Alterations of Fas (Apo-1/CD95) gene in non-small cell lung cancer

Abstract

Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling. The key role of the Fas system in negative growth regulation has been studied mostly within the immune system, and somatic mutations of Fas gene in cancer patients have been described solely in lymphoid-lineage malignancies. However, many nonlymphoid tumor cells have been found to be resistant to Fas-mediated apoptosis, which suggests that Fas mutations, one of the possible mechanisms for Fas-resistance, may be involved in the pathogenesis of non-lymphoid malignancies as well. In this study, we have analysed the entire coding region and all splice sites of the Fas gene for the detection of the gene mutations in 65 human nonsmall cell lung cancers by polymerase chain reaction, single strand conformation polymorphism and DNA sequencing. Overall, ®ve tumors (7.7%) were found to have the Fas mutations, which were all missense mutations. Four of the ®ve mutations identi®ed were located in the cytoplasmic region (death domain) known to be involved in the transduction of an apoptotic signal and one mutation was located in the transmembrane domain. This is the ®rst report on the Fas gene mutations in non-lymphoid malignancies, and the data presented here suggests that alterations of the Fas gene might lead to the loss of its apoptotic function and contribute to the pathogenesis of some human lung cancers.

Loss of Fas (CD95/APO-1) Regulatory Function Is an Important Step in Early MALT-Type Lymphoma Development

“…Fas mutations resulting in loss of function imply that Fas may act as a tumor suppressor gene. This hypothesis is supported by recent findings of genomic instability as detected by LOH in the Fas promotor region in solid tumors (Lee et al, 1999a(Lee et al, , 1999bShin et al, 1999), but is in contrast to results with MALT-type lymphoma, because we could not find LOH in any of the cases investigated. However, hypermutation and ongoing mutations of MALT-type lymphoma antigen receptors support the notion that clonal growth of malignant B cells occurred during or after the germinal center development (Hallas et al, 1998;Qin et al, 1997).…”

Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias

“…The acute leukaemias consisted of 95 acute myelogenous leukaemia, 33 acute lymphoblastic leukaemia (ALL) (29 B-ALL and 4 T-ALL) and 1 undifferentiated acute leukaemia. For the solid tumours, malignant cells and normal cells were selectively procured from haematoxylin and eosin-stained slides by a microdissection as described previously (Lee et al, 1999), whereas for the leukaemia non-fixed fresh bone marrows were directly used. Because the AKT1 E17K mutation was detected in the exon 3, genomic DNA each from tumour cells and corresponding normal cells were amplified with one primer pair covering the exon 3.…”

New insights into apoptosis signaling by Apo2L/TRAIL

“…However, these observations should be interpreted with caution, given that heterotypic preassociation has not been confirmed with endogenously expressed receptors. Rare ECD mutations in DR4 and DR5 have been identified in lung cancers (Lee et al, 1999;Fisher et al, 2001), although it is unknown whether these mutations enhance or diminish receptor-receptor association. Better understanding of how preligand assembly of DR4 or DR5 is regulated may spawn new strategies to sensitize tumors to Apo2L/TRAIL-mediated apoptosis.…”