Forum F126

Practice Gaps: Genetic Testing Jennifer L. Hand, M.D. Associate Professor Dermatology, Clinical Genomics, Pediatrics Mayo Clinic, Rochester, MN, USA

DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY

Jennifer L. Hand, MD F126 Practice Gaps in Dermatology: Are We Doing What the Evidence Tells Us We Should? Tips for Your Practice DISCLOSURES

I do not have any relevant relationships with industry.

PHOTOGRAPHY & VIDEOTAPING ARE STRICTLY PROHIBITED IN ALL EDUCATIONAL SESSIONS CELL PHONES MUST BE PLACED ON VIBRATE OR TURNED OFF Violations of this policy will result in removal from the session and possible revocation of meeting registration. Session directors will be closely monitoring such occurrences.

FOTOGRAFIA E FILMANDO SÃO ESTRITAMENTE PROIBIDOS EM TODAS AS SESSÕES EDUCACIONAIS TELEFONES CELULARES DEVEM SER COLOCADOS EM VIBRAR OU DESLIGADOS Violações desta política resultará na remoção de sessão e possível revogação do registo da reunião. Diretores de sessão irão acompanhar de perto tais ocorrências.

Objectives  Recognize cancer syndromes that have actionable genetic mutations (eg. MSH2)  Learn to access the NCCN (National Comprehensive Cancer Network) guidelines for surveillance  Access local genetic resources for multiple disorders

A 65-year-old man has a diagnosis of sebaceous carcinoma on his right back

Audience Response Question #1 Which inherited cancer syndrome is most likely?

A) Rombo B) Peutz-Jeghers C) Cowden (PTEN hamartoma) D) Lynch syndrome (HNPCC) E) Gorlin syndrome

Lynch syndrome • Caused by Mismatch Repair (MMR) Mutations • Detect and repair microsatellite DNA during replication – Microsatellites contain repetitive DNA – Increased errors  cancer

• Colon (proximal), endometrial, brain, ovary, pancreas, hepatobiliary & uroepithelial tract, breast, lung, skin John AM, Schwartz RA. Muir-Torre syndrome. 74(3). 2016: 558-566.

Dr. Henry T. Lynch, MD

Dr. Henry T. Lynch, MD Accessed Lynch Syndrome Int., 7/10/2017

• Born: Massachusetts, 1928 • US Navy at 16- falsified birth certificate • gunner on WWII ship; “Wonderful, caring man” • Used statistics to prove genetic link to certain cancers- Novel for time

Audience Response Question #2

65-year-old with sebaceous carcinoma. What is the recommended next step? a) Blood test for Lynch syndrome mutations b) Immunohistochemical stain of skin biopsy specimen c) Obtain family history d) Recommend colonoscopy

Lynch Syndrome

*Testing recommended in stepwise fashion* • Mismatch Repair Genes • MLH1, MSH2, MSH6, PMS2

• Microsatellites: repetitive DNA sequences • e.g. AAAAAAA

• Microsatellite instability (MSI) creates mutations, tumors Sebaceous Adenoma Used with permission. Modern Pathology (2006) 19, S93–S126

Human Pathology (2016), 49, 1-9

Audience Response Question # 3 Path report: IHC stains for DNA mismatch repair enzymes show loss of MLH1, partial loss of MSH6 with retention of MSH2 and PMS2. Offer the patient?

A) Genetics Consultation B) Order blood test for MSH1? MSH6? Both? Panel? C) Obtain insurance pre-authorization D) Draw pedigree

A 65-year-old man has a diagnosis of sebaceous carcinoma on his right back. • Immunohistochemical dropout of MSH 2 and MSH6 • Pedigree with no endometrial cancer, colon cancer, brain cancer. Personally, few adenomatous polyps. • MSH2 and MSH6 mutation blood test, negative. • Follow-up blood test for MLH1 and PMS2, negative

Sebaceous Neoplasms • The sensitivity and specificity of Immunohistochemical staining on sebaceous neoplasms is lower than for colorectal cancer – Sensitivity is 85% (vs. 93%) – Specificity is 48% (vs. 95%) – False positive rate reported as 56%

I.

Age, 50 Stomach Cancer

II. Endometrial

Brain

III. Endometrial Colon Increased cancer of colon (40-70%), endometrium (25-60%), ovary (8-11%), GI tract, urinary tract, brain

Audience Response Question #4

The most likely diagnosis is: A) Muir Torre Syndrome B) Lynch Syndrome, Muir-Torre Variant C) Hereditary Non-Polyposis Colon Cancer (HNPCC) D) Li-Fraumeni Syndrome

Lynch Syndrome, Muir-Torre Variant Age, 50 Stomach Cancer

I. II. Endometrial

Brain

III. Colon

Endometrial

= Skin Sebaceous Neoplasm or Keratoacanthoma

Accepted Names  Lynch syndrome  Lynch syndrome, MuirTorre Variant  Hereditary Nonpolyposis Colon Cancer (HNPCC)

Resources Lynchcancers.com

Resources Patient Support Meetings 4 minute video for patients (and students). Google MuirTorre.

Audience Response Question #5 The mutation most closely associated with sebaceous carcinomas in Lynch syndrome is: A) MLH1 B) MSH2 C) MSH6 D) PMS2

Muir-Torre Variant Immunohistochemical Staining • MSH2 most common Normal MSH1 uptake

Decreased MSH2 uptake

mutation – Also MLH1 and MSH6 • Confirms Somatic Mutation in tumor • Blood test needed to confirm germ-line mutation

Practice Gap Tumor mutations are: Somatic  Mosaic Post-zygotic Are not necessarily: heritable germ-line

Incidence of cancer (penetrance) by mutated gene MLH1 MSH2 MSH6

PMS2

Audience Response Question #6 Where are current clinical guidelines for patients with actionable gene mutations? A) National Comprehensive Cancer Network (www.NCCN.org) B) Foundation for Ichthyosis and Related Skin Types (FIRST) C) Gene Cards (www.genecards.org) D) Online Mendelian Inheritance in Man (OMIM)

National Comprehensive Care Network

 Non-profit Alliance cancer centers  most are designated by National www.nccn.org Cancer Institute (NCI)

Evidence based: skin exam recommended • BRCA2: increased risk of melanoma. Screening individualized based on personal/ family history

• STK11, Peutz-Jeghers: provisional guideline only. Overall risk of cancers increased 10%.

• PTEN, Cowden: Dermatologic management may be needed for some patients

• P53, Li-Fraumeni: Annual dermatologic exam starting at age 18 www.nccn.org

www.nccn.org

Detection, Prevention and Risk Reduction Genetic Familial, High Risk --> surveillance Diagnosis Directed Skin exam syndromes e.g. Cowden, Lynch, Peutz-Jeghers

 A 6-year-old girl has multiple café-au-lait macules and axillary freckling.  Extensive evaluation for Neurofibromatosis with gene testing is negative.  At age 24, she develops bright red blood per rectum, and has numerous adenomatous polyps

Audience Response Question #7 Which syndrome is most likely? A) Neurofibromatosis type I B) Constitutional Mismatch Repair (CMMR) Deficiency C) Cowden (PTEN hamartoma) D) Lynch (HNPCC) Ramachandra C et al. Indian J Hum Genet 2014; 20(2):192-194

Constitutional Mismatch Repair Deficiency . • Homozygous Lynch syndrome mutations – MLH1, MSH2, MSH6, PMS2

• Café-au-lait macules most common feature; in 97% from early childhood • Associated with pilomatricomas Wimmer K, Rosenbaum T, Messian L. Connections between CMMRD and NF1. Clin gen doi:10.11111/cge.12904

Constitutional Mismatch Repair Deficiency

.

• Homozygous Lynch syndrome mutations – MLH1, MSH2, MSH6, PMS2

• Café-au-lait macules most common feature; in 97% from early childhood patients • CALM with more diffuse borders, hypopigmentation • Parents likely consanguineous

In Summary….  Recognize cancer syndromes that have actionable genetic mutations (eg. MSH2)  Learn to access the NCCN (National Comprehensive Cancer Network) guidelines for surveillance  Access local genetic resources for multiple disorders