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Clinical relevance of MYD88 mutations in B-NHL
1B
OthermatureB-cellneoplasmswith
Ocular adnexal marginal zone lymphoma
Primary bone DLBCL
Primary breast DLBCL
Primary cutaneous marginal zone lymphoma Primary DLBCL of the thyroid
Primary testicular lymphoma
Vitreoretinal lymphoma
MYD88(L265P) MYD88(L265P) Total
Range
36 – 71%
0 – 15% 35 – 71% 0 – 4% N.A. 14 – 82% 50 – 82%
Number References of studies
6 22, 23, 105
3 100-102 3 22, 99 3 103, 104 1 22
6 22, 23, 96, 108
9 22, 97, 98
prevalence
9.0%
5.8% 54.3% 2.0% 0% 68.4% 72.7%
incidence sequenced
23 255
3 52 38 70 2 100 0 21 65 95 88 121
* No data found in a literature search of articles published from January 2011 until August 2019.Terms used:‘WHO terms’ (MeSH terms) AND MYD88 | ‘WHO terms’ (MeSH Terms) AND Genetic. Additionally, all articles found by the ‘WHO terms’ (MeSH terms) were screened for lymphomas with unknown status of the MYD88 L265P mutation. DLBCL: diffuse large B-cell lymphoma; NOS; not otherwise specified; EBV: Epstein-Barr virus; ALK: anaplastic lymphoid kinase; HHV8: human herpes virus 8.
downstream of MYD88(L265P) and that HCK should be regarded as a potential therapeutic target in B-NHL with MYD88(L265P).
Prevalence
The described oncogenic mechanisms largely depend on the prevalence of MYD88(L265P) in B-NHL. Several studies, using Sanger sequencing, allele-specific poly- merase chain reaction (PCR) analysis, or (targeted) next- generation sequencing, have demonstrated that the occurrence of MYD88(L265P) varies highly among the different subtypes of B-NHL (Table 1).2,3,18,22-108 The highest prevalence of MYD88(L265P) is found in lymphoplasma- cytic lymphoma/WM, with approximately 85% of the patients being affected.18,22-37 In DLBCL, the prevalence of MYD88(L265P) is highest (range, 44% to 73%) in extran- odal DLBCL, in immune-privileged sites,96 such as pri- mary DLBCL of the central nervous system18,22,23,86-88,96 and primary testicular lymphoma,22,23,96,108 primary cutaneous DLBCL, leg type,22,71,89-91 orbital/vitreoretinal DLBCL,22,97,98 intravascular large B-cell lymphoma,95 and primary breast DLBCL.22,99 The high prevalence of MYD88(L265P) in extranodal site-specific lymphomas, lymphoplasmacytic lymphoma, and WM may provide an indication for the origin of these lymphomas. Interestingly, B-NHL entities with a high prevalence of MYD88(L265P) are character- ized by a monoclonal immunoglobulin M. Furthermore, the high occurrence of MYD88(L265P) in extranodal DLBCL may imply that B cells need to gain this mutation for survival and manifestation in extranodal sites.
In DLBCL in general, a recent meta-analysis by Lee et al.,22 comprising 18 studies with a total of 2002 DLBCL patients, documented that 255 of 1236 (21%) cases of ABC-DLBCL harbored MYD88(L265P), compared with 44 of 766 (6%) cases of germinal center B-cell-like (GCB) DLBCL. Large sequencing studies, such as those by Reddy et al.,80 Schmitz et al.,81 Chapuy et al.,77 and Intlekofer et al.,79 have compared with 44 of 766 (6%) cases of GCB DLBCL with archaic cell-of-origin classifica- tion, based on immunohistochemistry or gene expression profiling, and have shown that MYD88(L265P) and other mutations transcend these classifications and should be put into context with emerging genomic classification systems. These large sequencing studies underscore the need to evaluate the status of not only MYD88, but also
other genes involved in B-cell lymphomagenesis for diag- nosis and during treatment with targeted therapies, as proposed by Sujobert et al.109
Overall, these results identify MYD88(L265P) as a diag-
nostic classifier for specific B-NHL subtypes. This is sup-
ported by a recent study by our group that identified
MYD88 mutations as an independent marker, in a cohort
of 250 patients with DLBCL, in addition to the routinely
used MYC and BCL2 and/or BCL6 rearrangements and
Epstein-Barr virus status (according to the 2016 World
Health Organization classification110).83 Furthermore,
MYD88(L265P) is absent in primary mediastinal large B-
cell lymphoma2,3,94 and primary cutaneous follicle center
lymphoma,71-73 and rarely present in hairy cell leukemia
(1.1%),22,30,57-59 plasma cell myeloma (1.5%),18,22,23,43,106,107
Burkitt lymphoma (1.5%),2,74 follicular lymphoma (1.9%),18,22,23,67,68 and CLL (2.5%).18,22-24,28,38-52
Prognostic impact
In addition to its role as a diagnostic classifier, the prog- nostic value of MYD88(L265P) has been a topic of many studies involving B-NHL patients. Lee et al. performed a meta-analysis of three studies with accurate multivariate hazard ratios to investigate the prognostic value of MYD88(L265P) in DLBCL.22 This analysis, involving a total of 275 DLBCL patients, showed that DLBCL patients with MYD88(L265P) had a statistically signifi- cant inferior overall survival compared with DLBCL patients with wildtype MYD88. In addition, MYD88(L265P) was significantly associated with older age, high International Prognostic Index (IPI)-score risk groups, and extranodal localization. We also demonstrat- ed this association of MYD88(L265P) with an inferior sur- vival in our recent study in which we evaluated MYD88 status, together with CD79B, MYC, BCL2, BCL6 and Epstein-Barr virus status and clinical characteristics in 250 DLBCL patients.83 Additionally, we showed that the per- formance of the IPI score is improved by adding MYD88(L265P) as a poor risk factor.
The correlation of MYD88 mutations with an inferior overall survival is also observed in several subtypes of extranodal DLBCL, such as primary cutaneous DLBCL, leg type111 and immune-privileged DLBCL.22,83,112 On the other hand, in a study by Xu et al.,84 MYD88 mutations were significantly more frequent in DLBCL patients who
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