Molecular Genetics of Tumours

Question 1

Molecular Biomarkers in Lung Cancer

Answer 1

EGFR
ALK
ROS1
KRAS
BRAF V600E
MET

Question 2

Genes involved in GIST

Answer 2

CKIT (exons 9 & 11, imatinib Rx)
PDGFRa
SDH A, B, C, D (young, do well)
NF1

Question 3

Molecular Alterations in Spitz Naevi

Answer 3

NTRK 1,2,3
ALK
ROS1
RET
MET

Malignant Spitz - TERT promoter, p53

Question 4

MDM2 Amplified Tumours

Answer 4

ALT / WDLPS / DDLPS
Low grade central osteosarcoma
Parosteal osteosarcoma
Intimal sarcoma

Question 5

Molecular Changes in Adipocytic Tumours

Answer 5

MDM2 amplification: ALT / WDLPS / DDLPS
RB1 deletion in spindle cell lipoma
DDIT3 -FUS myxoid LPS
PLAG1 lipoblastoma

Question 6

SMARCB1 (INI1) Deficient Tumours

Answer 6

Malignant rhabdoid tumour of kidney and soft tissue
CNS AT / RT
Epithelioid sarcoma (conventional and proximal)
Medullary renal carcinoma
SMARCB1-deficient sinonasal carcinoma
Poorly differentiated chordoma

Question 7

SMARCA4 (BRG1) Deficient Tumours

Answer 7

SMARCA4 deficient thoracic carcinosarcoma
Small cell carcinoma of the ovary, hypercalcaemic type
SMARCA4 deficient undifferentiated uterine sarcoma

Question 8

BCOR Rearranged Tumours

Answer 8

Kidney - Clear cell sarcoma (young children)

Uterus - HG ESS

Bone / Soft tissue - BCOR rearranged sarcoma

CNS - High grade neuroepithelial tumours with BCOR alteration

Question 9

Molecular Changes in Bone Tumours

Answer 9

Osteochondroma: EXT1, EXT2 loss of function mutations
Enchondroma: IDH1, IDH2 mutations
Osteoid osteoma & OB: FOS, FOSB rearrangements

NOF: KRAS, FGFR1, NF1 alterations
Desmoplastic fibroma: CTNNB1, APC mutations

GCT of bone: H3 G34M mutation, RANKL overexp.
Chondroblastoma: H3 K36M mutation
ABC: USP6 rearrangement

LCH: BRAF V600E
Fibrous dysplasia: GNAS activating mutations

LG central & Parosteal OS: MDM2 amp, CDK4 (chr 12)

LG central CS: IDH1 / 2
LG peripheral CS: EXT1 / EXT2

Ewing Sarcoma: EWSR1 rearrangements
PMT: FGF gene rearrangements
Mesenchymal CS: HEY1-NCOA2 fusion

Question 10

Molecular Changes in Thyroid Tumours

Answer 10

PTC:
BRAFV600E mutations
RAS mutations in encapsulated follicular variant
RET, ALK and NTRK 1,3 fusions
TERT promoter mutations

Follicular carcinoma:
RAS mutations
TERT promoter mutations
PAX8-PPAR fusion

Medullary:
RET activating mutations

Anaplastic carcinoma:
Same as above plus TP53, PTEN and Beta cat

Question 11

Molecular Changes in Colorectal Carcinoma

Answer 11

BRAF V600E mutation
KRAS / NRAS / HRAS mutations
APC inactivation

Question 12

Molecular Changes in Neuroblastoma

Answer 12

Poor prognosis:
MYCN amplification
1p, 11 q deletion, 17q gain
Diploidy

Better prognosis:
Hyperploidy

Question 13

ETV6 Rearranged Tumours

Answer 13

Secretory carcinoma (breast, skin, salivary gland)
Congenital mesoblastic nephroma
Infantile fibrosarcoma

Question 14

BRAF Altered Tumours

Answer 14

Mutations:
PTC, CRC, Melanoma, Histiocytic lesions, NSCLC, Metanephric adenoma, papillary craniopharyngioma

Fusions:
Spitzoid melanoma, Pilocytic astrocytoma

Question 15

ALK Rearranged Tumours

Answer 15

ALK + ALCL
ALK + DLBCL
IMT
Lung adenocarcinomas
Neuroblastomas (some, point mutations)

Question 16

EWSR1 Rearranged Tumours

Answer 16

Ewing sarcoma (FLI1, ERG, etc)
ESMC (NR4A3)
Desmoplastic small round cell tumour (WT1)
Myoepithelial tumour of soft tissue (ANF44, POU5F1)
Myxoid liposarcoma (DDIT3 / CHOP)
Clear cell sarcoma of soft tissue (ATF1)
Clear cell carcinoma of salivary gland (ATF1)
Angiomatoid fibrous histiocytoma (ATF1, CREB1)
Primary pulmonary myxoid sarcoma (CREB1)
Sclerosing epithelioid fibrosarcoma (CREB3L1)

Question 17

FUS Rearranged Tumours

Answer 17

Angiomatoid fibrous histiocytoma (EWSR1)
LGFMS (CREB3L1/2)
Sclerosing epithelioid fibrosarcoma (CREB3L2)
Myxoid liposarcoma (DDIT3 / CHOP)

Question 18

USP6 Rearranged Tumours

Answer 18

Primary ABC
Giant cell lesion of the small bones
Nodular fasciitis
Myositis ossificans
Fibroosseous pseudotumour of digits
Cellular fibroma of tendon sheath

Question 19

Molecular Alterations in Salivary Gland Tumours

Answer 19

Adenoid cystic carcinoma (MYB-NFIB, MYBL1-NFIB)
Acinic cell carcinoma (NR4A3)
Basal cell adenoma (CTNNB1)
Clear cell carcinoma (EWSR1-ATF1)
Epithelial - myoepithelial ca (HMGA2, PLAG1, HRAS)
Low grade intraductal carcinoma (RET)
Mucoepidermoid carcinoma (MAML2)
Pleomorphic adenoma (HMGA2, PLAG1)
Polymorphous adenocarcinoma (PRKD1)
Secretory carcinoma (ETV6-NTRK3)

Question 20

Molecular Alterations in Adult Kidney Tumours

Answer 20

Clear cell RCC - 3p deletion
Metanephric adenoma - BRAFV600E mutations

Molecularly Defined Tumours (WHO 2022)
TFE3 rearranged RCC
TFEB rearranged RCC
ELOC mutated RCC
FH deficient RCC
SDH deficient RCC
ALK rearranged RCC
SMARCB1 deficient renal medullary carcinoma

Question 21

Molecular Alterations in Paediatric Kidney Tumours

Answer 21

Wilms tumour - WT1 deletion / mutation (15%)
Cellular congenital mesoblastic nephroma (ETV6)
Malignant rhabdoid tumour of kidney (SMARCB1/ A4)
Clear cell sarcoma (BCOR ITD, YWHAE-NUTM)

Question 22

Molecular Prognostic Markers in Gliomas

Answer 22

Better prognosis:
IDH1 / 2 mutations
MGMT methylation
BRAFV600E mutations
C-GIMP methylation
1 p / 19 q co -deletion (by virtue that oligos do better)

Worse prognosis:
TERT promoter mutations
EGFR amplication
Histone mutations