Familial cancer syndromes

Section: Surgical Oncology Curriculum: Curriculum, page 64

Stratified by organ

Endocrine

• Genetic Endocrine disorders

Thyroid

• MEN 2B syndrome/MEN 2A syndrome
• Gardner syndrome
• Cowden’s syndrome
• Carney complex

Adrenal

• ACC
  • MEN 1 syndrome
  • Beckwith-Wiedemann Syndrome in childhood
    • Exophthalmos, microglassia, nephromegaly
  • Li-Fraumeni syndrome
• Pheo
  • MEN 2 syndrome
  • Von-Hippel-Lindau disease
  • Neurofibromatosis Type 1
  • Paraganglioma syndrome

Parathyroid

• MEN 1 syndrome
• MEN 2A syndrome

Breast

• BRCA2
• BRCA1
• PALB2
• Cowden’s syndrome
• Li-Fraumeni syndrome
• Peutz-Jeghers syndrome
• Hereditary diffuse gastric carcinoma syndrome
• Muir-Torre Syndrome
• Ataxia Telangiectasia
• CHEK2
• Neurofibromatosis Type 1

Colorectal

• Lynch syndrome
• Familial adenomatous polyposis
• Cowden’s syndrome
• Peutz-Jeghers syndrome
• MUTYH-associated polyposis
• Serrated polyposis syndrome
• Li-Fraumeni syndrome

Gastric

• Hereditary diffuse gastric carcinoma syndrome
• Li-Fraumeni syndrome
• Cowden’s syndrome
• Lynch syndrome
• Peutz-Jeghers syndrome
• Juvenile polyposis
• BRCA2

Pancreatic adenocarcinoma

• Peutz-Jeghers syndrome (SK11)
• Li-Fraumeni syndrome
• Fanconi’s syndrome
• Familial adenomatous polyposis (APC)
• Lynch syndrome (MMR pathway)
• Von Hippel Lindau Syndrome
• BRCA1/BRCA2
• CDKN2A (familial atypical mole and melanoma syndrome)
• PALB2 (familial breast cancer syndrome)
• ATM (familial breast cancer syndrome)
• PRSS1 and SPINK1 of hereditary pancreatitis
• MEN syndromes

Pancreatic NET

• Von Hippel Lindau Syndrome
• MEN 1 syndrome
• Neurofibromatosis Type 1
• Tubular sclerosis

HCC

• Hereditary haemochromatosis
• α1-Antitrypsin Deficiency

Sarcom

• Neurofibromatosis Type 1
• Li-Fraumeni syndrome
• Hereditary retinoblastoma
• FAP (Desmoids)

Melenoma

• Familial Atypical Mole and Melanoma Syndrome
• Xeroderma Pigmentosum

SCC

• Xeroderma Pigmentosum

BCC

• Gorlin Syndrome
• Xeroderma Pigmentosum

Syndrome outline

Lynch syndrome Mutation: Mutation in MMR genes MLH1, MSH2, MSH6, PMS2 Inheritance: AD Sequele: COUGRS. C - colorectal, O - ovarian, U - uterine 50%, G - gastric, R - renal (urothelial), S - Small bowel and skin Screening: Colonoscopy from 25, Gastroscopy, TVUSS, Annual LFTs, Ca19-9, CEA, CA125, Annual urinalysis/cytology

Familial adenomatous polyposis + Gardner syndrome (Subtype) Mutation: APC Inheritance: AD Sequele: Endoderm: adenomas of stomach, duodenum, small bowel and colon. Thyroid. Hepatoblastoma. Mesoderm: desmoid, osteoma, odontoma. Ectoderm: CHRPE, epidermoid cyst Screening: Colonoscopy (age 12) until surgery then +/- cuff. Gastroscopy from 25, Thyroid USS from 18.

Cowden’s syndrome Mutation: PTEN Inheritance: AD Sequelae: HOT-BRET. H - Haemartomas, O - oral fibromas, T - Trichilemmoma, B - breast, R - renal, E - endometrial , T - thyroid, Screening: Colonoscopy (age 35), Breast MRI - age 30, Renal USS - age 40, TVUS - Age 35, Thyroid USS - age 7

Peutz-Jeghers syndrome Mutation: STK11 Inheritance: AD Sequelae: BCHOMPT. Beast, Colorectal, cervical, Hamartomatous, Ovarian, Mucocutaneous lesions, Pancreatic cancer, Testicular cancer (sertoli) Screening: Annual breast MRI and mamm from age 30, Upper and lower GI endoscopies + capsule endoscopy (from age 8). MRI enerography is an option, Annual cervical smear from 18 or annual testicular exam

MUTYH-associated polyposis Mutation: MYH gene Inheritance: AR Sequelae: Colorectal adenomas, duodenal adenoma +/- FAP extracolinc Screening: Colonoscopy (age 20), OGD (Age 35)

Serrated polyposis syndrome Mutation: N/A - WHO criteria Inheritance: N/A Sequelae: 20% risk of CRC Screening: Colonoscopy age 40 or 10 year prior to relative.

MEN 1 syndrome Mutation: MEN1, encodes the menin protein Inheritance: AD Sequelae: 3p - parathyroid, pancreas, pituitary Screening: Annual Ca/PTH, Annual NET tumour markers, Annual Pitutary markers. Conisder MRI pancreas and Pituitary

MEN 2A syndrome Mutation: RET1 Inheritance: AD Sequelae: 2p - parathyroid, pheochromocytoma, MTC Screening: Thyroidectomy (timing based on risk), Annual pheo and PTH/Ca screening. MRI or CT every 4-5 years for image the adrenals looking for phaeo.

MEN 2B syndrome Mutation: RET1 Inheritance: AD Sequelae: 1p - pheochromocytoma, MTC, Mucosal neuromas, mafanotid Screening: Thyroidectomy (timing based on risk), Annual pheo. MRI or CT every 4-5 years for image the adrenals looking for phaeo.

Carney complex Mutation: Protein kinase A type I-alpha regulatory subunit (PRKAR1A) gene Inheritance: AD Sequelae: Adrenal, Lentiginous skin pigmentation, myxomas Screening:

Carney-Stratakis dyad Mutation: SDHB, SDHC, or SDHD Inheritance: AD Sequelae: Paragangliomas, GIST

Carney triad Mutation: No genetic link - ssomatic epigenetic silencing of the SDHC promoter Inheritance: N/A Sequelae: Paragangliomas, GIST, Pulmonary chondroma

Li-Fraumeni syndrome Mutation: p53 Inheritance: AD Sequelae: Breast cancer, gastric cancer, sarcoma, ACC, leukaemia, lymphoma, brain tumours Screening: From age 20, Annual MRI whole body, breast and brain, colonoscopy, gastroscopy

Von-Hippel-Lindau disease Mutation: VHL gene Inheritance: AD Sequelae: Paragangliomas, Pheochromocytomas, pNETs, Hemangioblastomas, Renal carcinoma or cysts Screening: Annual plasma metanephrines and regular pancreatic imaging

Neurofibromatosis Type 1 Mutation: NFT1 mutation Inheritance: AD Sequelae: Café-au-lait macules, Freckling, Neurofibromas, Lisch spots, Optic Glioma / Meningiomas / Astrocytomas, pheochromocytoma, Sarcoma, GIST, learning disabilities

Paraganglioma syndrome Mutation: SDH genes mutation Inheritance: Typically AD Sequelae: Phaeochromocytomas, paragangliomas, GIST Screening: N/A

BRCA1 Mutation: BRAC1 gene Inheritance: AD Sequelae: Breast (ER/PR -), ovarian, colon, prostate, pancreas
Screening: MRI breast age 30, BSO (eariler)

BRCA2 Mutation: BRACA2 gene Inheritance: AD Sequelae: Breast (ER/PR +), ovarian, prostate, pancreas, male breast cancer, laryngeal, bladder
Screening: MRI breast age 30, BSO

PALB2 Mutation: PALB2 (Partner and Localizer of BRCA2) encodes a BRAC2-interacting protein Inheritance: AD Sequelae: Breast, ovarian, pancreatic Screening: Breast MRI starting age 30

Hereditary diffuse gastric carcinoma syndrome Mutation: CDH1, Encodes the cell adhesion protein E-cadherin Inheritance: AD Sequelae: Diffuse gastric cancer, Lobular breast, Signet ring colon cancer Screening: OGD 16, Gastrectomy >20, MRI breast from age 30, colonoscopy

Muir-Torre Syndrome Mutation: MMR or MUTYH Inheritance: AD Sequelae: Sebaceous cutaneous neoplasms, colorectal, breast, endometrial, ovarian, urothelial Screening: Colorectal cancer screen from age 25

Ataxia Telangiectasia Mutation: ATM gene Inheritance: AR Sequelae: Childhood lymphoma and leukaemia, breast, gastric, pancreas, ovarian Screening: Life expectancy poor - age 25

CHEK2 Mutation: CHEK2 Inheritance: AR Sequelae: Moderate increased risk of breast cancer Screening: Breast MRI starting age 30

α1-Antitrypsin Deficiency Mutation: SERPINA1 gene Inheritance: Aco-D Sequelae: Hepatocellular carcinoma, emphysema Screening: LFTs + fibroscan

Hereditary retinoblastoma Mutation: RB1 gene Inheritance: AD Sequelae: Rеtiոοblаѕtomа, Sarcoma Screening: Nil

Familial Atypical Mole and Melanoma Syndrome/Dysplastic Nevus Syndrome Mutation: CKDN2A gene Inheritance: AD Sequelae: Many Naevi → melenoma Screening: Regular skin check

Xeroderma Pigmentosum Mutation: Nucleotide excision repair (NER) genes Inheritance: AR Sequelae: BCC, SCC, Melanoma → 1000 x increased risk Screening: 3 monthly review, < 40% survive beyond age 20

Gorlin Syndrome Mutation: Human homolog of the patched (PTCH1) gene Inheritance: AD Sequelae: BCC, Odontogenic keratocysts, Ovarian fibromas, Medulloblastoma Screening: Regular skin checks