A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH genes and includes patients with good prognosis, nonnodal disease

Orchard, Jenny; Garand, Richard; Davis, Zadie; Babbage, Gavin; Sahota, Surinder S.; Matutes, Estella; Catovsky, Daniel; Thomas, Peter; Avet-Loiseau, Hervé; Oscier, David

doi:10.1182/blood-2002-06-1864

Cited by 265 publications

(217 citation statements)

References 45 publications

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“…In our study, we primarily employed FR1c, which has been reported to be more sensitive than the other commonly used IGH primer sets. 20 In keeping with this concept, at least one of the previous studies reported that successful amplification of the monoclonal IGH gene was found in only 65 of 80 cases evaluated, 17 whereas our study successfully amplified all but one case. We also have considered the possibility that different IGH primers may have bias toward amplifying different V H regions.…”

Section: Discussionsupporting

confidence: 63%

“…We also have considered the possibility that different IGH primers may have bias toward amplifying different V H regions. Lastly, all of the four previous large studies were from European centers, [15][16][17][18] and we cannot exclude the possibility that the North American population (as in this study) may have different characteristics than their European counterparts.…”

Section: Discussionmentioning

confidence: 90%

“…24 Second, DNA templates were used uniformly in all cases in our study, whereas a mixture of RNA and DNA templates were used in most of the previous studies. 15,17,18 We believe that results from the use of RNA templates may yield different results from the use of DNA templates, as different rearranged IGH species may be transcribed at different rates and thus they may be represented differently at the RNA level. To this point, we have recently performed parallel studies using RNA template as well as DNA templates from 12 cases of mantle cell lymphoma, and our results are in keeping with this concept (manuscript in preparation).…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][14] More recently, several large studies were performed to examine the V H mutation status in mantle cell lymphoma; using o98% homology (compared to the germline sequences) as the cutoff, it was found that 29-34% of mantle cell lymphoma have relatively high rates of V H mutation. [15][16][17][18] In contrast to chronic lymphocytic leukemia, no strong correlation was identified between the degree of V H homology and patient survival, although one study revealed a significant correlation between the use of V H 3-21 and a better clinical outcome. 15 These studies also identified a bias in the utilization of specific V H gene segments in mantle cell lymphoma, with V H 3-21 being the most frequently utilized region.…”

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confidence: 99%

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Immunoglobulin V somatic hypermutation in mantle cell lymphoma: mutated genotype correlates with better clinical outcome

et al. 2006

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Mantle cell lymphoma is an aggressive B-cell lymphoma for which the biology is incompletely understood. Previous studies have reported that somatic hypermutation of the variable region of the immunoglobulin heavy chain gene (V H ), as commonly defined as o98% homology, can be detected in approximately one-third of mantle cell lymphoma, although the V H mutation status has not been found to significantly correlate with patient survival. In this study, we assessed V H mutation in 55 mantle cell lymphomas using a method slightly different from those used in the previous studies, and we came to different conclusions. Using DNA extracted from formalin-fixed/paraffin-embedded tumors in all cases, we identified monoclonal IGH bands in 54 of 55 cases with the FR1c/J H primer; a monoclonal IGH band was amplified using another IGH primer set, FR256/J H , in the remaining case. Cloning was performed in all cases, and an average of six clones were sequenced and analyzed for each case. Intraclonal heterogeneity was detected in 45 (82%) cases. Further analysis was performed in 53 cases, in which a predominant IGH species was identified. Most (32 of 53 cases, 60%) cases were 'mutated', with o98% homology. V H 1-69, V H 4-59 and V H 3-74 were utilized in 29 (55%) cases. Intraclonal evolution and nonproductive V H rearrangements were more frequent in the mutated group. Patients with the 'mutated' genotype had longer overall survival (P ¼ 0.017, Log rank) that is independent of the international prognostic index. To conclude, our data suggest that the V H mutation frequency in mantle cell lymphoma may be higher than previously believed. Importantly, using our methodology, we found that the V H mutation status may be a useful prognostic marker for these patients. Mantle cell lymphoma is a distinct clinicopathologic entity recognized by the World Health Organization Classification Scheme. 1 The genetic hallmark of this disease is the chromosomal abnormality, the t(11;14)(q13;q32), which results in cyclin D1 overexpression. 2 Using transgenic mouse models, two research groups have shown that enforced cyclin D1 expression in B cells is not sufficient for lymphomagenesis. 3,4 Recent studies, including a number of oligonucleotide array studies, revealed additional biochemical abnormalities in mantle cell lymphoma, such as defects in the apoptotic pathway, cell cycle progression and DNA repair. [5][6][7][8][9][10] To further understand the biology of this type of B-cell neoplasm, one approach is to examine the somatic hypermutation of the variable region of the immunoglobulin heavy chain (V H ) gene. In chronic lymphocytic leukemia, it has been shown that a subset of cases has relatively high levels of V H somatic mutation, and mutated cases were associated with better clinical outcome when using o98% homology as the cutoff. 11-14 More recently, several large studies were performed to examine the V H mutation status in mantle cell lymphoma; using o98% homology (compared to the germline sequences) as the cutoff, it was found that 29-34% of

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Immunoglobulin V somatic hypermutation in mantle cell lymphoma: mutated genotype correlates with better clinical outcome

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“…18 Similarly, Pittaluga et al 19 21 Compared to these studies, we found a higher percentage (60%) of mutated cases. This discrepancy may be due to our referral patient population or to the relatively small size of our series, rather than reflecting the biology of MCL cases that subsequently undergo histologic progression.…”

Section: Discussionsupporting

confidence: 51%

Sequence analysis proves clonal identity in five patients with typical and blastoid mantle cell lymphoma

et al. 2007

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Mantle cell lymphoma (MCL) is typically composed of small irregular lymphoid cells. Blastoid variants, composed of lymphoblast-like (classic type) or large (pleomorphic type) cells, arise de novo or in patients with typical MCL. Although it has been assumed that blastoid variant represents histologic transformation of typical MCL, the clonal relationship between the two tumors has rarely been assessed at the molecular level. We identified five patients with typical MCL who subsequently developed the blastoid variant. There were two men and three women with a median age of 65 years (range, 34-70) at diagnosis of typical MCL involving lymph nodes. The median interval between typical and blastoid MCL was 36 months (range, 11-103). Subsequent blastoid variant MCL involved soft tissue (two), lymph node (one), ileum (one), or rectum (one). All typical and blastoid neoplasms were positive for CD20, cyclin D1, and monotypic surface immunoglobulin light chain, and all typical cases were positive for CD5. Two blastoid neoplasms lost CD5 expression, one of which aberrantly expressed CD10. Immunostaining for Ki-67 showed a median proliferative fraction of 20% in typical and 70% in blastoid neoplasms. Sequence analysis of the VDJ regions of the rearranged IgH allele proved clonal identity in each set of paired samples in all five patients. These results support the concept that blastoid MCL arising in patients with typical MCL represents histologic transformation of the original neoplastic clone. Keywords: mantle cell lymphoma; blastoid; histologic transformation Mantle cell lymphoma (MCL) is a distinct type of B-cell lymphoma characterized by the t(11;14)(q13; q32) and cyclin D1 overexpression. Histologically, MCL is typically composed of a monotonous population of small to medium-sized lymphoid cells with slightly irregular nuclear contours and a relatively low mitotic rate. Immunophenotypically, MCL expresses monotypic surface immunoglobulin, pan-B-cell antigens, and CD5, and is usually negative CD10 and CD23. 1,2 A histologically more aggressive form of MCL, blastoid variant, also occurs, either de novo or in patients with typical MCL. Two types of blastoid MCL are described, consisting of either lymphoblast-like (classic type) or large (pleomorphic type) cells with a high proliferative fraction. [3][4][5][6] In patients who have both typical and blastoid variant MCL, either simultaneously or sequentially, the relationship between these neoplasms is not well studied. One might assume that both the typical and blastoid variant MCL are clonally related, analogous to low-grade follicular lymphoma and diffuse large B-cell lymphoma. However, in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who develop diffuse large B-cell lymphoma, so-called Richter's syndrome, molecular genetic analysis indicates that the CLL/SLL and diffuse large B-cell lymphoma are clonally related in approximately 50% of cases. 7,8 In our review of the literature, we have identified only three patients in which the clonal...

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Chronic Lymphocytic Leukaemia and other B‐Cell Disorders

Catovsky

Montserrat

2005

Postgraduate Haematology

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A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH genes and includes patients with good prognosis, nonnodal disease

Cited by 265 publications

References 45 publications

Immunoglobulin V somatic hypermutation in mantle cell lymphoma: mutated genotype correlates with better clinical outcome

Immunoglobulin V somatic hypermutation in mantle cell lymphoma: mutated genotype correlates with better clinical outcome

Sequence analysis proves clonal identity in five patients with typical and blastoid mantle cell lymphoma

Chronic Lymphocytic Leukaemia and other B‐Cell Disorders

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