Immunogenicity of P/Q-type calcium channel in small cell lung cancer: investigation of alpha1 subunit polyglutamine expansion.
The ectopic expression of neuronal P/Q-type voltage-gated calcium channels in small cell lung carcinoma (SCLC) is thought to induce antisynaptic autoimmunity in the paraneoplastic Lambert-Eaton myasthenic syndrome. The gene CACNL1A4, encoding the principal (alpha1A) subunit of this calcium channel, is mutated in several inherited neurological disorders. One of these disorders (spinocerebellar ataxia, type 6, or SCA-6) involves the expansion of a trinucleotide (CAG) repeat unit. We hypothesized that a somatic CAG repeat instability of this gene in neoplastic cells might generate a non-self epitope capable of initiating autoimmunity to P/Q-type calcium channels. We therefore analyzed the CACNL1A4 gene in SCLC lines established from metastases derived from seven individual patients (four associated with Lambert-Eaton myasthenic syndrome, one associated with myasthenia gravis, and two not associated with neurological autoimmunity). We compared their CAG repeat numbers (determined by polymerase chain reaction (PCR) amplification followed by separation of products on a 6% polyacrylamide/8M urea gel) to published norms and to DNA from a patient with SCA-6. The number of CAG repeats in SCLC DNA fell within a normal range whether or not the neoplasm was complicated by neurological autoimmunity. Therefore, it is unlikely that somatically unstable CAG repeat units in the gene encoding the P/Q-type voltage-gated calcium channel account for this tumor protein's immunogenicity in the Lambert-Eaton myasthenic syndrome.
Black
J L
JL
Department of Psychiatry, Mayo Clinic, Rochester, Minnesota 55905, USA.
Nelson
T R
TR
Snow
K
K
Lennon
V A
VA
D015551:Autoimmunity; D020864:Calcium Channels, N-Type / Q000235:genetics* / Q000276:immunology*; D018288:Carcinoma, Small Cell / Q000150:complications / Q000276:immunology*; D006801:Humans; D015624:Lambert-Eaton Myasthenic Syndrome / Q000276:immunology*; D008175:Lung Neoplasms / Q000150:complications / Q000276:immunology*; D009154:Mutation; D012091:Repetitive Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA
D020864:Calcium Channels, N-Type