Table 1.
Examples of common hereditary cancer predisposition syndromes
| Syndrome | Gene(s) | Inheritance | Clinical characteristics | Tumor types | Cancer risk |
|---|---|---|---|---|---|
| DNA damage repair defects/genetic instability | |||||
| Ataxia telangiectasia (AT) * | ATM | AR | Progressive ataxia, central nervous system degeneration, growth deficiency, ocular and facial telangiectasias, immunodeficiency, infertility, premature aging | Leukemia, lymphoma, carcinoma | 10–38 % overall cancer risk 70-fold increased leukemia risk (T-ALL, T-PLL) 250-fold increased lymphoma risk (B cell) |
| Bloom syndrome (BS) | BLM | AR | Short stature, immunodeficiency, malar rash, microcephaly, high-pitched voice, hypogonadism | Leukemia, lymphoma | 50 % overall cancer risk 15 % leukemia risk 15 % lymphoma risk |
| Constitutional mismatch repair-deficiency syndrome (CMMR-D) | MLH1, MSH2, MSH6, PMS2 | AR | Multiple café au lait (CAL) spots, features reminiscent of NF1 | Pediatric brain tumors, colorectal cancers, ALL, AML, lymphoma, early onset gastrointestinal or gynecological cancers | Biallelic mutations at very high risk |
| Fanconi anemia (FA) | FANCA, C, D1, D2, E, F, G, I, J, L, M, RAD51C, SLX4/BTBD12 FANCB |
AR X-linked |
Bone marrow failure, growth failure, radial ray abnormalities, renal abnormalities, CAL spots, hypopigmentation, congenital heart disease, microphthalmia, ear anomalies/deafness, hypogonadism; up to 25 % phenotypically normal | Leukemia (MDS, AML), squamous cell carcinoma, gynecological tumors, brain tumors, Wilms tumor, neuroblastoma | 25 % cumulative risk of hematologic malignancy by age 45 7 % MDS 9 % (500-fold increased risk of) AML |
| Li-Fraumeni syndrome (LFS) | TP53 | AD up to 25 % de novo mutations | beyond classical LFS malignancies phenotypically normal | Soft tissue sarcoma, osteosarcoma, breast cancer, adrenocortical carcinoma (ACC), leukemia, brain tumors (glioblastoma multiforme, high-grade astrocytoma/primitive neuroectodermal tumor, medulloblastoma, choroid plexus carcinoma) | 90 % lifetime risk to develop cancer 1–3 % ALL (hypodiploid ALL) |
| Nijmegen breakage syndrome (NBS) | NBS1 | AR | Microcephaly, prominent midface, receding mandible, CAL, recurrent infections, bone marrow failure | NHL, DLBCL, Burkitt lymphoma, T-LBL/-ALL, AML, Hodgkin lymphoma, medulloblastoma, rhabomyosarcoma | 40 % cancer risk by the age of 20 years |
| Bone marrow failure (BMF) syndromes: ribosome biogenesis and/or telomere maintenance anomalies | |||||
| Congenital amegakaryocytic thrombocytopenia (CAMT) type I / II | MPL | AR | Thrombocytopenia and megakaryocytopenia with no physical anomalies | MDS/AML | Unknown |
| Diamond blackfan anemia (DBA) | RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS26, RPS10, GATA1 | AD Majority sporadic | Normochromic macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow, growth retardation, craniofacial, upper limb, heart, and urinary system congenital malformations, persistence of hemoglobin F | Adenocarcinoma of the colon, sarcoma, genital cancer, MDS/AML, ALL | 5.4 %-fold increased cancer risk |
| Dyskeratosis congenital (DC) | DKC1, CTC1, TERC, TERT, TINF2, NOP10, NHP2, WRAP53 | X-linked | Triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa | MDS/AML | 3–33 % leukemia risk |
| Shwachman-Diamond syndrome (SDS) | SBDS | AR (considered) | Exocrine pancreatic insufficiency, hematologic abnormalities (pancytopenia), skeletal abnormalities | MDS/AML, ALL | 5–24 % leukemia risk |
| Severe congenital neutropenia (SCN) (Kostmann syndrome) * | ELANE, HAX1 | AD AR | Congenital neutropenia, recurrent/persistent infections, omphalitis | MDS/AML | 8–25 % leukemia risk |
| Thrombocytopenia and absent radii syndrome (TAR) | RBM8A and/or microdeletion 1q21.1 | Unclear | Reduction in the number of platelets and absence of the radius | MDS/AML | Unknown |
| Cell cycle/differentiation defects (RAS pathway dysfunction) | |||||
| CBL syndrome | CBL | AD | Dysmorphic facial features, short neck, developmental delay, hyperextensible joints, and thorax abnormalities with widely spaced nipples | JMML | Unknown |
| Neurofibromatosis type I (NF1) | NF1, SPRED1 | AD | CAL, axillary/inguinal frecking, Lisch nodules, bony dysplasia, seizures, learning difficulties, sphenoid wing abnormalities | CMML/JMML, AML, neurofibroma, optic pathway glioma, peripheral nerve sheath tumor, astrocytoma, paraganglioma/pheochromocytoma | 200–500-fold increased JMML risk 11 % MDS 5-fold increased brain tumor risk almost 100 % neurofibroma risk |
| Noonan/Noonan-like syndrome | PTPN11, HRAS, KRAS, NRAS, RAF1, SOS1, BRAF, SHOC2, MEPK1 | AD | Short stature, short webbed neck, lymphedema, hypertelorism, coarse facies, CAL, pulmonary valve stenosis, pectus excavatum, wide and low-set nipples, cardiomyopathy, bleeding disorders | Self-resolving myeloproliferative disease (MPD/TMD) and JMML, CMML, ALL, neuroblastoma, rhabdomyosarcoma | MPD/JMML in pts with PTPN11 |
| Transcription factors/pure familial leukemia syndromes | |||||
| Familial CEBPA leukemia | CEBPA | AD | None | MDS/AML | FAB M1/M2 highly penetrant |
| Familial ETV6 / ALL syndrome | ETV6 | AD | Thrombocytopenia | MDS/AML, MPAL, ALL, multiple myeloma, colon cancer | Unknown |
| Familial platelet disorder with predisposition to myeloid malignancy (FPD/AML) | RUNX1 (dominant) | AD | Mild to moderate thrombocytopenia, platelet function abnormalities | MDS/AML | 35 % AML risk |
| Familial PAX5 syndrome | PAX5 | AD | None | ALL | 30 % penetrance in PAX5 SNP allele carriers PAX5 c.547G > A |
| MonoMac | GATA2 | AD | Monocytopenia, NK cell lymphopenia, infections | MDS/AML | 50 % leukemia risk |
| Immunodeficiencies | |||||
| Wiskott-Aldrich syndrome (WAS) | WAS | X-linked | Eczema, thrombocytopenia, immunodeficiency | Diffuse large B cell lymphomas, non-Hodgkin’s lymphoma of larynx, leukemia, cerebellar astrocytoma, Kaposi sarcoma, smooth muscle tumors | 5–13 % lymphoid malignancies |
| X-linked lymphoproliferative (XLP) syndrome type I / II | SH2D1A XIAP, SAP | X-linked | Severe immune dysregulation often after viral infection, typically with Epstein-Barr virus (EBV), severe or fatal mononucleosis, acquired hypogammaglobulinema, (HLH), lymphomatoid granulomatosis | Hemophagocytic lymphohistiocytosis (HLH), non-Hodgkin lymphoma | Unknown |
| Autoimmune lymphoproliferative syndrome (ALPS) type IA/B/II | CD95 CD95L CASP10 IL12RB1 | AD AR in ALPS1A | Lymphadenopathy with hepatosplenomegaly and autoimmune cytopenias, hypergammaglobulinema | Hodgkin (HL) and non-Hodgkin (NHL) lymphoma, carcinoma (thyroid, breast, skin, tongue, liver), multiple neoplastic lesions (thyroid/breast adenomas, gliomas) | 14-fold NHL risk 51-fold HL risk |
| IL2-inducible T cell kinase deficiency | ITK | AR | Fever, lymphadenopathy, splenomegaly, EBV associated lymphoproliferation | Hodgkin lymphoma, | Unknown |
| Unknown | |||||
| Familial mosaic monosomy 7 | Unknown | Unknown | Early-childhood onset of bone marrow insufficiency / failure | MDS, AML | Very high, fatal outcome |
| Congenital syndromes/aneuploidy | |||||
| Beckwith-Wiedemann syndrome (BWS) | p57, H19, LIT1, ICR1, CDKN1C, NSD1 | complex (AD, genomic imprinting, pUPD) | Overgrowth syndrome, marcoglossia, omphalocele, hemihypertrophy, neonatal hypoglycemia | Wilms tumor, hepatoblastoma, adrenal carcinoma, rhabdomyosarcoma | 8.6 % cancer risk, depending on subtypes highest risk in patients with hemihypertrophy and organomegaly |
| Cowden syndrome type I-VI (CWS) | PTEN, SDHB, SDHD, KLLN | AD | Hamartomatous polyps of the gastrointestinal tract, mucocutaneous lesions, cobblestone-like papules of the gingiva and buccal mucosa, multiple facial trichilemmomas | Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos), colon, breast and thyroid cancer | Lifetime risk 25–30 % breast cancer 10 % thyroid cancer 5–10 % endometrial/uterine cancer |
| Denys-Drash syndrome (DDS) | WT1 (dominant) | Usually sporadic | Diffuse mesangial sclerosis leading to early endstage renal disease, disorder of sexual development in XY patients | Wilms tumor, gonadoblastoma | Almost 100 % Wilms tumor |
| Down syndrome (DS) | Trisomy 21 | n.a. | Facial dysmorphism, mental retardation, hypotonia, congenital heart disease | TMD, AML, ALL | 10 % TMD, 1–2 % ALL/AML 10–20-fold increased leukemia risk 500-fold increased risk of AMKL |
| Familial Adenomatous Polyposis (FAP) syndrome | APC | AD | Intestinal polyposis, osteomas, fibromas, sebaceous cysts, dental abnormalities | Colon, thyroid, stomach, and intestinal cancer, hepatoblastoma, desmoid tumors, medulloblastoma | Almost 100 % colorectal cancer |
| Familial neuroblastoma | ALK, PHOX2B | AD | None | Neuroblastoma | Unknown |
| Familial Pleuropulmonary blastoma tumor predisposition syndrome | DICER1 | AD | Pulmonary cysts, multinodular goiter | PPB, cystic nephroma, Sertoli-Leydig cell tumors, rhabdomyosarcoma, supratentorial primitive neuroectodermal tumor, intraocular medulloepithelioma | Variable penetrance, exact rest unknown |
| Hereditary paragangliomas and pheochromocytoma syndrome (HPPS) | SDHB | AD | None | Paraganglioma, pheochromocytoma, renal, thyroid | >70 % with metastatic disease 12 % GISTs |
| Multiple endocrine naeoplasia type I (MEN1) | MEN1 | AD | None | Pancreatic islet cell tumor, pituitary adenoma, parathyroid adenoma | 10 % carcinoid tumors |
| Multiple endocrine neoplasia type II (MEN2A, MEN2B) | RET | AD | Mucosal neuroma (intestinal tract, tongue, lips), marfanoid habitus | Medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia | 100 % risk of developing medullary thyroid carcinoma in MEN2A |
| Nevoid basal cell carcinoma syndrome (NBCCS) / Gorlin syndrome | PTCH1, 2, SUFU | AD | Macrocephaly, hypertelorism, palmar or plantar pits, rib abnormalities, ectopic calcification of the falx cerebri | Basal cell carcinoma, desmoplastic medulloblastoma, ovarian fibromas | 90 % basal-cell carcinoma, 5 % medulloblastoma |
| Peutz Jeghers syndrome (PJS) | STK11 | AD | Melanocytic macules of the lips, buccal mucosa, digits, multiple gastrointestinal hamartomatous polyps | Intestinal, ovarian, pancreatic, breast cancers | 55 % gastrointestinal cancer 45 % breast cancer |
| Familial retinoblastoma syndrome (RB) | RB1 | AD | Leukocoria | Retinoblastoma, osteosarcoma, melanoma, glioma, carcinoma | 80 % bilateral retinoblastoma 20 % unilateral retinoblastoma |
| Rhabdoid tumor predisposition syndrome | SMARCB1/INI1 | Unclear, up to 21 % de novo mutations | None | Rhabdoid tumor, medulloblastoma, choroidplexus tumor, schwannoma | Penetrance unclear |
| Rubinstein-Taybi syndrome (RSTS) | CREBBP | AD | Short stature, learning difficulties, distinctive facial features, broad thumbs and first toes, microcephaly, growth retardation | Neuroblastoma, medulloblastoma, oligodendroglioma, meningeoma, pheochromocytoma, rhabdomyosarcoma, leiomyosarcoma, leukemia, lymphoma | Unknown |
| Tuberous sclerosis complex (TSC) | TSC1/TSC2 | AD | Tubers, heterotopia, central nervous system migrational/psychomotor delay, seizures, renal/bone cysts | Subependymal giant cell astrocytoma, hamartoma, renal angiomyolipoma, renal cell carcinoma, cardial rhabdomyoma, renal angiomyolipoma | 4 % renal cell carcinoma 14 % giant cell astrocytoma |
| Lynch syndrome type I / II | MLH1, MSH2, MSH6, PSM2 | AD | CAL | Colorectal cancer, glioblastoma multiforme, medulloblastoma | Depending on subtype 50.4 % cumulative risk for colorectal cancer at the age of 70 |
| WAGR syndrome | WT1 | AD | Aniridia, genitourinary abnormalities, mental retardation | Wilms tumor, gonadoblastoma | High percentage of bilateral Wilms tumors |
*And cell cycle regulation