The promyelocytic leukemia (PML) gene is an important tumor suppressor gene. We tested the hypothesis that germline disruption of the PML gene may be associated with a cancer predisposition syndrome. Mutation analysis of the PML gene was performed in 111 patients with familial adult cancer or young age-onset adult cancer. These were mostly breast and colon cancer, or colon polyposis patients in whom mutation analyses of the BRCA1, BRCA2, MLH1, MSH2, APC or TP53 genes did not detect a pathogenic germline mutation. Heteroduplex analysis and direct sequencing were used for mutation screening. Mutation-specific methods were designed for frequency determination of novel variants in the general population. No deleterious nonsense or frameshift germline mutations were detected. Several missense single-nucleotide substitutions were found, including two novel missense variants, c.83C>T (p.Thr28Ile) in exon 1 in a 42-year-old breast cancer patient and c.1558C>T (p.Pro520Ser) in exon 6 in a 32-year-old colon cancer patient, that were not detected in 100 and 214 non-cancer persons, respectively. Frequency of the c.2260G>C (p.Ala754Pro) variant in isoform IV of the PML gene was higher in patients with colon polyposis and cancer than in the control group (P = 0.029). In conclusion, germline disruption of the PML gene is probably not associated with a highly penetrant susceptibility to adult-onset breast and colon cancer. Pathogenicity of c.83C>T and c.1558C>T variants in the PML gene is uncertain. Carriers of the c.2260 G>C variant in PMLIV isoform may be at an increased risk of colon polyposis and cancer.

Department of Medical Genetics Faculty Hospital of Ostrava Czech Republic

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