8. Other cancer syndromes

Question 1

What genes are involved in MEN and what type of mutations?

Answer 1

MEN1 & MEN4 - LoF variants in MEN1 and CDKN1B

MEN2 & MEN3 - GoF variants in RET

Question 2

What is the clinical phenotype of MEN1 & MEN4?

Answer 2

Parathyroid & pituitary tumours - cause over production of hormones

Late onset

Variable penetrance and interfamily heterogeneity

Question 3

What is the role of MEN1?

Answer 3

TSG - involved in regulating cell division, DNA replication & repair, transcription

Question 4

What is the role of CDKN1B?

Answer 4

TSG

Inactivates cyclin-dependent kinase

Negatively regulates cell cycle progression from G1 to S phase

Question 5

What is the clinical phenotype of MEN2 & MEN3

Answer 5

Medullary thyroid carcinoma (MTC) with phaeochromocytoma & parathyroid tumours

MEN2 = early childhood onset + adult onset MTC. Particular codons associated with FMTC

MEN3 = neonatal onset

Question 6

What type of mutations cause MEN2 and MEN3?

Answer 6

Activating/GoF mutations in RET (oncogene)

Cause activation of intracellular signalling

Question 7

What is the main mutation associated with MEN3 and what does it cause?

Answer 7

Met918Thr in 95% of cases

Located in catalytic pocket of tyrosine kinase domain

Causes aggressive MTC in neonates

Question 8

How does the location of a RET mutation impact treatment?

Answer 8

Impacts timing of prophylactic throidectomy

1. First tyrosine kinase sub-domain = lowest risk (FMTC)
2. Transmembrane domain = intermediate risk (MEN2)
3. Second tyrosine kinase sub-domain = highest risk (MEN3)

Question 9

What is the clinical phenotype of von Hippel-Lindau syndrome?

Answer 9

Hemangionblastomas, clear cell renal carcinoma (ccRCC), phaeochromocytoma, paraganglioma

Question 10

How do VHL types 1 & 2 differ?

Answer 10

Type 1 (typical) due to LoF variant = hemangioblastoma & ccRCC, no PCC

Type 2 (specific missense) = PCC & paraganglioma

Question 11

What genes are associated with paraganglioma/phaeochromcytoma syndromes?

Answer 11

SDHA, SDHB, SDHC, SDHD, SDHAF2, MAX, TMEM127

Question 12

What cancer syndrome is PTEN associated with?

What’s the phenotype?

Answer 12

Cowden syndrome

Increased risk of breast, thyroid, endometrial cancer

Question 13

What is the role of PTEN?

Answer 13

TSG

Tyrosine kinase phosphotase enzyme - negatively regulates P13K/Akt/mTOR & MAPK pathways

Inhibits cell survival, growth, and proliferation

Question 14

What causes Gorlin syndrome/basal cell nevus syndrome?

Answer 14

Deletion of PTCH1 or SNVs

20-30% de novo

Question 15

What cancer syndrome does FLCN cause?

What’s the phenotype?

Answer 15

Birt-Hogg-Dube syndrome

Skin lesions, lung cysts, renal tumours

Question 16

What causes Peutz-Jegher syndrome?

What’s the phenotype?

Answer 16

STK11 - serine/threonine kinase

Benign hamartomatous polyps in GI tract, mucocutaenous pigmentation, risk of breast, ovarian, CRC