Genetics

Patterns of Inheritance

 

Inherited vs acquired genetic disorders

 

Not all genetic disorders are inherited disorders

- many genetic defects are sporadic; acquired during oogenesis, spermatogenesis, or early embryogenesis

- for most genetic disorders, there are both inherited and sporadic forms, the latter termed "simplex" cases

- such sporadic defects are usually "germline" nevertheless; that is, the defect is present in all cells of the organism

- other genetic defects arise within a differentiated cell; such "somatic" defects are not found in germline DNA and are unlikely to be passed to offspring

 

Most common inheritance patterns

 

Autosomal dominant disorders

- at least 1 parent is affected

- males and females affected with equal frequency

- both males and females have a 50% chance of transmitting the condition to offspring

- modified by penetrance and expressivity. "Penetrance" refers to the proportion of persons with the mutation who manifest a phenotypic abnormality. "Expressivity" refers to the severity and range of manifestations

- often involve genes that encode structural proteins, receptor proteins, or transmembrane channels

 

Autosomal recessive disorders

- often generations are skipped (parents unaffected, but both parent are implied carriers)

- males and females are equally affected

- if a couple has an affected child, the likelihood of a 2nd affected child is 25%

- usually do not vary in terms of penetrance or expressivity

- usually involve genes that encode enzymes

 

X linked recessive disorders

- expressed almost exclusively in males

- males cannot pass the trait to their male offspring, but daughters are obligate carriers

- females have a 50% chance of passing the trait to their male offspring (who will be affected) and to their female offspring (who will be carriers)

- females may be affected if homozygous (can happen in regions of very high mutant gene frequency); asymmetric lyonization; or Turner syndrome (monosomy X)

 

21-hydroxylase - CYP21 gene [6p21]

- in the HLA locus

 

p53 (17p) - seen in lots o sporadic tumors

 

Achondrogenesis type IA - TRIP11

 

Achondrogenesis type IIB - DTDST

 

Alagille syndrome (aka arteriohepatic dysplasia)

AD, JAG1 mutation

- assoc c bile duct paucity, pulmonary artery stenosis, tetralogy, atrial septal defects, aortic stenosis, coarctation

 

ALCL - NMP-ALK [t(2;5)(p23;q35), in 4/5, good px], TMP3-ALK [t(2;other), in 1/10]

- no translocation seen in primary cutaneous ALCL

 

Alport syndrome - a5 chain of type IV collagen [COL4A5 mutation on Xp22.3]

- X-linked recessive

 

ALS - Copper / zinc superoxide dismutase (SOD1), cr 21; in 1/5 familial ALS cases (2% of all ALS cases)

 

Alveolar soft parts sarcoma - ASPSCR1-TFE3 [t(X;17)(p11;q25), in 9/10, TFE3 from Xp11.2]

- also in RCC c Xp11.2

- TFE3 can be done by IHC

 

Alzheimer disease, Early onset (genetic) - APP [21] thus assoc c Down syndrome, presenilin-1 [14], presenilin-2 [1]

 

Alzheimer disease, Late onset - ApoE4 [19]

- ApoE2 [19] protective bc is a chaperone protein that helps B-pleated sheet formation

 

AML M0 - Undifferentiated AML

AML M1 - AML with minimal maturation

 

AML (formerly M2) - AML1(RUNX1)-ETO(RUNX1T1) [t(8;21)(q22;q22), 1/20 AML cases, good px]

- aka AML with maturation

- can present c granulocytic sarcoma

- ***ETO = Eight Twenty One !! ***

 

AML (formerly M3) - PML-RARA [t(15;17)(q22;q12), responds to ATRA], NPM1-RARA [t(5;17)(q35;q12), can also be responsive to ATRA], ZBTB16(PLZF)-RARA [t(11;17)(q23;q12), does not respond to ATRA], NUMA1-RARA [t(11;17)(q13;q12)], STAT5B-RARA [t(11;17)(q11;q12), no ATRA response]

- in 1/20, very good px

- aka Acute promyelocytic leukemia

 

AML (formerly M4) - CBFB-MYH11a [inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), good px, in 1/20, in 1/20, good px]

- assoc c granulocytic sarcoma and inc abnormal eos

 

AML (formerly M4 / M5) - MLLT3-MLL [t(9;11)(p22;q23)], MLL rearrangements (11q23 rearrangements)

- poor px

- has >80 translocations in >50 genes

- may be 2/2 tx effects of topo II inhibitors and kiddos c pre-B ALL

 

AML (M5 and s/p topo II therapy) - MLL [11q23]

 

AML (formerly M7) - RBM15-MKL1 [t(1;22)(p13;q13), <1/100, fair px]

- no assoc c Down syndrome; MC in kiddos

 

AML (various FAB numbers) - DEK-NUP214 [t(6;9)(p23;q34), in ~1/100, poor px, has monocytic features], RPN1-EVI1 [t(3;3)(q21;q26.2) or inv(3)(q21;q26.2), ~1/100, super poor px, has atypical megs and normal or inc platelets], FLT3 internal tandem duplications or point mutations (poor px)

 

Tx assoc AML - Alkalating tx (cyclophosphamide) [-7, del(7q), del(5q), -5, in 4/5, poor px, seen up to a decade after tx]; Topo II inhibitors (doxorubicin) - MLL [11q23, in 1/3, poor px, up to 5 yr after tx, no MDS phase just presents as AML]

 

Angelman - Maternal 15q11.2 microdeletion

- hyperactivity, inappropriate laughter, aphasia, ataxia, MR, seizures

 

Angiomatoid Fibrous Histiocytoma - EWS-ATF1 [t(12;22)(q13;q12)], EWS-CREB1 [t(2;22)(q33;q12)], FUS/TLS-ATF1 [t(12;16)(q13;p11), most specific]

- same as Clear cell sarcoma

 

Asphyxiating thoracic dystrophy - DYNC2H1

 

Atypical teratoid / rhabdoid tumor (AT/RT) - INH(hSNF5) [22q11.2 del or mut, in 3/4]

- nearly all have INI1 expression lost

 

(precursor) B-ALL - BCR-ABL [t(9;22)(q34;q11), in 1/4 adults, 1/20 kiddos, poor px]; MLL-AF4 [t(4;11)(q21;q23), MC in infants and adults, poor px], MLL-AF9 [t(9;11)(p22;q23)], PBX1-E2A [t(1;19)(q23;q13), 1/20 kiddos, poor px], hypodiploidy [in 1/20, poor px], TEL(ETV6)-AML1(RUNX1) [t(12;21)(p13;q22), good px, blasts are CD19+/10+/34+/9-/34-], hyperdiploidy [good px, in 1/4 kiddos], ETV6-AML1 [t(12;21)];

- Ph p190 >> p210; finding p210 should lead to thinking about CML blast crisis

 

B-cell lymphomas - Igk (2), IgL (22), IgH (14)

 

Birt-Hogg-Dube syndrome - AD, 17p11.2, BHD gene (folliculin)

 - Kidney cancer (multifocal, bilateral, hybrid oncocytoma and chromophobe renal cell carcinoma [HOCT, nearly 10/10]), renal and pulmonary cysts / pneumothorax, and fibrofolliculomas (trichodiscomas), acrocordon

 

Breast cancer - HER2 (ErbB2) amplification [17]

- can be targeted c trastuzumab (Herceptin)

- Her2 amplification in 20% of breast ca and assoc c higher nuclear grade and poor outcomes, though anti Her2 (trastuzumab) mitigates these aggressive features

 

BRCA -  AD, high penetrance, 80% lifetime risk of breast ca (vs 10% in general population), c additional inc risk of neoplasms of ovary, fallopian tube, colon, uterus and pancreas

- inc risk of prostate ca in males

- in a woman c breast ca who is found to harbor a BRCA mutation, the risk of cancer developing in the contralateral breast is 25%

- BRCA1 has neg ER/PR

- BRCA2 has pos ER/PR

 

Luminal A

ER and/or PR (+), HER2 negative, Ki67 < 14%; CK8/18+

- low grade ductal NOS, good px; little benefit of giving chemotx

 

Luminal B

ER and / or PR (+), HER2 negative, Ki67 >14%

or

ER and / or PR (+) and HER2 (+) (luminal HER2)

- also CK8/18+

 

HER2

ER / PR negative, HER2 (+), high Ki67

 

Basal-like

Triple negative, high Ki67, CK5/6 and / or EGFR (+)

- BRCA1 related

 

Burkitt lymphoma - MYC-IGH [t(8;14)(q24;q32) in 17/20], MYC-IGL [t(8;22)(q24;q11), rare], MYC-IGK [t(2;8)(p12;q24), rare]

- should not have concurrent BCL2 and BCL6 translocations

 

CADASIL - AD, 2/2 mutations in NOTCH3 (cr 19) which is involved c vascular sm muscle differentiation / development

- presents c migraine headaches, transient ischemic attacks, and strokelike events, progressing eventually to dementia

 

Cardiac defects - single gene mutations (NKX2-5 [5q34], GATA-4 [8p], TBX-5 [12q], TBX-1 [22q], PTPN11, JAG1); structural chromosomal disorders (Trisomy 21 Down syndrome, 45 X Turner syndrome, 22q11 microdeletion DiGeorge syndrome, 7q11.23 microdeletion William syndrome); and many multifactorial

 

Celiac disease - HLA-DQ2 and HLA-DQ8, which lovingly present gliadin to Th cells (absence of HLA-DQ2 and DQ8 have high neg-predictive values)

 

Chondroid lipoma - C11orf95/MKL2 [t(11;16)(q13;p12-13)]

 

Chondrosarcoma - mutations in IDH1 and IDH2

 

Chronic myeloproliferative dz - JAK2 V617F [invariably in PV, PMF (1/2), ET (1/2) and chronic eosinophilic leukemia (rarely)], del(13)(q12-22) or der(6)t(1;6)(q21-23;p21.3) highly suggestive of PMF, KIT point mutations (usually D816V) in mastocytosis and D816V is resistant to imatinib, also +8, +9, del(13q), del(20q), del(9p)

 

Chromophobe RCC - Loss of Y, 1, 2, 6, 10, 13, 17, 21

- CD10 -/+, vimentin - , CD117+, CK7+

 

Ewing-like sarcoma - CIC-DUX4 t(4;19)(q35;q13), or t(10;19)

- also BCOR (BCL6 corepressor) and CCNB3 rearrangements

 

Clear cell sarcoma (Melanoma of Soft Parts) - EWS-ATF1 [t(12;22)(q13;q12)], EWS-CREB1 [t(2;22)(q34;q12)]

- same as angiomatoid fibrous histiocytoma

- either translocation can be seen in >9/10

 

CML - BCR-ABL [der(22)t(9;22)(q34;q11), Philadelphia cr, in 9/10, very good px], +Ph / +8 / i17q (all seen in blast crisis)

- Ph p210 > p230 >> p190

- p190 also seen in B-ALL

 

Clear cell renal cell carcinoma - VHL tumor suppressor gene [3p- (98%)]

- CD10+, vimentin +

 

CLL/SLL - del 13q14.3 (in 1/2, good px), trisomy 12 (in 1/5 fair px),  del 11q22-23 (poor px), del 17p (poor px), del 6q (poor px)

- good px: mutated IgVh; poor px: (+) CD38 and ZAP70

 

Collecting (Bellini) Duct Carcinoma - del(1q)

- CD10-, vimentin-, HMWK+

 

Colorectal carcinoma (CRC) - 2 pathways

(1) APC gene  (Adenomatous Polyposis Coli) [5q]

- in 4/5 sporadic CRCs, B-catenin inhibited by APC, detecteable by IHC

- (2) hMLH1, hMSH2, hMSH6, PMS2 [DNA mismatch repair genes, germline mutation leads to HNPCC / Lynch syndrome, in 3/20, can use IHC], KRAS [in 1/3, can use mutation testing to see which tumors will not respond to EGFR-targeted tx], BRAF (7)

 

Congenital mesoblastic nephroma - ETV6-NTRK3 [t(12;15]

- also seen c secretory ca of breast, mammary analogue secretory carcinoma of salivary glands, infantile fibrosarcoma, congenital mesoblastic nephroma

 

Congenital Nephrotic syndrome of the Finnish type

Nephrin affected on NPHS1 gene [19q13.1]

- nephrin is a key compoenent of the glomerular slit diaphragm

 

Cowden syndrome - AD, PTEN/MMAC1 (a tumor suppressor), 10q23

- hamartomas involving organs from all 3 germ layers

- Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)

 

Cri du chat - 5p15.2 microdeletion

- Abnormal cat cry, microcephaly, MR

 

Criggler-Najjar, Type I - Absent UDP-glucoronyl transferase (mutations in coding sequence of UGT1A1) causes unconjugated bilirubinemia (due to absent bilirubin conjugation)

 

Cystic fibrosis - AR, CFTR gene, [7q31] in ATP-binding cassette family member; >1k mutations, which are usually unique, though MC is delF508 (up to 7/10 mutations

- MC CFTR gene mutations: delta-F508 (2/3), G542X (2%), G551D (1.6%), N1303K (1.3%)

- R117H mutation causes severe dz when on same allele that has an increased alternate splicing from 5T intron 8 polymorphism (also assoc c absent vas deferens)

- longer alleles like 7T and 9T assoc c lung dz later on but less severe dz overall

- when R117H mutation seen on 5T pt, may have to do testing of family members to see on which alllele located

- prevalence rates highest in whites and Askenazi-Jews

- screened c DNA analysis and immunoreactive trypsinogen measurement

- if trypsinogen elevated, then do DNA analysis to confirm (otherwise no reason to run DNA analysis)

-- if only 1 mutation found of DNA test, must do another confirmatory test (sweat chloride); 2 mutations is sufficient to dz cystic fibrosis

- detection rates highest in Askenazi Jews, lowest in Asian Americans

 

Denys-Drash syndrome / Frasier syndrome - WT1 gene [11p13]

- Wilms tumor (9/10), gonadoblastoma, male pseudohermaphroditism, diffuse mesangial sclerosis causing rapidly progressive renal failure

 

Dermatofibrosarcoma protuberans (DFSP) - COL1A-PDGFRB [t(17;22)(q22;q13), in >9/10], ringed cr 17 seen in >3/4

- same as giant cell fibroblastoma (basically DFSP in kiddos)

 

Desmoid-type fibromatosis - CTNNB1 mutation

 

Desmoplastic small round cell tumor - WT1 [t(11;22) / EWS-WT1]

- has "p"s for petite (ie small round cell tumor) vs Ewings which has p and q

 

DiGeorge syndrome

- aka velocardiofacial syndrome, or Shprintzen syndrome

22q11 microdeletion, TBX1 gene. 75% c cardiac abnormalities, esp conotruncal malformations including tratralogy of Fallot, interrupted aortic arch, ventricular septal defects and truncus arteriosis

 

DLBCL - IGH-BCL2 [t(14;18)(q32;q21), in 1/3]

- cytogenetic changes variable and can see BCL6 and MYC abnormalities

 

Duchenne muscular dystrophy - XR, variety of mutations / deletions on DMD gene [Xp21.2]

 

Dilated cardiomyopathy - X-linked, MYH7 gene encoding B myosin heavy chain

 

Endometrial stroma sarcoma - JAZF1-JJAZ1 [t(7;17)(p15;q21)], seen in 3/5

 

Ewing sarcoma - EWS [t(11;22]/ EWS-FLI1]

 

Extranodal marginal zone lymphoma of MALT - API2-MALT1 [t(11;18)(q21;q21) in lung and GI, resistant to abx], IGH-MALT1 [t(14;18)(q32;q21) in ocular adnexa / orbit and salivary gland], FOXP1-IGH [t(3;14)(p14.1;q32) in thyroid, ocular adnexa / orbit and skin], and trisomy3 in 1/5 of splenic MZL

 

Extraskeletal myxoid chondrosarcoma - EWS-NR4A3 [t(9;22)(q22;q12), in ~3/4], RBP56-CHN(TEC) [t(9;17)(q11;q11)]

 

Ewing Sarcoma / PNET - EWS-FLI1 [t(11;22)(q24;q12), in 9/10], EWS-ERG [t(21;22)(q22;q12), in 1/20], EWS-ETV1 [t(7;22)(p22;q12), rare], EWS-E1AF [t(17;22)(q12;q12), rare]

- FLI1 and EWS have several breakpoints, but the MC one is assoc c best px

 

Familial Autosomal Recessive Corticosteroid-Resistant Nephrotic Syndrome

- Podocin, encoded by NPHS2 gene

- onset proteinuria in early childhood

 

Familial Autosomal Dominant Focal Segmental Glomerulosclerosis

- a-actinin, ACTN4 gene; also transient receptor potential cation channel 6 by TRPC6 gene

- onset of nephrotic syndrome in adolescence or young adulthood

 

Follicular lymphoma - IGH-Bcl2 [t(14;18)(q32;q21)]

- BCL2 can be done by IHC; this translocation can also be seen in DLBCL, but cannot be seen in pediatric or (rarely) cutaneous FL

 

GATA2 deficiency syndrome include AutoZone will dominant, variably penetrate MonoMAC syndrome, Emberger syndrome, familial AML/MDS, dendritic cells, monocyte, B, and NK cell deficiency

 

GATA-4 - [8p], encodes transcription factor important in embryogenesis; assoc c inherited septal defects, esp ostium secundum atrial septal defects

 

Giant cell tumor of tendon sheath - CSF1 gene translocations on cr 1

 

Gilbert syndrome - mutations in the 5' TATA box of the UGT1A1 promoter

- AR c underactive bilirubin-UGT

- causes prob c bilirubin uptake leading to unconjugated bilirubinemia

 

GIST - c-kit (cr 4, in 4/5), PDGFR (cr 4, in 1/20)

- mutation in KIT exon 11 is highly assoc c imatinib response; mutations in exons 9, 13, and 17 are somewhat less like (40-50%) to be imatinib sensitive; tumors c no KIT mutation may be imatinib sensitive in up to 30% of cases

- the MC PDGFRA mutation (D842V) is completely insensitive to imatinib, while others may be responsive

 

Glioblastoma - MGMT promoter methylation

- DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) inhibits killing of tumor cells by alkylating agents; thus MGMT promoter methylation assoc c tumor regression and inc survival in response to alkylating agents

 

Gorlin Goltz syndrome (nevoid basal cell carcinoma syndrome (NBCCS)) - AD / sporadic, mutation to PTCH1 gene cr 9q22.3

 

Sx: 2+ basal cell cas before age 20, body overgrowth, jaw keratocystic odontogenic tumor (KCOT or OKC), ovarian fibromas, congenital skeletal abnormalities, palmoplantar pits, desmoplastic medulloblastoma, other cancers (cardiac)

 

Hepatosplenic T-cell lymphoma - iso(7q) [common]

 

Hemangioendothelioma -  t(1;3)(p36;q25), WWTR1-CAMTA1 fusion

 

Hemochromatosis - HFE (C282Y, H63D) [6p21.3]

Juvenile hemochromatosis A - HFE2 (hemojuvlin) [1q21]

Juvenile hemochromatosis B - HAMP (hepcidin) [19q13]

Hemochromatosis type 3 - TFR2 (transferrin receptor) [7q22]

Familial iron overload - FTH1 (ferritin heavy chain) [11q13]

 

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu) syndrome - AD, ACVRL1 (ALK1, 12q11-14) or ENG (endoglin, 9q33-34), both involved in TGF-B pathways

 

Hereditary motor and sensory neuropathy (Charcot-Marie-Tooth) - AD. assoc c duplication of a 1.5 Mb region of DNA on 17p12 containing the Peripheral Myelin Protein 22 (PMP22) gene

- biopsy shows prominent onion bulb formation

 

Hirschsprung's disease - RET [10q11.2], EDNRB [13q], GDNF [5p]

 

Holt-Oram syndrome (heart-hand syndrome) - AD, TBX-5 [12q]

- characteristic heart and upper limb abnormalities

 

Hypertrophic cardiomyopathy - defective B myosin heavy chain gene (MYH7 gene, MC mutation is R403Q) on chr 14 (50%), AD inheritance

 

Infantile fibrosarcoma - ETV6-NTRK3 [t(12;15)(p13;q25)]

- also seen c congenital mesoblastic nephroma, secretory ca of breast, mammary analogue secretory carcinoma of salivary glands

 

Inflammatory myofibroblastic tumor - ALK [lots of 2p23 translocations, in 1/2]

- ALK gene also rearranged in ALCL by t(2;5)

 

Intimal sarcoma - MDM2 gene locus, amplification of 12q13

- MC primary cardiac sarcoma

 

Intraabdominal Desmoplastic Small Round Cell Tumor - EWS-WT1 [t(11;22)(p13;q12), seen in 99%]

- WT! (+) by IHC

 

Juvenile polyposis syndrome - AD, SMAD4/DPC4 (18q21), BMPR1A (10q22), and PTEN (10q23)

 

Kallmann syndrome - KAL1 gene [Xp22.3] microdeletion

-Affects males with hypogonadotropic hypogonadism and anosmia

 

Kearns-Sayre Syndrome (KSS) - 2/2 single del in mitochondrial DNA

- nearly all pts have different deletions causing DNA loss, though interestingly they all present similarly

- best detected c Southern blot analysis

 

Leber's Hereditary optic neuropathy (LHON) - missense point mut in complex 1 encoding gene

 

Li-Fraumeni - p53 (17p)

 

Lipoblastoma - PLAG1 [8q12] rearrangement c COL1A2 (7q21), RAD51L1 (14q24), HAS2 (8q24)

- has also been reported in tumors of salivary gland

 

Liposarcoma, myxoid and round cell - FUS/TLS-DDIT3 [t(12;16)(q13;p11), in >9/10], EWS-CHOP [t(12;22)(q13;q12), rare]

 

Liposarcoma, well diff - HMGA2, MDM2 amplification [ringed cr 12, in 4/5]

- MDM2 (+) by IHC, whereas lipoma is MDM2 neg

 

Long QT syndromes (LQTS)

LQT1 (KCNQ1) - 11p15.5, encodes a portion of a voltage gated potassium channel, MC mutated gene in LQT syndrome

- exercise (esp swimming) triggered arrhythmias

 

LQT2 (KCNH2, HERG) - 7q35-36, encodes a second voltage activated potassium channel; 2nd MCC LQTS

- auditory stimulus or emotional stimulus triggered arrhythmia

 

LQT3 (SCN5A) - 3p21-25, sleep triggered arrhythmias

 

LQT7 (KCNJ2) - Encodes portions of a channel shared c skeletal muscle; mutations cause Andersen-Tawil syndrome (triad of episodic paralysis, long QT interval, and dysmorphic features)

 

Low grade fibromyxoid sarcoma (Evan's tumor) - FUS-CREB3L2 [t(7;16)(q34;p11)], FUS-FUS-CREB3L1 [t(11,16)(p11;p11)], seen in almost 8/8

- in hyalizing spindle cell tumor c giant rosettes (now thought to be a variant of this tumor) and sclerosing epithelioid fibrosarcoma can see same translocation

- MUC4 highly sens and spec

 

Lymphoplasmacytic Lymphoma (LPL) - t(9;14)(p13;q32) involving PAX5 gene and C region of IgH

 

Lung adenocarcinoma - EML4-ALK

 

Lung cancer - EGFR (7, in 3/20, assoc c females, Asians, non-smokers, adeno c BAC, predicts response to Gefitinib [Iressa] afatinib, and Erlotinib [Tarceva])

- KRAS [in 1/3, assoc c smoking and mucinous histo, strong predictor for no response to EGFR inhibitors]

- EML4-ALK [inv(2), in 1/20, assoc c young, non-smokers, high stage, solid histology c signet-ring cells  and mucin, can be targeted c Crizotinib]

- ROS1 mutations - Similar to ALK mutations, may respond to tyrosine kinase inhibitor therapy (Crizotinib)

 

Malignant hyperthermia (MH) - defective RYR1 calcium channels due to RYR1 gene mutation

 

Mammary analogue secretory carcinoma of salivary glands - ETV6-NTRK3 [t(12;15]

- also seen c secretory ca of breast, infantile fibrosarcoma, congenital mesoblastic nephroma

 

Mantle cell lymphoma - CCND1-IGH [t(11;14)(q13;q32) in 3/4]

- CCND1 is cyclinD1 or Bcl1 and can been done c IHC

 

mastocytosis - c-kit (4)

- can target c-kit c TK inhibitor (Gleevec [imatinib])

 

McCune-Albright syndrome - activating mutation on GNAS1 gene [20]

***the 3 P's ****

Polyostic fibrous dysplasia (multiple unilateral bone lesions)

Pigmented skin lesions (cafe-au-lait spots)

Precocious Puberty

 

MDS - loss of EGR1, CTNNA1, RPS14 [isolated del(5q), good px, middle-aged women, severe macrocytic anemia, inc plts, monolobated micromegakaryocytes], isolated del(20q) [good px, erythroid and meg lines involved], -7, del(7q), -5, del(5q) [poor px, distinct from 5q- syndrome], del(17p) [poor px, MDS and AML c pseudo Pelger-Huet cells and small vacuolated PMNs]

 

medullary thyroid carcinoma - RET (10, activating)

 

medulloblastoma - iso(17q) in 1/2

 

melanoma - BRAF V600E (7), NRAS Q61, c-kit (4)

- can target c-kit c TK inhibitor (Gleevec [imatinib])

 

Mitochondrial Encephalomyopathy, Lactic Acidosis, Strokelike episodes (MELAS) - point muts in several mitochondrial tRNA genes or genes encoding subunits of respiratory chain (MT-TL1 gene)

 

MEN1 (aka Wermer's syndrome) - AD, MEN1 gene, Menin protein (tumor suppressor gene, 11q13)

 ***3 P's: Pancreas, Pituitary, Parathyroid ***

 Pancreatic neuroendocrine tumors (ZE, insulinomas, VIPomas, glucagonomas), Pituitary adenoma, Parathyroid adenoma/hyperplasia, duodenal carcinoids (make gastrin,  causing ZE)

 

MEN2a (aka Sipple's syndrome) - AD inherited RET gene abnormality, 10q10-11

***2P's and 1 M: Pheochromocytome, Parathyroid, Medullary thyroid ****

 

MEN2b (Gorlin syndrome) - AD, RET gene abnormality, 10q16

*** 1 P, 3 M's: Pheochromocytoma, Medullary thyroid, Mucous, Marfinoid habitus ***

 

Meningioma - monosomy 22

 

Miller-Dieker syndrome - 17p13 microdeletion

- Microcephaly, type 1 lissencephaly, heart malformations, renal malformations, seizures, prominent forehead, vertical furrowing of brow

 

Mucoepidermoid Carcinoma - MECT1(CRTC1)/MAML2 [t(11;19)(q21;p13)]

 

Myoclonus Epilepsy and Ragged Red Fibers (MERRS) - 2/2 muts in mitochondrial lysine RNA

 

Multiple myeloma - 14q32 (IgH) is MC abnormality, while CCND1-IGH [t(11;14)(q13;q32), MC rearrangement (in 3/20), good px, usually has complex karyotypes)

 

Myeloid dz c PDGFRB rearrangement (ie CMML c eosinophilia) - ETV6-PDGFRB [t(5;12)]

 

Myeloid / lymphoid neoplasms c eosinophilia and PDGFRB abnormalities (CMML c eosinophilia) - ETV6(TEL)-PDGFRB [t(5;12)(q31-33;p13)]

- can tx c gleevec

 

Myeloid / lymphoid neoplasms c eosinophilia and PDGFRA abnormalities (chronic eosinophilic leukemia) - FIP1L1-PDGFRA [cryptic del(4)(q12;q12)]

- clinically similar to chronic eosinophilia, can tx c gleevec

 

Myotonic muscular dystrophy (MMD) - AD, 2/2 CTG trinucleotide expansion in Dystrophia Myotonia Protein Kinase (DMPK) gene on 19q or 3q

 

Myxoid liposarcoma - EWS-CHOP [t(12;22)], FUS-CHOP [t(12;16)]

 

Myxoinflammatory Fibroblastic Sarcoma (MIFS) - TGBFR3-MGEA5 t(1;10)(p22;q24)

 

(Intramuscular) Myxoma - GNAS1 mutation

 

Nail-patella syndrome - Transcription factor that regulates transcription of COL4A3, LMX1B gene [9q34.1]

- AD, manifests c skeletal and ocular anomalies, abnormalities of the nails and renal disease (variable)

 

Neuroblastoma - -1p or del(1p32-36) [unknown gene, seen in 1/3, poor px]. n-Myc amplification [2, in 1/3, poor px], +17q [poor px, in 1/2], hyperdiploidy [poor px, in 2/5]

 

Nodular fasciitis (NF) - MYH9-USP6 [t(17;22)]

 

Noonan syndrome

AD, mutated protein tyrosine phosphatase, non-receptor type 11 (PTPN11) gene (same as LEOPARD syndrome and some cases of Juvenile Myelomonocytic Leukemia [JMML])

- right-sided heart defects including pulmonic stenosis and hypertrophic cardiomyopathy

- lymphatic malformations also common

- aka "the male version of Turner's syndrome"

 

NKX2-5 - [5q34] encodes transcription factor expressed very early in cardiogenesis and is responsible for activating transcription of most genes involved in the process

- can have large variety of structural malformations

 

oligodendroglioma - 1p/19q del [loss of heterozygocity] in 4/5 [der(1;19)(q10;p10)]

- can distinguish from astrocytoma

 

Osteogenesis imperfecta - COL1A1, COL1A2, CRTAP, LEPRE1

 

papillary thyroid carcinoma - RET (10, activating), BRAF V600E (7, more aggressive course), RAS

- cause unregulated MAPK stimulation

- nearly all c RAS mutation have follicular architecture

 

papillary RCC (hereditary and sometimes sporadic) - loss of Y, gain of 7 and 17 (similar to urothelial ca)

- CD10+, vimentin+, AMACR+, CK7+

 

PEComas - TFE3 [Xp11.2, in 1/5]

- TFE3 (+) by IHC, though not specific for translocation

 

Peutz-Jeghers syndrome (aka Hereditary intestinal polyposis syndrome) - AD; STK11/LKB1 [19p13]

 

Pick disease - mutated MAPT gene that encodes the microtubule assoc protein tau

 

Pierson syndrome - B2 laminin, encoded by LAMB2 [3p21]

- B2 laminin is a component of the glomerular basement membrane

- associated with microcoria (fixed, narrow pupils)

 

Pilocytic astrocytoma - BRAF-KIAA1549 fusion leading to BRAF activation [7q34 dup, in 4/5 of juvenile type, specific for juvenile pilo astrocytomas]

 

Pleuropulmonary blastosis (PPB) familial tumor syndrome - Germline mutations in DICER1

- have PPB in the lung (solid or cystic) with ovarian stromal tumors, cystic nephroma, and thyroid lesions

- can also have chondromesenchymal hamartomas, cervical emryonal rhabdomyosarcomas, pituitary blastoma, pineoblastoma, renal sarcoma, ciliary body medulloepithelioma

 

Prader-Willi - Paternal 15q11.2 microdeletion

- hyperphagia, obesity, hypogonadism, mild MR

 

Rhabdoid tumors - INI1 or hSNF5/BAF47 [22q11.2 del/mut, in 7/10]

- also seen in AT/RT

- INI1 expression is lost by IHC

 

Rhabdomyosarcoma, alveolar - PAX3-F0X01 [t(2;13)(q35;q14), in 7/10, poor px], PAX7-F0X01 [t(1;13)(p36;q14), rare, better px]

 

Rhabdomyosarcoma, embryonal - 11p15 loss, no recurrent translocations

- 11p15 also seen in Beckwith-Wiedman syndrome

 

RCC (sporadic and hereditary) - 3p

 

RCC c Xp11.2 - ASPL-TFE3 [t(X;17) from Xp11.2]

- translocations of the transferrin receptor TFE3 gene

- also in alveolar soft parts sarcoma

 

Retinoblastoma - RB inactivation [13q14 del/mut, in nearly 8/8]

- also seen in spindle cell fibroma, cellular angiofibroma, and Mammary-Type Myofibroblastoma (MTMF)

 

Schwannoma - NF2 gene [del(22q12)]

 

Secretory ca of breast - ETV6-NTRK3 [t(12;15]

- also seen c infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analogue secretory carcinoma of salivary glands

 

Seminoma (and other germ cell tumors) - iso(12p)(p10), seen in almost 8/8

 

Smith-Magenis syndrome - 17p11.2 microdeletion

- Moderate MR, prominent forehead, flat broad midface, self-multilating behavior, disturbed REM sleep

 

Spinal Muscular Atrophy (SMA) - AR, mutations in survival motor neutron 1 (SMN1) gene [5q11-q13] responsible for all forms

- lower motor neuron defects

 

Splenic B-cell marginal zone lymphoma - loss of 7q21-32 in 2/5

- not in extranodal or nodal marginal zone lymphoma

 

Steroid sulfatase deficiency - steroid sulfatase (STS) [Xp22.3]

 

Superficial fibromatosis - CTNNB1 gene mutated (inc B-catenin)

- also assoc c Garner syndrome, APC gene 5q22

 

Synovial sarcoma (SS)- SYT-SSX1 [t(X;18)(p11;q11), in 4/5 monophasic or biphasic SS], SYT-SSX2 [t(X;18)(p11;q11), in 1/3 monophasic SS, localized tumors have more favorable px]

 

T-ALL - deltaTAL1 or TAL1-TCRa/d [t(1;14)(p32;q11), MYC-TCRa/d [t(8;14)(q24;q11)], HOX11 (TLX1)-TCRa/d [t(10;14)(q24;q11), in up to 1/3], HOX11L2(TXL3)-TCRa/d [t(5;14)(q35;q11, in up to 1/5], loss of CDKN2A [del(9p), in up to 1/3]

 

T-cell leukemia / lymphoma - TCR a/d (14), TCR b (7q), TCRy (7p)

 

T-cell prolymphocytic leukemia - TCRa/d - TCL1A/B [t(14;14)(q11;q32), in 1/10], MTCP1-TCRa/d [t(X;14)(q28;q11), uncommon]

- assoc c cr 8 abnormalities

 

Thymoma types A and AB - GTF21; correlates c better survival

 

Trisomy 13 - microcephaly, sloping forehead, polydactyly, ocular abnormalities, cleft lip and forehead

 

Trisomy 18 - hypertonia, prenatal growth deficiency, fist clench (second and fifth fingers overlapping third and fourth), receding jaw, low-set eyes

 

Trisomy 21 - Down syndrome; palmer crease, duodenal atresia, loose skin on nape, Brushfield spots

 

Tuberous sclerosis - AD, TSC1, 9q34, hamartin,

TSC2 (MC) 16p13.3, tuberin

- TSC2 expression leads to inc mTOR activity

 

Turner syndrome - 45, X

 

vHL - AD; vHL tumor gene suppressed on 3p25-26, involved in ubiquination

- CNS hemangioblastoma (Lindau's tumor in cerebellum) / cavernous hemangioma, retinal angiomas, renal cysts, RCC (clear cell type), pancreatic cysts, pancreatic serous cystadenoma, islet cell tumors, epididymal/ovarian papillary cystadenoma(1/3 of males, can be Pax2+), endolymphatic sac tumor in ear (Heffner tumor), Adnexal Papillary Cystadenoma of Probable Mesonephric Origin (APMO, 8/8)

 

William syndrome - elastin gene, 7q11.23 microdeletion

- dysmorphic facial features, MR, short stature, hypercalcemia, abnormalities of CT (hernias, diverticula, joint laxity, skin laxity) and structural cardiac and vascular defects

- most distictive cardiac anomaly is supravalvar aortic stenosis (hourglass stenosis)

 

Wilms tumor - WT1 [11p13 mut or del, in 3/20, same mut as in WAGR or Denys-Drash], WT2 locus [11p15 mut, in 1/20, assoc c Beckwith-Wiedman syndrome], trisomy 12 [in 1/4]

 

Wilson disease (hepatolenticular degeneration)- AR mutation of ATP7B (a transmembrane copper receptor) cr 13 causing : 1) dec Cu secretion into bile; 2) dec Cu incorp c ceruloplasmin; 3) dec ceruloplasmin secretion in blood

 

Wolf syndrome - 4p deletion

- IUGR, heart malformation, microcephaly, cleft lip and palate, broad nasal root, severe MR

 

 

 

References

 

1.