DLBCL update for genetic subgroups

[rdmorin]

DLBCL (DOID:0050745) currently has terms for the subgroups that are defined by gene expression analysis. For example, DOID:0080996 and DOID:0080997.

There are now some new entities defined within DLBCL based on the presence of specific combinations of mutations.

Can each of these be added as children under DLBCL?

MCD DLBCL

EZB DLBCL

BN2 DLBCL

N1 DLBCL

More information for how they relate to DLBCL is provided here

I can be contacted by email if any clarification is needed: rdmorin@sfu.ca

[lschriml]

Hello Ryan, Thank you for the new disease terms !! I will review and get them added to the DO.

Please let us know if we can add any additional terms. The new terms will become publicly available with our next release at the end of March.

Cheers, Lynn

[rdmorin]

You're welcome! There were a few additional ones defined in a subsequent paper from the group that defined these ones. I wonder if those additional groups can be added at the same time? Not all of them have a code in NCI Thesaurus. The missing groups are:

ST2 DLBCL

A53 DLBCL

There's also a further division of EZB DLBCL into EZB M+ and EZB M-. Happy to chat about how to incorporate these, depending on what criteria are needed.

https://www.cell.com/cancer-cell/pdfExtended/S1535-6108(20)30155-0

[lschriml]

Hello Ryan, I added the four DLBCL subtypes.

Can you look over (and edit as needed) the following definitions for these other subtypes?

ST2 diffuse large B-cell lymphoma ST2 DLBCL A diffuse large B-cell lymphoma that is characterized by the presence of SGK1 gene mutations and TET2 gene mutations.

A53 diffuse large B-cell lymphoma A53 DLBCL A diffuse large B-cell lymphoma that is characterized by the presence of aneuploid with TP53 inactivation.

 **EZB-MYC+ diffuse large B-cell lymphoma** 
 EZB-MYC+
          A diffuse large B-cell lymphoma that is characterized by BCL2 and MYC rearrangements.

**EZB-MYC+ diffuse large B-cell lymphoma** 
     EZB-MYC–
           A diffuse large B-cell lymphoma that is characterized by the lack of the BCL2 and MYC rearrangement.

--> should these definitions include the double-hit gene expression signature (DHIT)- positive/negative

Cheers, Lynn

References: https://pubmed.ncbi.nlm.nih.gov/30523716/ https://pubmed.ncbi.nlm.nih.gov/32289277/

[rdmorin]

Hi Lynn. This is a great synopsis of those two categories. I would change "aneuploid" to "aneuploidy" in the A53 description. The EZB-MYC+ and EZB-MYC- are a lot trickier. The differentiation of the two is most accurately described in the context of the DHITsig expression status rather than MYC and BCL2 rearrangements. Describing them based solely on MYC/BCL2 is definitely insufficient. These cases are also both, by definition, subgroups of EZB rather than directly of DLBCL. Perhaps we need to make them children of EZB DLBCL rather than of DLBCL? If not, we'll need the genetic definition of EZB rolled into these too. I also think that these cases must be GCB DLBCL but I'm not sure if that's been established in the literature. I'll ask a colleague to chime in on this thread to clarify.

EZB-MYC+ diffuse large B-cell lymphoma EZB-MYC+ A diffuse large B-cell lymphoma that is characterized by expression of the double-hit gene expression signature (DHITsig+).

EZB-MYC- diffuse large B-cell lymphoma EZB-MYC– A diffuse large B-cell lymphoma that is characterized by lack of expression of the double-hit gene expression signature (DHITsig-).

[lkhilton]

Hi Lynn,

Ryan asked me to chime in to make sure the definitions of EZB-MYC+/- get characterized correctly (there has been a lot of confusion in the DLBCL community). If they can be children of EZB as Ryan suggested, I would go with these definitions:

EZB-MYC+ diffuse large B-cell lymphoma A sub-category of EZB diffuse large B-cell lymphoma that is characterized by expression of the double-hit gene expression signature (DHITsig+).

EZB-MYC- diffuse large B-cell lymphoma A sub-category of EZB diffuse large B-cell lymphoma that is characterized by lack of expression of the double-hit gene expression signature (DHITsig+).

If they can't be "children" of EZB, then we need to roll in the EZB definition:

EZB-MYC+ diffuse large B-cell lymphoma A category of diffuse large B-cell lymphoma that is characterized by a high frequency of EZH2 gene mutations and BCL2 gene translocations as well as expression of the double-hit gene expression signature (DHITsig+).

EZB-MYC- diffuse large B-cell lymphoma A sub-category of EZB diffuse large B-cell lymphoma that is characterized by a high frequency of EZH2 gene mutations and BCL2 gene translocations as well as the lack of expression of the double-hit gene expression signature (DHITsig+).

I am not aware that having a GCB cell-of-origin is a requirement for membership in any of the genetic subgroups, but EZB is certainly highly enriched for GCB COO and that could also be stated in the definition.

I have to say the way these NCI Thesaurus definitions are written is not as precise as I would like. There are many tumours in each of these genetic classes that lack one or more of the mutations named in the definition - those mutations were used as seeds to identify the shared genetics of members of these groups beyond the "defining" mutations. For example, the MCD genetic subgroup is characterized by frequent mutations of MCD and CD79B, but there are MCD tumours that lack one or both of these, and it is certainly not a requirement for them to co-occur. Is it possible to change them and cite the LymphGen paper as well to minimize the confusion that they may cause? Can we adjust the definitions for the sake of CIVIC even if they don't exactly match the NCI Thesaurus definitions?

[lschriml]

Thank you Ryan, I will incorporate these updates. Much appreciated, Lynn

On Wed, Mar 9, 2022 at 7:51 PM rdmorin @.***> wrote:

Hi Lynn. This is a great synopsis of those two categories. I would change "aneuploid" to "aneuploidy" in the A53 description. The EZB-MYC+ and EZB-MYC- are a lot trickier. The differentiation of the two is most accurately described in the context of the DHITsig expression status rather than MYC and BCL2 rearrangements. Describing them based solely on MYC/BCL2 is definitely insufficient. These cases are also both, by definition, subgroups of EZB rather than directly of DLBCL. Perhaps we need to make them children of EZB DLBCL rather than of DLBCL? If not, we'll need the genetic definition of EZB rolled into these too. I also think that these cases must be GCB DLBCL but I'm not sure if that's been established in the literature. I'll ask a colleague to chime in on this thread to clarify.

EZB-MYC+ diffuse large B-cell lymphoma EZB-MYC+ A diffuse large B-cell lymphoma that is characterized by expression of the double-hit gene expression signature (DHITsig+).

EZB-MYC- diffuse large B-cell lymphoma EZB-MYC– A diffuse large B-cell lymphoma that is characterized by lack of expression of the double-hit gene expression signature (DHITsig-).

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[lschriml]

Hello Laura, Thank you for these definitions. Yes, they can be child terms of EZB. Please post here any definitions you want updated and I will revise them and cite the LymphGen paper. We do not have to have the same definition as NCI.

Cheers, Lynn

On Thu, Mar 10, 2022 at 12:29 PM Laura Hilton @.***> wrote:

Hi Lynn,

Ryan asked me to chime in to make sure the definitions of EZB-MYC+/- get characterized correctly (there has been a lot of confusion in the DLBCL community). If they can be children of EZB as Ryan suggested, I would go with these definitions:

EZB-MYC+ diffuse large B-cell lymphoma A sub-category of EZB diffuse large B-cell lymphoma that is characterized by expression of the double-hit gene expression signature (DHITsig+).

EZB-MYC+ diffuse large B-cell lymphoma A sub-category of EZB diffuse large B-cell lymphoma that is characterized by lack of expression of the double-hit gene expression signature (DHITsig+).

If they can't be "children" of EZB, then we need to roll in the EZB definition:

EZB-MYC+ diffuse large B-cell lymphoma A category of diffuse large B-cell lymphoma that is characterized by a high frequency of EZH2 gene mutations and BCL2 gene translocations as well as expression of the double-hit gene expression signature (DHITsig+).

EZB-MYC+ diffuse large B-cell lymphoma A sub-category of EZB diffuse large B-cell lymphoma that is characterized by a high frequency of EZH2 gene mutations and BCL2 gene translocations as well as the lack of expression of the double-hit gene expression signature (DHITsig+).

I am not aware that having a GCB cell-of-origin is a requirement for membership in any of the genetic subgroups, but EZB is certainly highly enriched for GCB COO and that could also be stated in the definition.

I have to say the way these NCI Thesaurus definitions are written is not as precise as I would like. There are many tumours in each of these genetic classes that lack one or more of the mutations named in the definition - those mutations were used as seeds to identify the shared genetics of members of these groups beyond the "defining" mutations. For example, the MCD genetic subgroup is characterized by frequent mutations of MCD and CD79B, but there are MCD tumours that lack one or both of these, and it is certainly not a requirement for them to co-occur. Is it possible to change them and cite the LymphGen paper as well to minimize the confusion that they may cause? Can we adjust the definitions for the sake of CIVIC even if they don't exactly match the NCI Thesaurus definitions?

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[rdmorin]

EZB diffuse large B-cell lymphoma (DLBCL) is a sub-category of DLBCL that is categorized as EZB according with high probability by the LymphGen algorithm. This is based on a combination of genetic features and EZB DLBCLs often, but do not always, have hot spot mutations in EZH2 and/or a BCL2 translocation. This class can be further subdivided into two sub-classes EZB-MYC+ and EZB-MYC- using the double hit gene expression signature (DHITsig).

EZB-MYC+ diffuse large B-cell lymphoma (DLBCL) is a sub-category of EZB DLBCL that expresses the double hit gene expression signature (DHITsig+) according to gene expression profiling. In addition to the features characteristic of EZB, these cases commonly, but do not always, harbour MYC translocations and DDX3X mutations.

EZB-MYC- diffuse large B-cell lymphoma (DLBCL) is a sub-category of EZB DLBCL that does not express the double hit gene expression signature (DHITsig-) according to gene expression profiling. These cases tend to have few MYC translocations or DDX3X mutations.

[rdmorin]

If the way the three definitions are written above will be acceptable then I can draft one for the other subgroups also.

[rdmorin]

@lschriml should I go ahead and draft these for the other genetic subgroups?

[lschriml]

Yes, please !!

Sent from my iPhone

On Apr 6, 2022, at 9:31 AM, rdmorin @.***> wrote:

 @lschriml should I go ahead and draft these for the other genetic subgroups?

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[rdmorin]

All in one place

@lkhilton Can you review?

EZB diffuse large B-cell lymphoma (DLBCL) is a sub-category of DLBCL that is categorized as EZB with high probability by the LymphGen algorithm. This is based on a combination of genetic features and EZB DLBCLs often, but do not always, have hot spot mutations in EZH2 and/or a BCL2 translocation. This class can be further subdivided into two sub-classes EZB-MYC+ and EZB-MYC- using the double hit gene expression signature (DHITsig). This subgroup also commonly has mutations due to aberrant somatic hypermutation affecting IRF8, which can be coding or non-coding.

EZB-MYC+ diffuse large B-cell lymphoma (DLBCL) is a sub-category of EZB DLBCL that expresses the double hit gene expression signature (DHITsig+) according to gene expression profiling. In addition to the features characteristic of EZB, these cases commonly, but do not always, harbour MYC translocations and DDX3X mutations.

EZB-MYC- diffuse large B-cell lymphoma (DLBCL) is a sub-category of EZB DLBCL that does not express the double hit gene expression signature (DHITsig-) according to gene expression profiling. These cases tend to have few MYC translocations or DDX3X mutations.

MCD diffuse large B-cell lymphoma (DLBCL) is a sub-category of DLBCL that is categorized as MCD with high probability by the LymphGen algorithm. This is based on a combination of genetic features and MCD DLBCLs often, but do not always, have the most common hot spot mutation in MYD88 (L265P) and/or activating mutations in CD79B. This subgroup also commonly has mutations due to aberrant somatic hypermutation affecting PIM1 and/or ETV6, which can be coding or non-coding.

BN2 diffuse large B-cell lymphoma (DLBCL) is a sub-category of DLBCL that is categorized as BN2 with high probability by the LymphGen algorithm. This is based on a combination of genetic features and BN2 DLBCLs often, but do not always, have a translocation involving the BCL6 locus and/or some combination of mutations affecting NOTCH2, TNFAIP3, BCL10 and UBE2A. This subgroup also commonly has mutations due to aberrant somatic hypermutation affecting CD70, which can be coding or non-coding.

ST2 diffuse large B-cell lymphoma (DLBCL) is a sub-category of DLBCL that is categorized as ST2 with high probability by the LymphGen algorithm. This is based on a combination of genetic features and ST2 DLBCLs often, but do not always, have missense or nonsense mutations affecting TET2 and NFKBIA. This subgroup also commonly has mutations due to aberrant somatic hypermutation affecting some combination of SGK1, ZFP36L1, SOCS1, HIST1H1E and CD83, which can be coding or non-coding.

N1 diffuse large B-cell lymphoma (DLBCL) is a sub-category of DLBCL that is categorized as N1 with high probability by the LymphGen algorithm. This is based on a combination of genetic features. Although N1 DLBCLs always have an activating mutation affecting NOTCH1, LymphGen can assign cases with this mutation to other classes, depending on the presence of other genetic features.

[lkhilton]

Looks great, @rdmorin.

[lschriml]

The definitions are all in the DO's April release. Cheers, Lynn

[rdmorin]

Great! It looks like the EZB subtypes (EZB-MYC+ and EZB-MYC-) didn't make it in. The ones that were added also don't appear to use the definitions I had drafted in my earlier comment. Can they be updated in a subsequent release?

[lschriml]

The data files have been updated, the website has not yet been updated. Likely next week.

Sent from my iPhone

On Apr 28, 2022, at 4:31 PM, rdmorin @.***> wrote:

 Great! It looks like the EZB subtypes (EZB-MYC+ and EZB-MYC-) didn't make it in. The ones that were added also don't appear to use the definitions I had drafted in my earlier comment. Can they be updated in a subsequent release?

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[rdmorin]

Understood. Thanks for clarifying!