosis. Mutations in BCL10 presumably disrupt binding of the C terminus of BCL10 to pro-caspase-9, causing abrogation of its pro-apoptotic function. BCL10 is the first CARD protein implicated in tumorigenesis. The two insertion/deletion mutations in the coding mononucleotide repeats of BCL10 in the colorectal cancer cell lines LoVo and LS513 described by Willis et al¹ are characteristic of the type of mutations found in mismatch repair defective colorectal cancers. These cancers are characterised by high-level microsatellite instability (MSI-H). Mutational targets of MSI-H colorectal cancers include the coding repeat sequences of CDX2,² the proapoptotic gene BAX,³ genes involved in the regulation of cell growth such as the transforming growth factor β receptor type II (TGFBRII),⁴ the insulin-like growth factor II receptor (IGFIIR)⁵ and CHK1,⁶ the transcription factors E2F4⁷ and TCF-4,⁸ the mismatch repair genes MSH3 and MSH6⁹ and the putative mismatch repair gene MBD4.¹⁰ The importance of defining the molecular basis of MSI-H colorectal cancers by identifying new mutation targets is emphasised by several studies showing patients with tumours displaying MSI-H have a favourable prognosis.^11,12

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