BWS: Methylation defects or uniparental disomy of 11p15 10% lifetime risk of several cancers, including 1. Wilms tumor (43%) 2. Hepatoblastoma (20%) 3. Adrenal cortical carcinoma (7%) 4. Neuroblastoma 5. RMS

DICER1 syndrome: Mutations in DICER1 disrupt the processing of miRNAs and predispose to: 1. PPB 2. Thyroid/multinodular goiter 3. Cystic nephroma 4. Botryoid RMS 5. Sertoli-Leydig sex cord-stromal tumors Ciliary body medulloepithelioma

Inherited Retinoblastoma: Associated with: 1. Osteosarcoma (25-40%; radiation!) 2. Pineoblastoma (trilateral retinoblastoma) 3. Soft tissue sarcomas (10-15%; leiomyosarcoma > fibrosarcoma > NRSTS > RMS) 4. Melanoma (15-20%)

Li-Fraumeni syndrome: Very high risk of cancer: 1. Sarcomas (soft tissue and osteosarcoma) 2. Malignant glioma 3. Low-hypodiploid ALL (31-39 chromosomes) 4. Choroid plexus carcinoma 5. Adrenocortical carcinoma

Tuberous sclerosis: Mutations in TSC1/2 Hypopigmented lesions (ash-leaf macules), facial angiofibromas, benign hamartomas (tubers) throughout the body, subependymal giant cell astrocytomas (MTOR inhibitor), renal cell carcinoma.

Ataxia-telangiectasia syndrome: ATM is vital in DNA repair Characterized by: 1. Ataxia and chorea when young 2. Telangiectasia later in life 3. Immunodeficiency and infections 4. Risk of developing leukemia and lymphoma 5. Sensitivity to ionizing radiation

Gorlin syndrome: Aka. nevoid basal cell carcinoma syndrome Associated with: 1. Basal cell carcinoma 2. 2. Benign jaw tumors (keratocystic odontogenic tumors) 3. An increased incidence of medulloblastoma (SHH subtype, as PTCH1 is in the SHH pathway)

Cowden syndrome: Characterized by 1. Benign hamartomas 2. Predisposition to breast and endometrial cancer (85%) 3. Thyroid cancer (35%) 4. Papillary RCC (35%) Most common mutations in PTEN

Rothmund-Thomson syndrome: Biallelic mutations Significant predispo to osteosarcoma (30% incidence) Associated with facial/extremity rash in infancy, sparse scalp hair, juvenile-onset cataracts, musculoskeletal defects

Multiple endocrine neoplasia type 2 (MEN2): Both type 2A and 2B have an increased risk of medullary thyroid carcinoma and pheochromocytoma MEN 2A also involves an increased risk for parathyroid adenoma MEN 2B is associated with mucosal neuromas and a marfanoid habitus

Familial platelet disorder with predisposition to AML: Have qualitative and quantitative platelet defects

von Hippel-Lindau disease: Autosomal dominant Associated with benign (hemangioblastomas in the CNS) and cancerous (renal cell carcinoma, pheochromocytoma) tumors Tumors occurrence in young adulthood

WHIM syndrome: Gain of function mutation Characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (neutrophils stuck in the bone marrow)

MonoMAC syndrome: Monocytopenia, B and NK cytopenia, and atypical mycobacterial infection Familial AML Emberger syndrome: Lymphedema, warts, and predisposition to AML/MDS

Hermansky-Pudlack syndrome type 2: Autosomal recessive Characterized by: 1. Albinism 2. Neutropenia and immune deficiency 3. Platelet defects (dense granules) 4. Propensity to develop HLH 5. Pulmonary fibrosis

Chediak Higashi: Autosomal recessive mutations Characterized by: 1. Albinism with giant granules in myeloid cells 2. Platelet defects (dense granules) 3. Propensity to develop HLH

Griscelli syndrome type 2: Autosomal recessive Characterized by partial albinism (silver hair) and a propensity to HLH

XLPS: Associated with 1. Immunodeficiency (B cells present but dys-/hypogammaglobulinemia) 2. Fulminant infections with EBV

Job's syndrome (aka. Hyper-IgE syndrome): autosomal dominant (STAT3) or recessive (TYK2, DOCK8) defects in JAK-STAT signaling Associated with defective 1. Immunodeficiency (neutrophil chemotaxis, T cell function, very elevated IgE, and eosinophilia) 2. Coarse facies 3. Severe skin, sinus, and pulmonary infections Patients require antimicrobial prophylaxis

X-linked sideroblastic anemia: ALAS2 encodes for the erythroid ALA-synthase that is part of the heme production synthesis Results in accumulation of erythroblasts with excess iron Visualization with Prussian Blue stain in the bone marrow Peripheral blood has two RBC populations (normocytic and microcytic)

Cytochrome b5 reductase deficiency: Autosomal recessive methemoglobinemia Type 1: Only RBCs are deficient in cytochrome b5 reductase resulting in lifelong methemoglobinemia, cyanosis, physiologic adaptation Type 2: All cells are deficient resulting in Type 1 symptoms, neurological complications, and death within the first year of life

Hemophilia A: Factor VIII intron 22 inversion with truncated protein Causes severe hemophilia A in 50% of patients

Cancer Predisposition Syndromes Flashcards by Laurie Davis

11p15
abnormalities

BWS: Methylation defects or uniparental disomy of 11p15
10% lifetime risk of several cancers, including
1. Wilms tumor (43%)
2. Hepatoblastoma (20%)
3. Adrenal cortical carcinoma (7%)
4. Neuroblastoma
5. RMS

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DICER1

DICER1 syndrome: Mutations in DICER1 disrupt the processing of miRNAs and predispose to:
1. PPB
2. Thyroid/multinodular goiter
3. Cystic nephroma
4. Botryoid RMS
5. Sertoli-Leydig sex cord-stromal tumors
Ciliary body medulloepithelioma

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RB1

Inherited Retinoblastoma: Associated with:
1. Osteosarcoma
(25-40%; radiation!)
2. Pineoblastoma (trilateral retinoblastoma)
3. Soft tissue sarcomas
(10-15%; leiomyosarcoma > fibrosarcoma > NRSTS > RMS)
4. Melanoma
(15-20%)

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TP53

Li-Fraumeni syndrome: Very high risk of cancer:
1. Sarcomas (soft tissue and osteosarcoma)
2. Malignant glioma
3. Low-hypodiploid ALL (31-39 chromosomes)
4. Choroid plexus carcinoma
5. Adrenocortical carcinoma

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TSC1/TSC2

Tuberous sclerosis: Mutations in TSC1/2
Hypopigmented lesions (“ash-leaf” macules), facial angiofibromas, benign hamartomas (“tubers”) throughout the body, subependymal giant cell astrocytomas
(MTOR inhibitor), renal cell carcinoma.

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ATM

Ataxia-telangiectasia syndrome: ATM is vital in DNA repair
Characterized by:
1. Ataxia and chorea when young
2. Telangiectasia later in life
3. Immunodeficiency and infections
4. Risk of developing leukemia and lymphoma
5. Sensitivity to ionizing radiation

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PTCH1

Gorlin syndrome: Aka. nevoid basal cell carcinoma syndrome
Associated with:
1. Basal cell carcinoma
2. 2. Benign jaw tumors (keratocystic odontogenic tumors)
3. An increased incidence of medulloblastoma (SHH subtype, as PTCH1 is in the SHH pathway)

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PTEN
KLLN
SDHB
SDHD

Cowden syndrome: Characterized by
1. Benign hamartomas
2. Predisposition to breast and endometrial cancer (85%)
3. Thyroid cancer (35%)
4. Papillary RCC (35%)
Most common mutations in PTEN

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PTPN11
SOS1
RAF1
RIT1

Noonan syndrome: Affect the RAS/MAPK pathway
Characterized by
1. Facial dysmorphism
2. Short stature
3. Congenital heart disease (e.g., pulmonary stenosis)
4. Increased risk of JMML, neuroblastoma, and ERMS

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RECQL4

Rothmund-Thomson syndrome: Biallelic mutations
Significant predispo to osteosarcoma (30% incidence)
Associated with facial/extremity rash in infancy, sparse scalp hair, juvenile-onset cataracts, musculoskeletal defects

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RET2

Multiple endocrine neoplasia type 2 (MEN2): Both type 2A and 2B have an increased risk of medullary thyroid carcinoma and pheochromocytoma
MEN 2A also involves an increased risk for parathyroid adenoma
MEN 2B is associated with mucosal neuromas and a marfanoid habitus

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RUNX1 (AML1)

Familial platelet disorder with predisposition to AML: Have qualitative and quantitative platelet defects

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VHL

von Hippel-Lindau disease: Autosomal dominant
Associated with benign (hemangioblastomas in the CNS) and cancerous (renal cell carcinoma, pheochromocytoma) tumors
Tumors occurrence in young adulthood

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CXCR4

WHIM syndrome: Gain of function mutation
Characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (neutrophils stuck in the bone marrow)

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GATA2

MonoMAC syndrome: Monocytopenia, B and NK cytopenia, and atypical mycobacterial infection
Familial AML
Emberger syndrome: Lymphedema, warts, and predisposition to AML/MDS

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HPS2 (aka AP3B1)

Hermansky-Pudlack syndrome type 2: Autosomal recessive
Characterized by:
1. Albinism
2. Neutropenia and immune deficiency
3. Platelet defects (dense granules)
4. Propensity to develop HLH
5. Pulmonary fibrosis

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LYST

Chediak Higashi: Autosomal recessive mutations
Characterized by:
1. Albinism with giant granules in myeloid cells
2. Platelet defects (dense granules)
3. Propensity to develop HLH

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RAB27A

Griscelli syndrome type 2: Autosomal recessive
Characterized by partial albinism (silver hair) and a propensity to HLH

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SH2D1A
XIAP

XLPS: Associated with
1. Immunodeficiency (B cells present but dys-/hypogammaglobulinemia)
2. Fulminant infections with EBV

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STAT3
TYK2
DOCK

Job’s syndrome (aka. Hyper-IgE syndrome): autosomal dominant (STAT3) or recessive (TYK2, DOCK8) defects in JAK-STAT signaling
Associated with defective
1. Immunodeficiency (neutrophil chemotaxis, T cell function, very elevated IgE, and eosinophilia)
2. Coarse facies
3. Severe skin, sinus, and pulmonary infections
Patients require antimicrobial prophylaxis

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ALAS2

X-linked sideroblastic anemia: ALAS2 encodes for the erythroid ALA-synthase that is part of the heme production synthesis
Results in accumulation of erythroblasts with excess iron
Visualization with Prussian Blue stain in the bone marrow
Peripheral blood has two RBC populations (normocytic and microcytic)

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CYB5R1-4

Cytochrome b5 reductase deficiency: Autosomal recessive methemoglobinemia
Type 1: Only RBCs are deficient in cytochrome b5 reductase resulting in lifelong
methemoglobinemia, cyanosis, physiologic adaptation
Type 2: All cells are deficient resulting in Type 1 symptoms, neurological complications, and death within the first year of life

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F8 Inv22

Hemophilia A: Factor VIII intron 22 inversion with truncated protein
Causes severe hemophilia A in 50% of patients

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GPI Deficiency

Glucose phosphate isomerase deficiency: 2nd most common hereditary nonspherocytic hemolytic anemia
Enzymopathy affecting anaerobic glycolysis and increased splenic clearance of RBCs
Associated with neurologic impairment

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HBM

* Inherited methemoglobinemia (α58 His→Tyr): Hgb variant with ferric iron * Patients are asymptomatic despite high levels of methemoglobin

P5N

* Pyrimidine 5'-nucleotidase deficiency: Autosomal recessive non-spherocytic hemolytic anemia * Characterized by basophilic stippling * Of note, lead toxicity inhibits pyrimidine 5'-nucleotidase and exhibits basophilic stippling

PKLR

* Pyruvate kinase deficiency: Most common hereditary non-spherocytic hemolytic anemia * Enzymopathy affecting anaerobic glycolysis and splenic clearance of RBCs

TMPRSS6

* Iron-refractory iron deficiency anemia (IRIDA): **Autosomal recessive** * Increased expression of the iron regulatory hormone hepcidin, which results in iron deficiency anemia that is refractory to oral iron and only partly responsive to parenteral iron

Adrenocortical Carcinoma

Li Fraumeni - TP53 Beckwith-Widemann - 11p15.5

Choroid Plexus Carcinoma, Anaplastic RMS, Hypodiploid ALL

Li Fraumeni - TP53

Desmoid Tumor

FAP - APC

Hepatoblastoma

Beckwith-Wideman - 11p15.5 FAP - APC

JMML

NF1 - NF1 Noonan - PTPN11, KRAS

Medullary Thyroid Carcinoma

MEN 2A/B - RET

Neuroblastoma

Familial - ALK Congenital central Hypovent synd - PHOX2B

Pleuropulmonary Blastoma

DICER1 Synd - DICER1

Pheochromocytoma/Paraganglioma

Pheo/paraganglioma syndrome - SDH NF1 - NF1 MEN2 A/B - RET von Hipple Lindau - VHL

Renal Cell Carcinoma

VHL - VHL

Rhabdoid Tumor, ATRT

Rhabdoid Tumor Syndrome - SMARCB1

Wilms Tumor

Beckwith-Wideman - 11p15.5 WAGR/Denys-Drash - WT1

Familial AML

CEBPA

alpha 1 Antitrypsin Deficiency

SERPINA1 - Hepatocellular Carcinoma

Bloom Syndrome

BLM - ALL/AML/Wilms

Bohring-Opitz Syndrome

ASXL1 - Wilms

CLOVES

PIK3CA - Wilms

CAMT

cMPL - AML

Congenital Hypoventilation Syndrome

PHOX2B - Neuroblastoma

Constitutional Mismatch Repair Def

PMS2, MLH1, MSH2/6 - ALL/High Grade Glioma/Early Colon Cancer

Costello

HRAS - Rhabdomyosarcoma

Cowden

PTEN - Papillary thyroid carcinoma

Denys Drash

WT1

Diamond- Blackfan

RPS19 - AML/MDS, ALL

Frasier Syndrome

WT1 - Wilms

Glycogen Storage Disease

Hepatoblastoma, Hepatocellular Carcinoma

Gonadal Dysgenesis

46XY Swyer, 45XO Turner - Germ Cell Tumors

Gorlin

PTCH1, SUFU - Basal cell carcinoma, Rhabdo, Medulloblastoma (SHH)

Klinefelter Synd

47 XXY - ALL, Germ Cell Tumor

Hereditary Leiomyomatosis

FH - Renal Cell Carcinoma

Li Fraumeni

Adrenocortical Carcinoma ERMS (anaplastic) Osteosarcoma Neuroblastoma Choroid Plexus Carcinoma Malignant Glioma Hypodiploid ALL AML

MEN -1

MEN1 - Pancreatic neuroendocrine, pituitary, parathyroid, adrenal cortical carcinoma

MEN-2A

RET - Medullary thyroid cancer

MEN-2B

RET - Medullary thyroid cancer, pheochromocytoma, paraganglioma

MEN4

CDKN1B - Pituitary adenoma, parathyroid tumor, GU tumors

Familial Neuroblastoma

ALK, RASopathies, PHOX2B

NF1

Optic glioma, MPNST, Pheochromocytoma, Rhabdomyosarcoma, GIST, Neuroblastoma, JMML, Early breast cancer, Adrenocortical carcinoma

NF2

NF2 - Acoustic schwannomas, meningiomas, astrocytoma, ependymoma

Nijmen Breakage Syndrome

NBN - ALL

Noonan

KRAS/PTPN11/CBL - JMML, ALL, Rhabdo, Neuroblastoma

Perlman

DIS3L2 - Wilms, Nephroblastoma

Peutz-Jegher

STK11 - Sex cord tumor w/ annular tubules

Pheochromocytoma/Paraganglioma

SDHx - Pheo, paraganglioma, renal cell carcinoma

Familial Platelet Disorder

RUNX1 - MDS/AML (Mono 7), anticipation

Heritable Retinoblastoma

RB - Retinoblastoma, Pineoblastoma, Osteosarcoma

Rhabdoid Tumor

SMARCB1 - Renal Rhabdoid, ATRT, Schwannomatosis

Rhabdoid Tumor Type 2

Small cell carcinoma of ovary (hypercalcemic), ATRT

Rothmund-Thompson

RECQL4 - Osteosarcoma

Schwachman - Diamond

SBDS, SBDSP++ - MDS/AML

Severe Congenital Neutropenia

ELANE, SCN7+ - MDS/AML (-7)

Simpson - Golabi - Behmel

GPC3 - Wilms

Sotos

NSD1 - Wilms

Thrombocytopenia 2

ANKRD26 - AML

Thrombocytopenia 5

ETV6 - Pre-B all (Hyperdiploid), MDS/AML

Tuberous Sclerosis

TSC1/2 - Subependymal giant cell astrocytoma (SEGA), Renal cell carcinoma

WAGR

11p- - Wilms

Risks of Germline TP53

75% - Anaplastic RMS, SHH Medulloblastoma 50% - ACC, Choroid plexus carcinoma, hypodiploid ALL 10% - Early onset breast cancer w/o BRCA 1/2

Cancer Predisposition Syndromes Flashcards

(85 cards)