Cancer Syndromes and Referral Indications

Question 1

Carney Complex

Answer 1

• Gene: PRKAR1A - Characterized by: pale brown to black lentigenes; myxomas of the heart, skin, and breast; primary pigmented nodular adrenocortical disease; large cell calcifying Sertoli cell tumors - Psammomatous melanotic schwannoma (a rare nerve sheath tumor) can also occur - 50%+ of patients with isolated primary pigmented nodular adrenocortical disease have a PRKAR1A mutation - REFERRAL: Personal hx or 1st-degree relative with i)primary pigmented nodular adrenocortical disease or ii) two or more diagnostic criteria

Question 2

Birt-Hogg-Dube Syndrome (BHD)

Answer 2

• Gene: FLCN - Characterized by the presence of classic skin lesions (fibrofolliculomas, perifollicular fibromas, trichodiscomas, or angiofibromas, and acrochordons); bilateral and multifocal renal tumors (chromophobe clear cell renal carcinoma, renal oncocytoma, oncocytic hybrid tumor, occasionally clear cell renal carcinoma); multiple bilateral lung cysts often associated with spontaneous pneumothorax - REFERRAL: individual with a personal or 1st-degree relative history of i) 5 or more BHD associated facial or truncal papules, ii) early onset (

Question 3

Constitutional mismatch repair deficiency

Answer 3

• Recessive condition caused by biallelic mutations in the MMR genes - Characterized by a high risk of developing cancers during childhood, including LS-associated cancers, hematologic malignancies, and embryonic tumors - Individuals affected with this have NF-1 type features with cafe-au-lait macules and skinfold freckling. Lisch nodules, neurofibromas, and tibial pseudoarthosis in occasional cases. - Individuals with this do not always have a fam. hx of cancer - REFERRAL: any individual with a personal hx or a 1st-degree relative with i) LS-associated cancer in childhood, ii)another type of childhood cancer AND one or more of the following features: i) cafe-au-lait macules, skinfold freckling, Lisch nodules, neurofibromas, tibial pseudoarthrosis, or hypopigmented skin lesions; ii) fam hx of LS-associated cancer; iii) a second primary cancer; iv) a sibling with a child hood cancer; or v) consanguineous parents

Question 4

Cowden Syndrome

Answer 4

• Gene: PTEN - Characterized by benign skin findings, macrocephaly, increased risk for breast (30 - 85%; often early-onset), follicular thyroid (10 - 38%), renal cell (34%), endometrial (5 - 28%), and CRC (9%), possibly melanoma (6%) - REFERRAL: Any individual with a personal hx or first degree relative with i) Lhermitte-Duclose disease dx after 18; ii) any three criteria from the major or minor diagnostic criteria list in the same person

Question 5

Familial Adenomatous Polyposis (FAP) and Attenuated FAP

Answer 5

• Gene: APC - Characterized by: adenomatous colon polyps and increased lifetime risk for CRC (nearly 100% for FAP and 70% for AFAP) - FAP = 100+ colon polyps; at increased risk for duodenal (4 - 12%), pancreatic (~2%), and papillary thyroid (cribriform morular variant) cancers as well as hepatoblastoma by age 5 and medullolastoma - AFAP: 30 - 100 colon polyps - REFERRAL: any individual with personal or 1st-degree relative with i) 10+ adenomatous colon polyps with or without a CRC or other FAP-associated cancer; ii) a cribriform morular variant of papillary thyroid cancer; iii) a desmoid tumor; or iv) hepatoblastoma dx before age 5

Question 6

Familial Gastrointestinal Stromal Tumor (GIST)

Answer 6

Genes: KIT, PDGFRA, SDHB, SDHC - Individuals with germline mutations in KIT can have hyperpigmentations, mast cell tumors, or dysphagia - PDGFRA mutations have been associated with large hands - Individuals with NF1 can also develop GISTs - Wild type GISTs are defined as GISTs that do not have detectable mutations in KIT, PDGFRA, or BRAF - No published guidelines for referral; recommendations based on expert opinion - REFERRAL: should be considered for any individual with a personal hx or 1st-degree relative with i)3+ close relatives with GIST; ii)wild-type GIST; or iii) individuals with 3+ GISTs

Question 7

Familial Pancreatic Cancer

Answer 7

• Most common cause of familial pancreatic cancer: BRCA2 mutations, other genes include CDKN2A, PALB2, or ATM - REFERRAL: any individual with a personal hx or 1st-degree relative with i) AJ ancestry and pancreatic cancer at any age; ii) pancreatic cancer and a close relative with pancreatic cancer; iii) 3+ cases of breast, ovarian, pancreatic, and/or aggressive prostate cancer; iv) 3+ cases of pancreatic cancer and/or melanoma

Question 8

Familial Prostate Cancer

Answer 8

• Autosomal dominant, recessive, and X-linked patterns of inheritance have been demonstrated in families with multiple cases of prostate cancer - REFERRAL: should be considered for any individiaul with a personal history of or 1st-degree relative with i) 3 or more first-degree relative with prostate cancer; ii) 2 or more cases of prostate cancer dx before 55; or iii) aggressive prostate cancer (Gleason score 7+) and 2+ cases of breast, ovarian, or pancreatic cancer

Question 9

HBOC

Answer 9

• Genes: BRCA1 and BRCA2 - Characterized by increased risks for early-onset breast, multiple breast primaries, male breast, and epithelial ovarian, fallopian tube, or primary peritoneal cancers, as well as pancreatic, prostate, and melanoma - Triple negative breast cancer has been strongly associated with BRCA1 mutations - REFERRAL: use NCCN guidelines for this

Question 10

Hereditary diffuse gastric cancer

Answer 10

• Gene: CDH1 - Increased risk for diffuse gastric cancer, lobular breast cancer, and signet ring CRC - CDH1 mutations occur in 25-50% of individuals who mee criteria - REFERRAL: any individual with a personal history of or 1st-degree relative with i) diffuse gastric cancer dx

Question 11

Hereditary leiomyomatosis and renal cell cancer

Answer 11

• Gene: FH gene - Characterized by increased risks for renal cancer and cutaneous and uterine leiomyomas - REFERRAL: Individuals with cutaneous leiomyoma and renal cell tumors of one of three types (papillary type 2, collecting duct, and tubulopapillary) - REFERRAL should also be considered for any individual with a personal hx or first-degree relative with i) cutaneous leiomyomas or ii) RCC with histology characteristic of hereditary leiomyomatosis and renal cell cancer

Question 12

Hereditary Melanoma, also known as familial atypical mole and malignant melanoma

Answer 12

• Genes: CDKN2A/ARF gene - Characterized by multiple melanocytic nevi (usually >50) and family hx of melanoma - Individuals with hereditary melanoma have a 17% risk for pancreatic cancer by age 75 - REFERRAL: should be considered for any individual with a personal hx or 1st-degree relative with i) 3 or more melanomas in the same person or ii) three or more cases of melanoma and/or pancreatic cancer

Question 13

Hereditary mixed polyposis syndrome

Answer 13

• Gene: The major gene(s) responsible have not been identified; however some cases are caused by mutations in BMPR1A and a founder mutation involving the GREM1 gene was identified in AJ patients - Characterized by multiple polyps of mixed histology (hyperplastic, adenomatous, and juvenile polyps) leading to an increased risk for CRC - Referral should be considered for any individual with a personal hx of or 1st-degree relative with 10+ colorectal polyps with mixed histology

Question 14

Hereditary Papillary RCC

Answer 14

• Gene: MET - Characterized by an increased risk of developing papillary type 1 RCC - REFERRAL: should be considered for any individual with a personal hx or 1st-degree relative with a papillary type 1 RCC

Question 15

Hereditary paraganglioma-pheochromocytoma syndrome

Answer 15

• Genes: SDHB, SDHD, SDHC, SDHAF2, MAX, TMEM127 - Characterized by an increased risk for paragangliomas and pheochromocytomas - REFERRAL: should be considered for any individual with a personal history of or a first-degree relative with a paraganglioma or pheochromocytoma

Question 16

Hereditary Retinoblastoma

Answer 16

• Gene: RB1 - Characterized by a malignant tumor of the retina, usually occurring before age 5 - Estimated ~40% of all retinoblastomas are hereditary - REFERRAL: any individual with a personal hx or a first-degree relative with a retinoblastoma

Question 17

Juvenile Polyposis Syndrome

Answer 17

• Genes: SMAD4 and BMPR1A - Characterized by juvenile-type hamartomatous polyps throughout the GI tract - The term “juvenile polyp” refers to a specific histologic type of polyp, not the age of dx - The risk for GI cancers (mainly CRC, though stomach, upper GI tract, and pancreas have been reported) range from 9 to 50% - Extraintestinal features such as valvular heart disease (11%), telangiectasia or vascular anomalies (9%, all in SMAD4 carriers), and macrocephaly (11%) can occur - Some individuals with JPS due to mutations in SMAD4 may also have symptoms of hereditary hemorrhagic telangiectasia - REFERRAL: should be considered for any individual with a personal hx or of 1st-degree relative with i) 3-5 cummulative histologically provin juvenile GI polyps; ii) any number of juvenile GI polyps with a positive fam hx of JPS; or iii) multiple juvenile polyps located throughout the GI tract

Question 18

Li-Fraumeni

Answer 18

• Gene: TP53 - Characterized by the core cancers of breast, brain, adrenocortex, and non-Ewing sarcoma with onset often before 50 and multiple primary tumors. - Young age of dx (

Question 19

Lynch Syndrome

Answer 19

• MMR genes (MLH1, MSH2 [including methylation due to an EPCAM deletion], MSH6, PMS2) - Characterized by CRC (risk 40 - 80%) and endometrial cancer (25 - 60%), ovarian (4 - 24%), and gastric (1 - 13%) cancers - Tumors associated with Lynch Syndrome: Colorectal adenocarcinoma, endometrial adenocarcinoma, urothelial carcinoma, gastric cancer, ovarian cancer, small bowel cancer, glioblastoma, sebaceous adenocarcinoma, biliary tract cancer, pancreatic cancer - REFERRAL: any individual with a personal hx or first-degree relative with i) colorectal or endometrial cancer dx before age 50; ii) colorectal or endometrial cancer dx at or after age 50 if there is a 1st-degree relative with CRC or endometrial cancer at any age; iii) synchronous or metachronous CRC or endometrial cancer; iv) sebaceous adenoma or carcinoma and one or more additional case of any LS-associated cancer in the same person or relatives; v) a tumor exhibiting MMR deficiency; vi) fam hx of 3+ LS-associated cancers

Question 20

Melanoma-Astrocytoma syndrome

Answer 20

• Genes: CDKN2A and p14ARF, p14ARF alone, and possibly the ANRIL antisense noncoding RNA - Leads to an increased risk for melanoma and astrocytoma tumors - REFERRAL: should be considered for any individual with a personal hx or first-degree relative with i) melanoma and astrocytoma in the same person or ii) one case of melanoma and one case of astrocytoma in 2 first-degree relatives

Question 21

Multiple Endocrine Neoplasia type I (MEN1)

Answer 21

• Gene: MEN1 - Characterized by increased risk of endocrine and nonendocrine tumors - No single MEN1-associated tumor is sufficient to warrant GC referral, with the exception of gastrinoma - REFERRAL: any individual with a personal hx or first-degree relative with i) 2+ different MEN1-associated tumors (adrenal, parathyroid, pituitary, pancreas, or thymic tumor or bronchial carcinoid tumor) in the same person; ii) gastrinoma; iii) multiple different pancreatic neuroendocrine tumors in the same person; iv) parathyroid adenoma dx before 30; v) parathyroid adenomas involving multiple glands; or vi) parathyroid adenoma with fam hx of hyperparathyroidism or MEN1-associated tumors

Question 22

Multiple Endocrine Neoplasia type II (MEN2)

Answer 22

• Gene: RET - Characterized by increased risks for medullary thyroid cancer [MTC] (~100%), pheochromocytomas (50% or lower), and parathyroid disease (30% or lower) - As many as 25% of individuals with MTC have a RET mutation - REFERRAL: any individual with a personal history of or first-degree relative with i) MTC; ii) pheochromocytomas; iii) oral or ocular neuromas (lips, tongue, sclera, or eyelids); iv) diffuse ganglioneuromatosis of the GI tract

Question 23

MUTYH-associated polyposis (MAP)

Answer 23

• Gene: MUTYH - Autosomal recessive - Characterized by an increased risk for adenomatous colon polyps and colorectal cancer (80%) - REFERRAL: any individual with a personal history of or a first-degree relative with i) 10+ cumulative adenomatous colon polyps with or without CRC or ii)MMR proficient CRC diagnosed

Question 24

Nevoid basal cell carcinoma syndrome

Answer 24

• Gene: PTCH - Characterized by the presence of multiple jaw keratocysts beginning in the teens and multiple basal-cell carcinomas beginning in the 20’s - Physical features such as macrocephaly, bossing of the forehead, coarse facial features, facial milia, and skeletal anomalies are present in most individuals - Less common features include cardiac fibromas (2%), ovarian fibromas (20%), medulloblastoma (primitive neuroectodermal tumor; 5%) - Dx made clinically when an individual has 2 major dx criteria and 3 minor dx criteria - REFERRAL: should be considered for any individual with a personal hx of or 1st-degree relative with any two criteria

Question 25

Peutz-Jeghers Syndrome (PJS)

Answer 25

• Gene: STK11 - Characterized by mucocutaneous hyperpigmentation of the mouth, lips, nose, eyes, genetalia, or fingers; multiple hamartomatous polyps in the GI tract; and increased risks for colorectal, pancreatic, gastric, and small intestinal cancers. Also increased risks for breast cancer, ovarian sex cord tumors with annular tubules, and adenoma malignum of the cervix and the testes, especially Sertoli cell tumors. - REFERRAL: any individual with a personal hx of or first-degree relative with i) 2+ histologically confirmed PJ GI polyps; ii) one or more PJ GI polyp and mucocutanous hyperpigmentation; iii) ovarian sex cord tumor with annular tubules; iv) adenoma malignum of the cervix; v) Sertoli cell tumor; vi) pancreatic cancer and one or more PJ GI polyp; vii) breast cancer and one or more PJ GI polyp; or viii) one or more PJ polyp and a positvie family history of PJS

Question 26

Rhabdoid tumor predisposition syndrome types I and II

Answer 26

• Gene: SMARCB1 (type 1); SMARCB4 (type 2) - Characterized by an increased risk for rhabdoid tumors (rare and aggressive tumors in children). - REFERRAL: any individual with a personal history of or first-degree relative with a rhabdoid tumor, including small cell carcinoma of the ovary, hypercalcemic type.

Question 27

Serrated Polyposis Syndrome (SPS)

Answer 27

• Unknown genetic cause; a genetics referral is indicated bc the diagnosis will affect future management and other polyposis syndromes should be ruled out - Syndrome characterized by serrated polyps and an increased risk for CRC. - REFERRAL: any individual with a personal hx of or 1st-degree relative with i) at least 5 serrated polyps proximal to the sigmoid colon, 2 of which are >1 cm in diameter, ii) >20 serrated polyps throughout the large bowel, or iii) any number of serrated polyps proximal to the sigmoid colon and a positive family hx of SPS

Question 28

Tuberous Sclerosis Complex

Answer 28

• Genes: TSC1 and TSC2 - Characterized by brain, kidney, and heart tumors, as well as skin and neurological abnormalities, among others. - Skin lesions occur in ~100% of individuals, although none are pathognomonic - REFERRAL: should be considered for any individual with a personal hx of or first-degree relative with any two criteria

Question 29

Von Hippel-Lindau Syndrome (VHL)

Answer 29

• Gene: VHL - Characterized by RCC (clear cell histology), hemangioblastomas, pheochomocytomas, and endolymphatic sac tumors. - Simplex cases of CNS hemangioblastoma, pheochromocytoma, and endolymphatic sac tumor are sufficient to warrant genetic counseling referral - REFERRAL: should be considered for any individual with a personal hx of or 1st-degree relative with i) clear cell RCC if he or she (a) has bilateral or multifocal tumors, (b) is diagnosed before age 50, or (c) has a close relative with clear cell RCC; ii) central nervous system hemangioblastoma; iii) pheochromocytoma; iv) endolymphatic sac tumor, or v) retinal capillary hemangioma