7q31-32 allelic loss is a frequent finding in splenic marginal zone lymphoma

Abstract

Splenic marginal zone lymphoma (SMZL) has been recognized as an entity defined on the basis of its morphological, phenotypic, and clinical characteristic features. Nevertheless, no characteristic genetic alterations have been described to date for this entity, thus making an exact diagnosis of SMZL difficult in some cases. As initial studies showed that chromosome region 7q22-32 is deleted in some of these cases, we analyzed a larger group of SMZL and other lymphoproliferative disorders that may partially overlap with it. To better define the frequency of 7q deletion in SMZL and further identify the deleted region, polymerase chain reaction analysis of 13 microsatellite loci spanning 7q21-7q36 was performed on 20 SMZL and 26 non-SMZL tissue samples. The frequency of allelic loss in SMZL (8/20; 40%) was higher than that observed in other B-cell lymphoproliferative syndromes (2/26; 7.7%). This difference was statistically significant (P < 0.05). The most frequently deleted microsatellite was D7S487 (5/11; 45% of informative cases). Surrounding this microsatellite the smallest common deleted region of 5cM has been identified, defined between D7S685 and D7S514. By comparative multiplex polymerase chain reaction analysis, we detected a homozygous deletion in the D7S685 (7q31.3) marker in one case. These results suggest that 7q31-q32 loss may be used as a genetic marker of this neoplasia, in conjunction with other morphologic, phenotypic, and clinical features. A correlation between 7q allelic loss and tumoral progression (death secondary to the tumor or large cell transformation) in SMZL showed a borderline statistical significance. The observation of a homozygous deletion in this chromosomal region may indicate that there is a tumor suppressor gene involved in the pathogenesis of this lymphoproliferative neoplasia.

Figure 1.

Summary of allelic loss data for 7q in SMZL. Graphic representation of the 13 microsatellite markers in 7q21-qter, giving the approximate position of each locus. Only cases showing LOH or allelic imbalance are illustrated. The results of the cytogenetic study are also included. Smallest common deletion region (SCDR) in the eight cases with allelic loss is shown, and spans about 5cM, from markers D7S685 to D7S514. A histogram shows the frequency of allelic loss for each of these markers in the informative samples.

Figure 2.

Representative examples of allelic loss in chromosome 7q. The presence of allelic losses in tumor (T) in comparison with matched normal (N) DNA is shown by arrows. Case S254 shows allelic loss in all informative loci. Case S1 shows loss of alleles for the loci mapping the 7q31-qter region (band intensity ratios of 3.1, 3.5, 1.6, and 2.7, respectively). Case S221 shows loss of alleles for loci D7S486, D7S2847, and D7S514 (band intensity ratios are 2.1, 2.8, 1.9 respectively) and retention of alleles for loci D7S518 mapped to 7q22. Case S74 shows loss of alleles for loci mapped to 7q32 (D7S514 and D7S530) and retention of alleles for loci D7S685 and D7S480, situated at the 7q31 band.

Figure 3.

Example of comparative multiplex PCR in cases S4 and S5. An internal control marker (D2S1360) shows the amount of tumor (T) and normal (N) DNA amplified. Case S5 shows a loss of the upper band, whereas case S4 has a loss of the lower band, as shown by arrows.

Figure 4.

Case number S5, showing homozygous deletion of microsatellite D7S685 (arrows). Autoradiography of multiplex PCR products showed that primer sets D7S550 and D7S685 amplified products from the normal (N) DNA, whereas only D7S550 amplified a product from the corresponding tumor (T) DNA. (The signal for D7S685 in the tumor lane was absent or very weak)