Inactivation of tumor suppressor genes p15(INK4b) and p16(INK4a) in primary cutaneous B cell lymphoma.
Primary cutaneous B cell lymphomas represent a distinct group of lymphoproliferative disorders that can be distinguished from systemic lymphoma by their good response to local treatment and favorable prognosis. In systemic B cell lymphoma, inactivation of p15(INK4b) and p16(INK4a) is frequently observed and may be associated with a poor prognosis. There have been no comprehensive studies in primary cutaneous B cell lymphomas, however. Mechanisms of p15/p16 inactivation include loss of heterozygosity, homozygous deletion, promotor region hypermethylation, and point mutation. We analyzed DNA from 36 cases of primary cutaneous B cell lymphomas, four systemic B cell lymphomas, and six benign B cell lymphoproliferative infiltrates for abnormalities of p15 and p16 using microsatellite markers for 9p21, methylation specific polymerase chain reaction, and polymerase chain reaction/single stranded conformational polymorphism analysis with exon specific primers. Expression of both p15 and p16 protein was assessed by immunohistochemistry. Loss of heterozygosity at 9p21 was identified in 2 out of 36 primary cutaneous B cell lymphomas. Hypermethylation of p15 and p16 promotor regions was identified in 8 of 35 (23%) and 15 of 35 (43%) cases, respectively. In two cases p16 hypermethylation was identified in recurrent disease but not in the initial tumor. No point mutations were identified. In seven patients, however, a polymorphism was observed in exon 3 of the p16 gene. In primary cutaneous B cell lymphomas with allelic loss or promotor hypermethylation of either p15 or p16, loss of expression in tumor cells was identified in 5 of 8 and 9 of 10 cases, respectively. Our findings suggest that p15(INK4b) and p16(INK4a) biallelic gene abnormalities are common in primary cutaneous B cell lymphomas, most frequently as a result of promotor hypermethylation. The presence of abnormalities in recurrent disease in some cases suggests that inactivation of p15 and p16 may be involved in disease progression.
Child
Fiona J
FJ
Skin Tumor Unit and Department of Dermatopathology, St John's Institute of Dermatology, St Thomas' Hospital, London, U.K. fionachild@hotmail.com
Scarisbrick
Julia J
JJ
Calonje
Eduardo
E
Orchard
Guy
G
Russell-Jones
Robin
R
Whittaker
Sean J
SJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000502:physiology; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025521:Tumor Suppressor Proteins