CHRONIC LYMPHOCYTIC LEUKEMIA (most mutations frequencies higher with time and with treatment) |
TP53 | Master regulator of cell cycle, DNA damage response and apoptosis (tumor suppressor); strong correlation with del17p | Deletions and inactivating point mutations | 7-12% | Poor prognosis; BCR pathway inhibitors, alemtuzumab and allogeneic HSCT only effective currently approved treatments |
NOTCH1 | Transmembrane receptors, signaling through which regulates cell death, proliferation and differentiation | Gain of function frameshift mutations lead to a truncated, constitutively active protein that lacks degradation signals | 10-12% | Strong correlation with trisomy 12; may predict for lack of benefit of adding rituximab to fludarabine plus cyclophosphamide (CLL8 trial); associated with unmutated IGHV and poor outcome |
FBXW7 | Ubiquitin ligase known to be a tumor suppressor | Loss of function mutations→impaired degradation of Notch1, c-Myc, c-Jun, cyclin E1, Mcl-1 | 2.5% (newly diagnosed patients) | Associated with trisomy 12 and with NOTCH1 mutations; nearly exclusive of SF3B1 mutations |
SF3B1 | RNA splicing protein – core component of U2 snRNP, which recognizes the 3’ splice site at intron-exon junctions | Spliceosome mutations→decreased or increased transcription of normal pre-mRNA, exon skipping, intron retention and cryptic splice sites; associated with aberrant DDR | 9-18% | Found primarily in patients with del11q and normal karyotype; confer adverse prognosis; almost mutually exclusive with NOTCH1 and FBXW7 mutations |
BIRC3 | Negative regulator of non-canonical NF-κB pathway | Inactivating mutations, deletions and insertions that disrupt gene function→non-canonical NF-κB activation | 4% (newly diagnosed patients) | Associated with fludarabine refractoriness (24%); mutually exclusive of TP53 abnormalities |
MYD88 | Critical adaptor molecule of the interleukin-1/toll-like receptor signaling (TLR) pathway | Mutations activate toll-like receptor pathway via IRAK1/4 to engage NF-κB and MAPK pathways | 1.5% (newly diagnosed patients) | Younger patients; associated with del13q, mutated IGHV and low CD38/ZAP-70 expression; favorable outcome |
XPO1 | Exportin; controls localization of cyclin B and members of MAPK pathway | | 3.4% (newly diagnosed patients) | May be associated with CD38/ZAP-70 positivity, NOTCH1 mutations and unmutated IGHV |
SAMHD1 | Enzyme that degrades the intracellular pool of dNTPs, limiting DNA synthesis; involved in DDR | Inactivating mutations lead to loss of tumor suppressor function→increased cellular survival and proliferation | 3% (up to 11% in relapsed/refractory setting) | May serve as biomarker of chemoresistance, fludarabine in particular |
ATM | Proximal transducer of DNA damage signals within DDR network | Mutations disrupt DDR and impair apoptosis | 18% | ATM gene inactivation associated with del11q |
IGHV | Immunoglobulin heavy chain variable region | “Mutated” indicates sequence >2% different from germline sequence; indicative of antigen exposure of B-cells | 62% | Mutated IGHV generally confers favorable prognosis |
NFKBIE | Inhibitor of NF-κB activity with specific role in B-cell biology | | 11% (advanced phase patients) | |
EGR2 | Transcription factor that participates in control of cellular differentiation | Missense mutations affect transcription of target genes | 8% (advanced phase patients) | Associated with shorter time to treatment and poor survival |
Wnt pathway genes | Critical for proliferation and cell fate determination of many cell types, including B-cells | Activating mutations in different genes→greater dependence on Wnt pathway signaling (already hyperactive in CLL) | 14% overall | Not associated with any known CLL prognostic factor; multiple Wntpathway inhibitors being developed |
Ras/Raf/MAPK pathway genes | Major cellular pathway that controls proliferation, differentiation, transcription regulation and development | Activating mutations; some in subclones | <5% | May be amenable to therapeutic targeting by small molecule inhibitors |
HAIRY CELL LEUKEMIA (HCL) |
BRAF | Serine-threonine kinase; part of the Ras/Raf/MAPK signaling pathway which regulates cell survival, proliferation and differentiation | Activating V600E mutation | Nearly all cases | Efficacy of small molecule kinase inhibitors, e.g., vemurafenib, dabrafenib; may help distinguish from other B-cell lymphomas and leukemias |
B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL) |
RB1 | Tumor suppressor involved in cell cycle control | Various abnormalities lead to dysregulated cell cycle progression | 51% | |
p16 (CDKN2A) p15 (CDKN2B) | Endogenous CDK inhibitors | Various abnormalities (deletion, methylation) lead to unrestrained cell cycle progression | 40% 70% | Poor prognosis |
TP53 | Master regulator of cell cycle, DNA damage response and apoptosis (tumor suppressor) | Deletions and inactivating point mutations | 16% (92% in patients with low hypodiploidy, 63% with MYC translocations, 23% with complex karyotype) | Poor prognosis; more common in B-ALL than T-ALL; frequency increases with age; “double hit” of TP53 do worst |
IKZF1 | Transcription factor | Splicing abnormalities | >80% of patients with Ph+ ALL | Poor prognosis independent of Ph status |
“PHILADELPHIA CHROMOSOME LIKE” B-ALL (10-13% of children; 21-27% of adolescents /young adults) |
ABL1, ABL2, CSF1R, PDGFRB | Various rearrangements involving different fusion partners, e.g., EBF1-PDGFRB, NUP214-ABL1 | Signaling pathway activation (CRKL phosphorylation seen with fusions involving ABL1/2) | 12.6% | Sensitive to Bcr-Abl TKIs, e.g., imatinib, dasatinib |
EPOR | Various rearrangements involving different fusion partners, e.g., IGH-EPOR | Activation of JAK-STAT signaling | 3.9% | Sensitive to JAK1/2 inhibitor ruxolitinib |
JAK2 | Various rearrangements involving different fusion partners, e.g., PAX5-JAK2, ATF7IP-JAK2, BCR-JAK2, STRB3-JAK2 | Activation of JAK-STAT signaling | 7.4% | Sensitive to JAK1/2 inhibitor ruxolitinib |
CRLF2 | Various rearrangements involving different fusion partners, e.g., P2RY8-CRLF2, IGH-CRLF2 | Activation of JAK-STAT signaling | 49.7% | 55% have concomitant JAK1/2 mutation; sensitive to ruxolitinib even without concomitant JAK mutations |
IL7R, FLT3, SH2B3 (LNK), JAK1, JAK3, TYK2, IL2RB | Various alterations | Activation of JAK-STAT signaling | 12.6% | Role for therapeutic JAK inhibition? |
Ras/Raf/MAPK pathway genes | Major cellular pathway that controls proliferation, differentiation, transcription regulation and development | Activating mutations | 4.3% | MEK inhibitors? |
NTRK3, DGKH | | Fusion proteins, e.g., ETV6-NTRK3 | 0.9% | ETV6-NTRK3 sensitive to ALK inhibitor crizotinib |
IKZF1 | Transcription factor | Deletions or point mutations | 68% (vs. 16% in Bcr-Abl negative non-”Ph-like” ALL) | Inferior survival; more common in patients with kinase fusions than those with point mutations |
T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL) |
NOTCH1 | NOTCH1 signaling necessary for commitment to T-cell lineage and for thymic proliferation of T-cell progenitors | NOTCH1 may interact with PRC2, which influences stem cell renewal through epigenetic silencing of genes | >50% | NOTCH1 and FBXW7 mutant T-ALL may enjoy superior survival; miR223 appears to promote NOTCH1-driven T-ALL; gamma secretase inhibitors under study |
JAK1/JAK3/SH2B3 (LNK) Ras/Raf/MAPK pathway genes | Tyrosine kinases (JAK-STAT signaling critical to hematopoiesis) Major cellular pathway that controls proliferation, differentiation, transcription regulation and development | Enhanced cellular survival and proliferation | More frequent in early T-cell precursor (ETP) ALL; also FLT3, transcription factors (GATA3, ETV6, RUNX1, IKZF1) and histone modifiers (e.g., EZH2) often mutated in ETP ALL | ETP ALL carries a poor prognosis and has a mutational spectrum similar to myeloid tumors; V658F mutation in JAK1 homologous to V617F in JAK2 |
PHF6 | X-linked tumor suppressor | Deletions or inactivating mutations→aberrant expression of TLX1 (HOX11) transcription factor oncogene | 16% in children, 38% in adults | May explain greater incidence of T-ALL in males |
MULTIPLE MYELOMA (MM) |
KRAS, NRAS, BRAF | Major cellular pathway that controls proliferation, differentiation, transcription regulation and development | Activating mutations lead to activation of the MAPK pathway | 23%, 20% and 6% for KRAS, NRAS and BRAF, respectively | Can coexist, but usually only one clonal; combined MEK/BRAF inhibition worth exploring in clonal, BRAF-mutant multiple myeloma |
FGFR3 | Fibroblast growth factor receptor | Overexpression rather than mutation | 23% | |
MAF | Transcription factor | Overexpressed rather than mutation | 13% | c-MAF overexpression associated with poor survival |
DIS3 and FAM46C | Ribonuclease (DIS3) involved in RNA processing; both genes encode RNA-binding proteins; FAM46C functions in regulation of translation | Point mutations with loss of heterozygosity lead to loss of tumor suppressor function of DIS3 | 11% each | DIS3 aberrations more common in non-hyperdiploid cases; associated with del13q14 and IGH translocations and may predict for worse survival; these mutations rarely seen in other cancers |
LRRK2 | Serine threonine kinase that phosphorylates translation initiation factor 4EBP | Mutations lead to disruption of translational control | 8% | Protein homeostasis critical in MM because of high rate of immunoglobulin production; explains success of proteasome inhibitors |
TP53 | Master regulator of cell cycle, DNA damage response and apoptosis (tumor suppressor) | Deletions and inactivating point mutations | 8% | Poor prognosis; strong correlation with del17p |
TRAF3, BIRC2, BIRC3, CYLD, BTRC, CARD11, IKBIP, IKBKB, MAP3K1, LTB, MAP3K14, RIPK4, TLR4, TNFRSF1A | Genes associated with regulation of the NF-κB signaling pathway | Activation of NF-κB signaling, e.g., through deletions and mutations in CYLD or inactivating mutations in LTB | TRAF3 mutated in 5%; CYLD in 2%; others less frequent | Underlies fundamental role of NF-κB signaling and therapeutic efficacy of proteasome inhibitors |
MLL, MLL2, MLL3, UTX, WHSC1, WHSC1L1 | Histone modifying enzymes | Mutations lead to epigenetic derepression of transcription factor HOXA9 | | Aberrant HOXA9 expression could represent a new therapeutic target |
PRDM1 | Transcriptional repressor involved in plasmacytic differentiation | Missense and truncating frame shift or splice site mutations→loss of tumor suppressor function | 5% | |
RB1 | Tumor suppressor involved in cell cycle control | Mutations lead to dysregulated cell cycle progression | 3% | |
ACTG1 | Cytoplasmic actin found in nonmuscle cells | | 2% | |
EGR1 | Transcription factor | Somatic hypermutation | 3% | Not clear if “driver” or “passenger” mutations |
IRF4 (MUM1) | Transcription factor whose expression propels B-cells towards plasmacytic differentiation | Missense mutations, e.g., K123R, lead to gain of function | | |
SP140 | Transcription factor (tumor suppressor) | Missense, frame shift and splice site alterations | | |
CDKN2C, CDKN1B, CCND1 | Cell cycle regulatory genes | Overexpression of cyclins and/or deficiency of endogenous CDK inhibitors→enhanced proliferation | Cyclin D1 overexpressed in 36% | Efficacy of pharmacologic CDK inhibition, e.g., with dinaciclib, palbociclib |
PTPRD | Tyrosine phosphatase that dephosphorylates STAT3, which promotes IL-6 signaling | Homozygous deletions of tumor suppressor gene | | |
MAX | Transcription factor that functions as heterodimerization partner for MYC | Loss of heterozygosity of tumor suppressor gene | | |
WALDENSTROM’S MACROGLOBULINEMIA (WM)/LYMPHOPLASMACYTIC LYMPHOMA (LPL) |
MYD88 | Critical adaptor molecule of the interleukin-1/toll-like receptor (TLR) signaling pathway | Mutations, e.g., L265P, activate toll-like receptor pathway via IRAK1/4 to engage NF-κB and MAPK pathways | 91% of all patients with LPL | Can help diagnose WM/LPL in cases of uncertainty; explains high efficacy of BTK (ibrutinib) and proteasome (bortezomib) inhibitors in WM |
DIFFUSE LARGE B-CELL LYMPHOMA – GERMINAL CENTER B-CELL (GCB) AND ACTIVATED B-CELL (ABC) |
EZH2 | Histone methyltransferase (catalytic subunit of polycomb repressive complex, PRC2) | Gain of function mutations, e.g., at Y641, promote lymphomagenesis through transcriptional silencing of key antiproliferative tumor suppressor genes, e.g., CDKN1A | 22% of GCB DLBCL, not seen in ABC DLBCL | EZH2 inhibitors in early phase clinical trials |
PTEN | Negative regulator of PI3K/Akt/mTOR pathway (tumor suppressor) | PTEN deletion leads to constitutive activation of and addiction to PI3K/Akt/mTOR signaling | 11% of GCB DLBCL | Inhibtiors of PI3K (e.g., idelalisib), Akt and mTOR (e.g., everolimus, temsirolimus) being explored |
BCL-2 | Founding member of Bcl-2 family of mitochondrial apoptosis regulators; anti-apoptotic | Promotes cellular survival and a major determinant of resistance to chemotherapy | The most mutated gene in GCB DLBCL; t(14;18) found in 34% of cases of GCB DLBCL | Selective Bcl-2 antagonist (BH3-mimetic) venetoclax in clinical trials |
BCL-6 | Transcription factor; represses many target genes involved in proliferation, survival, cell growth and metabolism | Routinely overexpressed in DLBCL; activation may underlie resistance to treatment | Mutated (70%) or rearranged (40%) in essentially all cases of DLBCL | Small molecule inhibitors that disrupt Bcl-6 function in development |
CARD11 | Part of signaling complex of adaptor proteins that lead to BCR-dependent NF-κB activation upon antigenic stimulation | BCR signaling and NF-κB activation critical in ABC DLBCL | Up to 10% of cases of ABC DLBCL | CARD11 mutations predict for lack of efficacy of inhibition of upstream BCR pathway targets, e.g., BTK (ibrutinib) or PKC-beta |
CD79B | B-cell co-receptor | BCR signaling and NF-κB activation critical in ABC DLBCL | 21% of cases of ABC DLBCL | CD79B mutations correlate with sensitivity to selective PKC-beta inhibitor sotrastaurin |
MYD88 | Critical adaptor molecule of the interleukin-1/toll-like receptor (TLR) signaling pathway | Mutations, e.g., L265P, activate toll-like receptor pathway via IRAK1/4 to engage NF-κB and MAPK pathways→IL-6 /IL-10 production→autocrine JAK activation | 30% of cases of ABC DLBCL | |
TNFAIP3 (A20) | Negative regulator of NF-κB pathway (tumor suppressor) | Inactivating mutations and deletions | Biallelic inactivation occurs in 30% of cases of ABC DLBCL | Can coexist with mutations in both MYD88 and CD79B |
IRF4 (MUM1) | Transcription factor whose expression propels B-cells towards plasmacytic differentiation | A direct target of the NF-κB pathway that can induced by both the BCR and TLR pathways | Constitutive NF-κB activation is a pathogenic hallmark of ABC DLBCL | Lenalidomide selectively kills ABC DLBCL cells by cereblon-dependent IRF4 down-regulation |
c-MYC (cases harboring additional oncogenic rearrangements involving BCL2, BCL6 or CCND1 designated “double hit”) | Oncoprotein | Suppresses transcription of tumor suppressor tristetraprolin | 10% of patients with newly diagnosed DLBCL carry an underlying MYC rearrangement (translocation, amplification) | May be possible to target MYC using BET bromodomain BRD4 inhibitors |
BTK/Syk/Lyn/PKC-β/MALT1/JAK-STAT | Kinases involved in BCR signaling (JAK-STAT signaling driven by activating MYD88 mutations) | Therapeutic targets without activating mutations | “Chronic active” BCR signaling and NF-κB activation fundamental in ABC DLBCL | Multiple small molecule inhibitors being studied, e.g., ibrutinib (BTK), enzastaurin (PKC-β), ruxolitinib (JAK1/2) |
FOLLICULAR LYMPHOMA (FL) |
MLL2, CREBBP, EZH2, MEF2B | Histone modifying enzymes | CREBBP, MLL2, EZH2 alterations early events in lymphomagenesis and progression | Very high frequency overall; EZH2 mutated in 7-27% (gain of function mutations, e.g., at Y641) | Potential role for EZH2 inhibitors as in GCB DLBCL? |
HIST1H1B-E, OCT2 (POU2F2), IRF8, ARID1A | Linker histones – proteins that facilitate folding of higher order chromatin structures and regulate access of histone modifying enzymes and chromatin remodeling complexes to target genes | | 27% (HIST1H1B-E), 8% (OCT2/POU2F2), 6% (IRF8), 11% (ARID1A) | Mutations in HIST1H1B-E and in EZH2 or ARID1A largely mutually exclusive |
STAT6, SOCS1 | JAK-STAT signaling pathway genes | Mutations contribute to constitutive STAT6 activation and promotion of tumor cell survival | STAT6 12%, SOCS1 8% | Eventual role for JAK inhibitors? |
CARD11, CD79B, TNFAIP3 | NF-κB pathway genes - mutually exclusive mutations | Constitutive activation of NF-κB | CARD11 and TNFAIP3 each 11% (overall one third) | Implications for therapy as for ABC DLBCL |
EBF1 | Transcription factor important in B-cell development | Loss of function mutations lead to reduction in EBF1 target gene expression | 17% overall (genes important in B-cell development) | |
BCL2 | Founding member of Bcl-2 family of mitochondrial apoptosis regulators; anti-apoptotic | Promotes cellular survival and a major determinant of resistance to chemotherapy; overexpression characteristic of FL | Mutation frequency 12% at diagnosis; 53% at transformation (different from t(14;18) present in 80-90%) | Correlate with risk for transformation and death; Bcl-2 antagonist (BH3-mimetic) venetoclax in clinical trials in FL |
NOTCH1/2 | Transmembrane receptors, signaling through which regulates cell death, proliferation and differentiation | Gain of function mutations lead to truncated protein that lacks degradation signals | 6.3% | Female predominance, greater splenic involvement, lower frequency of t(14;18); gamma secretase inhibitors under study |
CDKN2A | p16(INK4a) and p14 (ARF) tumor suppressors | Inactivation of tumor suppressor gene through deletion or methylation | Deletion (8%), methylation (19%) | May predict for inferior survival, particularly in rituximab-treated patients |
MANTLE CELL LYMPHOMA (MCL) |
IGHV | Immunoglobulin heavy chain variable region | Mutations support antigen-driven selection in the clonogenicexplansion of MCL tumor cells | 15-40% | Correlate with SOX11 negativity, indolent clinical course, non-nodal presentation |
SOX11 | Transcription factor overexpressed (not mutated) in the vast majority of cases of MCL | Promotes angiogenesis via PDGF, regulates PAX5 expression and blocks terminal B-cell differentiation | >90% of cases of MCL, both cyclin D1 positive and negative (can help diagnose in latter situation) | Expression correlates with unmutated IGHV, aggressive clinical course and karyotypic complexity |
ATM | Proximal transducer of DNA damage signals within DDR network | Mutations disrupt DDR and impair apoptosis | 55% in SOX11+ MCL; 0% in SOX11- cases; 42% overall | Correlate with del11q |
CCND1 | Cyclin D1 | Activating mutations/overexpression drive cell cycle progression | Mutations more frequent in SOX11- cases (86% vs. 18%), and cases with mutated IGHV (58% vs. 19%); 14% overall | Likely acquired in germinal center microenvironment; CDK4/6 inhibitor palbociclib effective in MCL |
TP53 | Master regulator of cell cycle, DNA damage response and apoptosis (tumor suppressor) | Deletions and inactivating point mutations | 19-28% | Equally distributed regardless of SOX11 or IGHV status; correlate with del17p |
WHSC1 (MMSET), MLL2, MEF2B | Histone methyltransferases | WHSC1 mutations increase H3K36 methylation→genome wide hypomethylation of H3K27→ significant overexpression of proliferation and cell cycle regulation genes | Found virtually only in SOX11+/IGVH unmutated MCL (WHSC1 15%, MLL2 18%, MEF2B 5%); of all cases of MCL, WHSC1 mutated in 10%; MLL2 in 20% and MEF2B in 3.2% | WHSC1-mutant gene expression signature very similar to that seen in multiple myeloma with t(4;14); MLL2 and MEF2B mutations similar to those in DLBCL or FL |
TRAF2, BIRC3 | BIRC3 is a negative regulator of non-canonical NF-κB pathway; TRAF2 transduces signals from TNF receptors to NF-κB | Inactivating or splice site mutations (BIRC3) and activating mutations (TRAF2) lead to enhanced NF-κB activation | 6% (TRAF2); 10% (BIRC3) | BIRC3 mutations correlate with del11q; both suggest NIK (rather than BCR) signaling and alternative NF-κB pathway activation (resistance to BCR pathway inhibitors, e.g., ibrutinib) |
TLR2 | Toll-like receptor 2 (TLR pathway mediates innate immunity independent of antigenic stimulation) | Mutations lead to significantly increased production of IL-6, IL-1RA and IL-8 | Seen only in SOX11-/IGHV mutated MCL | |
NOTCH1/2 | Transmembrane receptors, signaling through which regulates cell death, proliferation and differentiation | Gain of function mutations lead to truncated protein that lacks degradation signals | 9.5% | A subset of tumors with adverse biological and clinical features; i.e., blastoid morphology and worse survival |
LARGE GRANULAR LYMPHOCYTIC LEUKEMIA (LGL leukemia) |
STAT3 | Signal transducer and activator of transcription, e.g., transducing signals from cytokine receptor-associated Janus kinases to the nucleus | Activating mutations | 40% | May correlate with greater prevalence of neutropenia and rheumatoid arthritis |