Genetic Syndromes and Thyroid Cancer by Pamela Brock, MS, LGC

Genetic Syndromes and Thyroid Cancer

Pamela Brock, MS, LGCLicensed Genetic CounselorAssistant Professor, ClinicalInternal Medicine

The Ohio State University Comprehensive Cancer Center –

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

No disclosures



• Review established genetic predisposition conditions associated with non-medullary thyroid cancer

• Discuss new genes and conditions thought to be associated with non-medullary thyroid cancer

• Explore emerging genetic testing options related to non-medullary thyroid cancer

Objectives



Part of PTEN hamartoma tumor syndrome spectrum Prevalence of ~1/200,000-1/250,000 Associated with both benign and malignant tumor

formation Can be diagnosed clinically based on criteria 25-80% of those meeting criteria have pathogenic

variants in the PTEN gene

Cowden Syndrome

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An Individual meeting any of the following: Three or more major criteria, but one must be

macrocephaly, LDD or GI polyps

Two or more major criteria plus three minor criteria

Family history of PHTS or PTEN mutation plus: Two major criteria One major and two minor criteria Three minor criteria

Pilarski, R., et al. J Natl Cancer Inst, 2013; 105(21):1607-1616.

Cowden Syndrome – NCCN Diagnostic Criteria

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Cowden Syndrome – NCCN Diagnostic Criteria

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Major criteria Breast cancer Endometrial CancerFollicular Thyroid cancerGI hamartomas, ganglioneuromasLhermitte-Duclos disease (LDD)Macrocephaly (OFC > 97th %ile) Macular pigmentation of penisMucocutaneous lesions:

Multiple TrichilemmomasAcral keratoses Oral papillomas or neuromasFacial Papules

Minor criteria Autism spectrum disordersColon cancerEsophageal glycogenic acanthosisLipomas Mental retardation (IQ ~ < 75) Renal cell carcinomaTesticular lipomatosisThyroid cancer (papillary or follicular variant)Thyroid structural lesionsVascular anomalies



Cowden Syndrome

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Cowden Syndrome

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Photo from Medscape

Wikipedia.org


Arthur G. James Cancer Hospital and Richard J. Solove Research Institute9 9

Risk assessment tool – Cleveland Clinic PTEN calculatorhttp://www.lerner.ccf.org/gmi/ccscore/

http://www.lerner.ccf.org/gmi/ccscore/

http://www.lerner.ccf.org/gmi/ccscore/



Cowden Syndrome

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Cancer Cowden Syndrome Risk

General Population Risk

Breast (Female) 25-50% 8-12%

Thyroid 3-10% <1%

Endometrial 5-28% 2-3%

Colorectal Up to 9% 5-6%

Melanoma Up to 5% 2%

Renal Increased 2%

Breast (Male) Slightly increased <0.1%



Lifetime risk for epithelial thyroid cancer is approximately 10%

Median age of onset was 37 years Youngest age at diagnosis was 7 years Follicular histology is over-represented in adults

compared to the general population in which papillary histology is over-represented

Tan, MH, et al. Clin Cancer Res. 2012;18:400–7. Ngeow, J, et al. J Clin Endocrinol Metab. 2011;96:E2063–71.

Thyroid Cancer in Cowden Syndrome

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Colon cancer predisposition syndrome in which hundreds to thousands of precancerous colonic polyps develop (risk for colon cancer ~100%)

Extracolonic manifestations may include gastric/small bowel polyps, osteomas, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and desmoid tumors

Caused by mutations in the APC gene 20-25% of cases result from a new mutation (de

novo) Attenuated FAP is a milder presentation

Familial Adenomatous Polyposis (FAP)

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High degree of variability in the reported frequency of thyroid cancer in individuals with FAP

Incidence in retrospective series of individuals with FAP was 0.4% to 6.1% (Steinhagen E, et al. 2012)

Prospective ultrasound screening studies have found a prevalence of 2.6% to 12% (Herraiz M, et al. 2007 and Jarrar AM, et al. 2011)

Most thyroid cancer in individuals with FAP is papillary Cribriform-morular variant of PTC is strongly suggestive

of FAP

Thyroid Cancer in FAP

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Rare condition characterized by skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas

Approximately 60-80% of cases with pathogenic variants in PRKAR1A

Approximately 30% of cases result from a new mutation

Carney Complex

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Photo credit: ASCO Carney Complex slides



Carney Complex

Clinical Features/Major Diagnostic Criteria Spotty skin pigmentation Myxoma (cutaneous and mucosal) Cardiac myxoma Breast myxomatosis Primary pigmented nodular adrenocortical disease (PPNAD) Acromegaly as a result of growth hormone (GH)-producing

adenoma Large-cell calcifying Sertoli cell tumor (LCCSCT) Thyroid carcinoma or multiple, hypoechoic nodules on thyroid

ultrasound in a child younger than age 18 years Psammomatous melanotic schwannomas (PMS) Blue nevus, epithelioid blue nevus Breast ductal adenoma Osteochondromyxoma



Up to 75% of individuals with CNC have multiple thyroid nodules

Most are nonfunctioning thyroid follicular adenomas Both papillary and follicular thyroid cancer can occur

Stratakis et al. GeneReviews. 2015.

Thyroid Cancer in Carney Complex

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Rare autosomal recessive condition

More common in Japan Associated with

premature aging, cataracts, cancer, and atherosclerosis

Increased risk for thyroid cancer (follicular …and papillary)

Werner Syndrome

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Photo credit: ASCO slide set



Hereditary Cancer Syndromes and Thyroid Cancer

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Syndrome Gene Thyroid Cancer Type

Lifetime Risk

Other Features

Cowden PTEN FTC, PTC 3-10% Breast cancer, endometrial cancer, goiter, macrocephaly

FAP APC PTC, cribiform morular variant

~2% Colon polyposis, CHRPE, desmoids

Carney complex

PRKAR1A FTC, PTC Unknown Pigmented abnormalities of the skin, myxomas, schwannomas, and endocrine tumors

Werner WRN FTC Unknown Premature aging, cataracts, DM, other cancers

Adapted from Nagy, R and Ringel, MD. Horm Canc (2015) 6:13-20.



Cell cycle checkpoint kinase 2 (CHEK2) Tumor suppressor gene CHEK2 mutations associated with a moderate

increase in the risk for various types of cancer Breast cancer - 2-4x increased risk Colorectal Prostate

Mutation frequencies differ by country/region

CHEK2 Gene

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CHEK2 Gene

1100delC and IVS2+1G>A Thyroid cancer (OR 4.9, p = 0.0006) Breast cancer (OR 2.2, p = 0.02)Prostate cancer (OR 2.2, p = 0.04)

I157TKidney cancer (OR 2.1, p = 0.0006)Colon cancer (OR 2.0, p = 0.001)Prostate cancer (OR 1.7, p = 0.002)Breast cancer (OR 1.4, p = 0.02)Thyroid cancer (OR 1.9, p = 0.04) Cybulski et al. 2004



Siolek et al 2015 studied CHEK2 gene in thyroid cancer patients

468 cases and controls (Polish population) CHEK2 mutations seen in 15% of unselected PTC

patients and 6% of controls (p=0.006) 7/11 women with breast and thyroid cancers had

CHEK2 mutations

Thyroid Cancer and the CHEK2 Gene

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DICER1-Related Disorders

Tumor susceptibility syndrome that confers increased risk most commonly for Pleuropulmonary blastoma (PPB) Ovarian sex cord-stromal tumors (such as Sertoli-

Leydig cell tumor or juvenile granulosa cell tumor) Cystic nephroma Thyroid gland neoplasia Rhabdomyosarcoma Pituitary blastoma

80% of the germline pathogenic variants were inherited from a parent and 20% were de novo

Doros et al. GeneReviews. 2014.

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Current data support an increased risk of developing thyroid cysts and/or multinodular goiter (MNG) in families with a germline DICER1 pathogenic variant

Current data also suggest a low risk of developing syndrome-associated thyroid cancer (papillary or follicular)

Doros et al. GeneReviews. 2014.

Thyroid Cancer and the DICER1 Gene

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Autosomal recessive colon polyp and colon cancer predisposition condition

Variable in presentation Also associated with gastric and

small bowel polyps Possible association with other

types of cancer (breast, ovarian, bladder)

MUTYH gene is included in polyposis genetic testing options

MUTYH-Associated Polyposis (MAP)

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Thyroid Cancer in MAP

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Preliminary evidence suggests that there is an increased risk for thyroid involvement including: Goiter Nodules Papillary thyroid cancer

Further studies are need to better define these risks



Conditions with Possible Thyroid Cancer Risks

Birt-Hogg-Dube syndrome - cutaneous manifestations, pulmonary cysts/history of pneumothorax, and various types of renal tumors

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) Hereditary Paraganglioma/Pheochromocytoma

(SDHB and SDHD) Multiple Endocrine Neoplasia Type 1

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Genetic Testing Technologies





Pros & Cons of Next Generation Sequencing

Can test multiple genes at one time• Cancer Gene Panels available with 6 – 52+ genes

Costs less than traditional Sanger testing methods• $1,500-$4,000 for multiple genes (50+) vs. ~$2,000 per gene using Sanger

sequencingTurn-around time can be longer• Up to 12 weeks at some laboratories

Higher chance of variant of uncertain significance (VUS) results• Unless you know what the additional genes do

More genes ≠ Better

Mutation detection rates may be lower than with traditional Sanger sequencing

Slide credit: Heather Hampel, ASCO University (2014)



Yield on clinical genetic testing in familial non-medullary thyroid cancer is low

Approach to genetic testing is often driven by the other types of cancer in the family Colon polyps (at least 10 adenomas) Breast cancer Unusual skin findings/benign tumors Multiple primary cancers

Genetic Testing and Thyroid Cancer

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Familial Papillary Thyroid Cancer Study Preferably looking for families with 3 or more family

members with history of PTC Gene hunting and other various studies For more information or to refer a family, please call

the PTC study research assistant (Nicole Chain) at 614-293-2459

Shameless Plug

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Questions?

Education

Genetic Syndromes and Thyroid Cancer by Pamela Brock, MS, LGC