Genetic predisposition to BCP-ALL
| Rare, highly penetrant germline variations . | ||||||
|---|---|---|---|---|---|---|
| Syndrome, gene(s) . | Alteration . | Consequence . | Pathogenic variants . | Presentation . | Frequency . | References . |
| ETV6 | Missense, nonsense, frameshift, splice site, deletion | LOF, loss of transcriptional repression, probably dominant negative | Various, distributed throughout and clustered in DNA-binding Ets domain | Variable, thrombocytopenia, bleeding tendency, red cell macrocytosis, multilineage dysplasia, ∼1/3 have hematologic malignancies (ALL, MDS, AML). Solid tumors can occur in adulthood. | ∼1% of “sporadic” ALL | 107–114 |
| IKZF1 | Missense, nonsense, frameshift | LOF, altered subcellular localization, adhesion, and responsiveness to chemotherapy | Various, distributed throughout, mostly outside zinc finger regions | Immunodeficiency (CVID), autoimmunity, ALL | ∼1% of “sporadic” ALL | 115–119 |
| Li-Fraumeni syndrome, TP53 | Missense, nonsense, frameshift | LOF, decreased transcriptional activity | Various, distributed throughout and clustered in DNA binding | Osteosarcoma, breast cancer, soft-tissue sarcoma, brain tumors, adrenocortical carcinoma, ALL (mainly hypodiploid) | ∼0.5% of “sporadic” ALL | 109,120,121 |
| PAX5 | Missense | Hypomorphic variants, decreased repressive transcriptional activity | Arg38His Gly183Ser | ALL, no common abnormalities noted | Few affected families known | 122–125 |
| SH2B3 | Biallelic frameshift | Increased JAK-STAT signaling, accelerated proliferation of lymphoid cells | c.671insGGCCCCG p. Asp231Gly fs*38 | Mild developmental delay, growth retardation, autoimmunity, ALL | 2 siblings reported | 126 |
| TYK2 | Missense | GOF, promotes TYK2 autophosphorylation and activation of downstream STAT family members | p.Pro760Leu p.Gly761Val affecting the pseudokinase domain | ALL and second primary ALL | 2 unrelated patients reported | 127 |
| CMMRD syndrome, MLH1, MSH2, MSH6, PMS2 | Biallelic mutations | LOF | PMS2 c.1831dupA | Early-onset solid cancer and leukemia, café-au-lait spots, hypopigmented skin lesions, adenomatous polyps, pilomatricomas, or impaired immunoglobulin class switch recombination | ∼30% develop ALL or AML | 128,129 |
| Down syndrome (trisomy 21) | Trisomy, translocations | Aberrant gene dosage | Full trisomy of chromosome 21 or chromosome 21 translocations | Intellectual disability, cardiac abnormalities, facial dysmorphologies, transient abnormal myelopoiesis, predisposition to MDS, AML, ALL | ∼1% develop ALL or AML | 130 |
| Noonan syndrome, PTPN11, SOS1 | Missense, indels | GOF, dysregulate the RAS-MAPK pathway | PTPN11: SH2 domain, PTP domain interacting surfaces; SOS1: PH domain and distributed | Skin manifestations, growth retardation, facial dysmorphologies, cardiac abnormalities, neurofibroma, rhabdomyosarcoma, JMML, ALL, AML | ∼0.5% develop high hyperdiploid ALL | 131 |
| Rare, highly penetrant germline variations . | ||||||
|---|---|---|---|---|---|---|
| Syndrome, gene(s) . | Alteration . | Consequence . | Pathogenic variants . | Presentation . | Frequency . | References . |
| ETV6 | Missense, nonsense, frameshift, splice site, deletion | LOF, loss of transcriptional repression, probably dominant negative | Various, distributed throughout and clustered in DNA-binding Ets domain | Variable, thrombocytopenia, bleeding tendency, red cell macrocytosis, multilineage dysplasia, ∼1/3 have hematologic malignancies (ALL, MDS, AML). Solid tumors can occur in adulthood. | ∼1% of “sporadic” ALL | 107–114 |
| IKZF1 | Missense, nonsense, frameshift | LOF, altered subcellular localization, adhesion, and responsiveness to chemotherapy | Various, distributed throughout, mostly outside zinc finger regions | Immunodeficiency (CVID), autoimmunity, ALL | ∼1% of “sporadic” ALL | 115–119 |
| Li-Fraumeni syndrome, TP53 | Missense, nonsense, frameshift | LOF, decreased transcriptional activity | Various, distributed throughout and clustered in DNA binding | Osteosarcoma, breast cancer, soft-tissue sarcoma, brain tumors, adrenocortical carcinoma, ALL (mainly hypodiploid) | ∼0.5% of “sporadic” ALL | 109,120,121 |
| PAX5 | Missense | Hypomorphic variants, decreased repressive transcriptional activity | Arg38His Gly183Ser | ALL, no common abnormalities noted | Few affected families known | 122–125 |
| SH2B3 | Biallelic frameshift | Increased JAK-STAT signaling, accelerated proliferation of lymphoid cells | c.671insGGCCCCG p. Asp231Gly fs*38 | Mild developmental delay, growth retardation, autoimmunity, ALL | 2 siblings reported | 126 |
| TYK2 | Missense | GOF, promotes TYK2 autophosphorylation and activation of downstream STAT family members | p.Pro760Leu p.Gly761Val affecting the pseudokinase domain | ALL and second primary ALL | 2 unrelated patients reported | 127 |
| CMMRD syndrome, MLH1, MSH2, MSH6, PMS2 | Biallelic mutations | LOF | PMS2 c.1831dupA | Early-onset solid cancer and leukemia, café-au-lait spots, hypopigmented skin lesions, adenomatous polyps, pilomatricomas, or impaired immunoglobulin class switch recombination | ∼30% develop ALL or AML | 128,129 |
| Down syndrome (trisomy 21) | Trisomy, translocations | Aberrant gene dosage | Full trisomy of chromosome 21 or chromosome 21 translocations | Intellectual disability, cardiac abnormalities, facial dysmorphologies, transient abnormal myelopoiesis, predisposition to MDS, AML, ALL | ∼1% develop ALL or AML | 130 |
| Noonan syndrome, PTPN11, SOS1 | Missense, indels | GOF, dysregulate the RAS-MAPK pathway | PTPN11: SH2 domain, PTP domain interacting surfaces; SOS1: PH domain and distributed | Skin manifestations, growth retardation, facial dysmorphologies, cardiac abnormalities, neurofibroma, rhabdomyosarcoma, JMML, ALL, AML | ∼0.5% develop high hyperdiploid ALL | 131 |
| Frequent, low-penetrant germline variations in BCP-ALL . | ||||||||
|---|---|---|---|---|---|---|---|---|
| Location . | Gene . | dbSNP . | Position . | Risk allele . | RAF . | OR (95% CI) . | Comments . | References . |
| 2q22.3 | Intergenic | rs17481869 | 2:145366886 | A | 0.03 | 1.74 (1.45-2.09) | ETV6-RUNX1 | 132,133 |
| 2p16.1 | Intergenic | rs2665658 | 2:60599667 | A | 0.34 | 4.0 (2.47-6.49) | TCF3-PBX1 | 134 |
| 3q28 | TP63, intronic, upstream | rs17505102 | 3:189683987 | G | 0.92 | 1.37 (1.25-1.48) | ETV6-RUNX1 | 135 |
| 5q31.1 | IRF1-AS1 intronic | rs886285 | 5:132429514 | T | 0.53 | 1.29 (1.18-1.41) | Hyperdiploidy | 133 |
| 6p21.31 | BAK1 intronic | rs210143 | 6:33579153 | C | 0.79 | 1.30 (1.19-1.43) | Hyperdiploidy | 133 |
| 7p12.2 | IKFZ1 intergenic | rs17133805 | 7: 50409816 | G | 0.21 | 1.65 (1.56-1-74) | — | 25,136–138 |
| 8q24.1 | CCDC26 intronic | rs4617118 | 8:129143897 | G | 0.21 | 1.28 (1.19-1.37) | — | 139 |
| 8q24.21 | CCDC26 intronic | rs75777619 | 8:129172930 | G | 0.12 | 1.26 (1.17-1.36) | — | 133 |
| 9p21.3 | CDKN2A p.Ala148Thr | rs3731249 | 9:21970917 | T | 0.01 | 2.23 (1.90-2.61) | — | 140–142 |
| 9q21.3 | CDKN2B-AS1 (intronic) | rs77728904 | 9:22057531 | C | 0.05 | 1.72 (1.50-1.97) | — | 143,144 |
| 10p14 | GATA3 intronic | rs3824662 | 10:8062245 | A | 0.20 | 1.29 (1.21-1.38) | Ph-like | 145,146 |
| 10p12.31-12.2 | PIP4K2A intronic | rs2296624 and others | 10:22568017 | C | 0.73 | 1.25 (1.18-1.32) | Hyperdiploidy, all ethnic groups, frequency: Hispanics > Europeans > Africans | 138,146,147 |
| 10q21.2 | ARID5B intronic, upstream variant | rs10821936 | 10:61963818 | C | 0.36 | 1.80 (1.71-1.89) | Hyperdiploidy, all ethnic groups, frequency: Hispanics > Europeans > Africans | 25,136–138 |
| 10q26.13 | LHPP | rs12779301 | 10:124604086 | C | 0.61 | 1.22 (1.15-1.29) | — | 144 |
| intronic | rs35837782 | 10:126293309 | A>C/G/T | |||||
| 11p11.2 | PTPRJ intronic | rs3942852 | 11:48093537 | T | 0.71 | 1.23 (1.11-1.32) | ETV6-RUNX1 | 135 |
| 12q23.1 | ELK3 intronic | rs4762284 | 12:96218984 | T | 0.43 | 1.15 (1.12-1.19) | — | 144 |
| 14q11.2 | CEBPE, SLC7A8, regulatory region | rs2239630 | 14:23120140 | A | 0.64 | 1.28 (1.22-1.35) | More frequent in Europeans | 25,148 |
| 17q12 | GSDMB intronic | rs2290400 | 17:39909987 | T | 0.58 | 1.18 (1.11-1.25) | — | 139 |
| 17q21.32 | IGF2BP1 Regulatory region | rs10853104 | 17:49014714 | T | 0.44 | 1.33 (1.21-1.47) | ETV6-RUNX1 | 133 |
| 21q22.2 | ERG intronic | rs9976326 | 21:38404563 | T | 0.22 | 1.33 (1.21-1.46) | High hyperdiploidy | 133 |
| 21q22.2 | ERG intronic | rs2836365 | 21:38396352 | G | 0.28 | 1.56 (1.33-1.83) | TCF3-PBX1, more frequent in Hispanics | 149 |
| Frequent, low-penetrant germline variations in BCP-ALL . | ||||||||
|---|---|---|---|---|---|---|---|---|
| Location . | Gene . | dbSNP . | Position . | Risk allele . | RAF . | OR (95% CI) . | Comments . | References . |
| 2q22.3 | Intergenic | rs17481869 | 2:145366886 | A | 0.03 | 1.74 (1.45-2.09) | ETV6-RUNX1 | 132,133 |
| 2p16.1 | Intergenic | rs2665658 | 2:60599667 | A | 0.34 | 4.0 (2.47-6.49) | TCF3-PBX1 | 134 |
| 3q28 | TP63, intronic, upstream | rs17505102 | 3:189683987 | G | 0.92 | 1.37 (1.25-1.48) | ETV6-RUNX1 | 135 |
| 5q31.1 | IRF1-AS1 intronic | rs886285 | 5:132429514 | T | 0.53 | 1.29 (1.18-1.41) | Hyperdiploidy | 133 |
| 6p21.31 | BAK1 intronic | rs210143 | 6:33579153 | C | 0.79 | 1.30 (1.19-1.43) | Hyperdiploidy | 133 |
| 7p12.2 | IKFZ1 intergenic | rs17133805 | 7: 50409816 | G | 0.21 | 1.65 (1.56-1-74) | — | 25,136–138 |
| 8q24.1 | CCDC26 intronic | rs4617118 | 8:129143897 | G | 0.21 | 1.28 (1.19-1.37) | — | 139 |
| 8q24.21 | CCDC26 intronic | rs75777619 | 8:129172930 | G | 0.12 | 1.26 (1.17-1.36) | — | 133 |
| 9p21.3 | CDKN2A p.Ala148Thr | rs3731249 | 9:21970917 | T | 0.01 | 2.23 (1.90-2.61) | — | 140–142 |
| 9q21.3 | CDKN2B-AS1 (intronic) | rs77728904 | 9:22057531 | C | 0.05 | 1.72 (1.50-1.97) | — | 143,144 |
| 10p14 | GATA3 intronic | rs3824662 | 10:8062245 | A | 0.20 | 1.29 (1.21-1.38) | Ph-like | 145,146 |
| 10p12.31-12.2 | PIP4K2A intronic | rs2296624 and others | 10:22568017 | C | 0.73 | 1.25 (1.18-1.32) | Hyperdiploidy, all ethnic groups, frequency: Hispanics > Europeans > Africans | 138,146,147 |
| 10q21.2 | ARID5B intronic, upstream variant | rs10821936 | 10:61963818 | C | 0.36 | 1.80 (1.71-1.89) | Hyperdiploidy, all ethnic groups, frequency: Hispanics > Europeans > Africans | 25,136–138 |
| 10q26.13 | LHPP | rs12779301 | 10:124604086 | C | 0.61 | 1.22 (1.15-1.29) | — | 144 |
| intronic | rs35837782 | 10:126293309 | A>C/G/T | |||||
| 11p11.2 | PTPRJ intronic | rs3942852 | 11:48093537 | T | 0.71 | 1.23 (1.11-1.32) | ETV6-RUNX1 | 135 |
| 12q23.1 | ELK3 intronic | rs4762284 | 12:96218984 | T | 0.43 | 1.15 (1.12-1.19) | — | 144 |
| 14q11.2 | CEBPE, SLC7A8, regulatory region | rs2239630 | 14:23120140 | A | 0.64 | 1.28 (1.22-1.35) | More frequent in Europeans | 25,148 |
| 17q12 | GSDMB intronic | rs2290400 | 17:39909987 | T | 0.58 | 1.18 (1.11-1.25) | — | 139 |
| 17q21.32 | IGF2BP1 Regulatory region | rs10853104 | 17:49014714 | T | 0.44 | 1.33 (1.21-1.47) | ETV6-RUNX1 | 133 |
| 21q22.2 | ERG intronic | rs9976326 | 21:38404563 | T | 0.22 | 1.33 (1.21-1.46) | High hyperdiploidy | 133 |
| 21q22.2 | ERG intronic | rs2836365 | 21:38396352 | G | 0.28 | 1.56 (1.33-1.83) | TCF3-PBX1, more frequent in Hispanics | 149 |
| Frequent, prenatal, low-penetrant somatic variations in childhood BCP-ALL . | ||||
|---|---|---|---|---|
| Variation . | Alteration . | Function . | Frequency . | References . |
| ETV6-RUNX1 | Translocation | Chimeric transcription factor | ∼25% of BCP-ALL | 13,150 |
| High hyperdiploidy | Aneuploidy | Aberrant gene dosage | ∼25% of BCP-ALL | 151 |
| TCF3-PBX1 | Translocation | Chimeric transcription factor | ∼5-10% of BCP-ALL, frequency: Hispanics > Africans > Europeans | 152,153 |
| BCR-ABL1 | Translocation | Chimeric transcription factor | ∼3% | 154 |
| Frequent, prenatal, low-penetrant somatic variations in childhood BCP-ALL . | ||||
|---|---|---|---|---|
| Variation . | Alteration . | Function . | Frequency . | References . |
| ETV6-RUNX1 | Translocation | Chimeric transcription factor | ∼25% of BCP-ALL | 13,150 |
| High hyperdiploidy | Aneuploidy | Aberrant gene dosage | ∼25% of BCP-ALL | 151 |
| TCF3-PBX1 | Translocation | Chimeric transcription factor | ∼5-10% of BCP-ALL, frequency: Hispanics > Africans > Europeans | 152,153 |
| BCR-ABL1 | Translocation | Chimeric transcription factor | ∼3% | 154 |
CI, confidence interval; CMMRD, constitutional mismatch repair deficiency; CVID, common variable immunodeficiency; dbSNP, single nucleotide polymorphism database; GOF, gain of function; JMML, juvenile myelomonocytic leukemia; LOF, loss of function; MDS, myelodysplastic syndrome; OR, overall risk; RAF, risk allele frequency.