Contributions
Type: Publication Only
Background
MYD88 p.L265P mutation has been recently reported to have predictive value for worse response and survival in diffuse large B-cell lymphoma (DLBCL). In lymphoplasmacytic lymphoma (LPL), that is characterized by a high presence of the MYD88 p.L265P change, different mutations in the C terminus of the CXCR4 gene have been lately described. These alterations, that affect almost a 30% of LPL cases, are similar to those found in the WHIM syndrome and virtually all of them coexist with the MYD88 p.L265P alteration, modifying the clinical presentation and outcome of the disease.
Aims
To study the occurrence of CXCR4 WHIM-like mutations in adult patients with DLBCL and their possible association with other frequent mutations affecting the MYD88 (p.L265) and CD79B (p.Y196) genes.
Methods
We analysed the mutational status of CXCR4 and CD79B in a series of 101 DLBCL (19 of them harbouring the MYD88 p.L265P mutation) diagnosed in our institution according to the WHO 2008 diagnostic criteria for lymphomas. DNA samples extracted from FFPE tissue were used and macrodissection was performed in those cases where tumoral tissue represented less than the 50% of the sample. The presence of the MYD88 p.L265P mutation was assessed by allele-specific real time-PCR. The mutational status of CXCR4 was determined by direct Sanger sequencing of the C terminus of the gene (aminoacidic positions Glu288 to Ser352, according to the NCBI reference sequence NM_003467.2). Mutations affecting the tyrosine 196 at the ITAM motif of CD79B were studied also by direct Sanger sequencing of the targeted region.
Results
A total of 101 DLBCL cases (54 male; 47 female) with a median age of 71 years (range 25-88) were included in the study. According to the Hans’ immunochemistry-based algorithm, 48% of the cases were ABC-type and 52% were GCB-type. CD79B p.Y196 mutations were found in 10 patients. Consistently with previous studies, most of the cases of the MYD88 p.L265P positive group (n=19) were ABC-type lymphomas (74%) and presented a primary extranodal origin (68.4%) besides of being more enriched in CD79B Y196 mutations than the MYD88 wild-type group (36.8% vs 3.7%, p<0.001).
Only one case with a mutation in the CXCR4 gene was detected in the MYD88 p.L265P positive group (5.26%) whereas no CXCR4 mutations were found within the MYD88 wild-type cases. The alteration consisted in the c.C1000T heterozygous substitution, leading to a nonsense mutation at the arginine 334 (p.R334*) and coexisted with a mutation in the CD79B ITAM motif (p.Y196C). Noteworthy, this mutation represents a rare CXCR4 WHIM-like alteration also in LPL, where the most frequent altered position is, by far, the serine 338. Regarding the clinical features of the mutated case, the patient was a 71 years old male that presented an ABC-DLBCL with primary testicular origin. After 26 months of follow-up, the patient has not presented monoclonal component, bone marrow affectation or any other meaningful alteration.
Summary
Our study shows that the CXCR4 WHIM-like mutations are a rare event in DLBCL, even within those patients bearing the MYD88 L265P mutation, despite the recently shown correlation between these two molecular alterations in patients with LPL. Although these findings require further validation in larger studies, these results suggest that the pathogenic events driven by the MYD88 L265P mutation might differ among both diseases.
Session topic: Publication Only
Type: Publication Only
Background
MYD88 p.L265P mutation has been recently reported to have predictive value for worse response and survival in diffuse large B-cell lymphoma (DLBCL). In lymphoplasmacytic lymphoma (LPL), that is characterized by a high presence of the MYD88 p.L265P change, different mutations in the C terminus of the CXCR4 gene have been lately described. These alterations, that affect almost a 30% of LPL cases, are similar to those found in the WHIM syndrome and virtually all of them coexist with the MYD88 p.L265P alteration, modifying the clinical presentation and outcome of the disease.
Aims
To study the occurrence of CXCR4 WHIM-like mutations in adult patients with DLBCL and their possible association with other frequent mutations affecting the MYD88 (p.L265) and CD79B (p.Y196) genes.
Methods
We analysed the mutational status of CXCR4 and CD79B in a series of 101 DLBCL (19 of them harbouring the MYD88 p.L265P mutation) diagnosed in our institution according to the WHO 2008 diagnostic criteria for lymphomas. DNA samples extracted from FFPE tissue were used and macrodissection was performed in those cases where tumoral tissue represented less than the 50% of the sample. The presence of the MYD88 p.L265P mutation was assessed by allele-specific real time-PCR. The mutational status of CXCR4 was determined by direct Sanger sequencing of the C terminus of the gene (aminoacidic positions Glu288 to Ser352, according to the NCBI reference sequence NM_003467.2). Mutations affecting the tyrosine 196 at the ITAM motif of CD79B were studied also by direct Sanger sequencing of the targeted region.
Results
A total of 101 DLBCL cases (54 male; 47 female) with a median age of 71 years (range 25-88) were included in the study. According to the Hans’ immunochemistry-based algorithm, 48% of the cases were ABC-type and 52% were GCB-type. CD79B p.Y196 mutations were found in 10 patients. Consistently with previous studies, most of the cases of the MYD88 p.L265P positive group (n=19) were ABC-type lymphomas (74%) and presented a primary extranodal origin (68.4%) besides of being more enriched in CD79B Y196 mutations than the MYD88 wild-type group (36.8% vs 3.7%, p<0.001).
Only one case with a mutation in the CXCR4 gene was detected in the MYD88 p.L265P positive group (5.26%) whereas no CXCR4 mutations were found within the MYD88 wild-type cases. The alteration consisted in the c.C1000T heterozygous substitution, leading to a nonsense mutation at the arginine 334 (p.R334*) and coexisted with a mutation in the CD79B ITAM motif (p.Y196C). Noteworthy, this mutation represents a rare CXCR4 WHIM-like alteration also in LPL, where the most frequent altered position is, by far, the serine 338. Regarding the clinical features of the mutated case, the patient was a 71 years old male that presented an ABC-DLBCL with primary testicular origin. After 26 months of follow-up, the patient has not presented monoclonal component, bone marrow affectation or any other meaningful alteration.
Summary
Our study shows that the CXCR4 WHIM-like mutations are a rare event in DLBCL, even within those patients bearing the MYD88 L265P mutation, despite the recently shown correlation between these two molecular alterations in patients with LPL. Although these findings require further validation in larger studies, these results suggest that the pathogenic events driven by the MYD88 L265P mutation might differ among both diseases.
Session topic: Publication Only