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Homozygous Deletions at Chromosome 9p21 Involving p16 and p15 Are
Associated With Histologic Progression in Follicle Center Lymphoma
Kojo S.J. Elenitoba-Johnson,
Randy D. Gascoyne,
Megan S. Lim,
Mukesh Chhanabai,
Elaine S. Jaffe, and
Mark Raffeld
From the Hematopathology Section, Laboratory of Pathology, National
Cancer Institute, National Institutes of Health, Bethesda, MD; and the
Department of Pathology, British Columbia Cancer Agency, Vancouver,
British Columbia, Canada.
Low-grade follicle center lymphoma (LGFCL) is characterized
genetically by the t(14;18) translocation and an indolent clinical course. Histologic progression from LGFCL to an aggressive diffuse large B-cell lymphoma (DLCL) occurs in 60% to 80% of cases, and this
transformation is associated with the accumulation of secondary genetic
alterations. Using 10 polymorphic microsatellite markers spanning the
chromosome 9p21 region harboring the p15
(p15INK4B/MTS-2/CDKN2B) and p16
(p16INK4A/MTS-1/CDKN2) tumor-suppressor gene loci, we
analyzed 11 matched pairs of LGFCL and their corresponding progressed
DLCL biopsies for loss of heterozygosity and homozygous deletions at
9p21. A comparative multiplex polymerase chain reaction assay was also used for the detection of homozygous deletions. Deletions were identified in 8 of the 11 cases studied (73%): 6 homozygous (54%) and
2 hemizygous (18%). The deletions were identified exclusively in the
progressed DLCL biopsies. Immunohistochemical studies showed an
excellent correlation with the results from the genetic analyses. Of
the 9 matched pairs of LGFCL and progressed DLCL with interpretable immunohistochemical staining, 9 of 9 (100%) of the LGFCL showed diffuse reactivity for p16. Four of the 9 (44%) immunohistochemically evaluable cases of progressed DLCL showed loss of or, in 1 case, markedly diminished p16 expression. All 4 of these cases
correspondingly showed homozygous deletions at 9p21. Five of the 9 progressed DLCL cases showed p16 expression and demonstrated retention
of one or both 9p21 alleles by genetic analysis. This is the first longitudinal series examining sequential biopsy specimens of low-grade and progressed FCL for genetic loss at 9p21 encompassing the p16 and
p15 loci. The high frequency and exclusive occurrence of deletions involving p16 in the progressed DLCLs suggests that genetic loss at
9p21 targeting p16 and/or p15 is an important secondary genetic event in the histologic progression of FCL.
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4677-4685
© 1998 by The American Society of Hematology.
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