Practice Gaps: Essential Genetics

Transcription

1 FRM F017 Practice Gaps: Essential Genetics Jennifer L. Hand MD Associate Professor of Dermatology, Clinical Genomics, and Pediatrics Section Head, Dermatology Genetics Mayo Clinic, Rochester, MN, USA

2 DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY Jennifer L. Hand, MD F017 Practice Gaps in Adult and Pediatric Dermatology Illustrative Cases DISCLOSURES UpToDate, Inc

3 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.

4 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

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

6 Audience Response Question Which inherited cancer syndrome is most likely? A) Rombo B) Peutz-Jegher C) Cowden (PTEN hamartoma) D) Lynch syndrome (HNPCC) E) Gorlin syndrome

7 Dr. Henry T. Lynch, MD Accessed from Lynch Syndrome International, 7/10/2017 Dr. Henry T. Lynch, MD Born: Massachusetts, 1928 Joined US Navy at 16- falsified birth certificate gunner on ship, World War II Wonderful, caring man Used statistics to prove genetic link to certain cancers- Novel for time

8 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, hepato-billiary & uroepithelial tract, breast, lung John AM, Schwartz RA. Muir-Torre syndrome. 74(3). 2016:

9 Incidence of cancer (penetrance) by mutated gene MLH1 MSH2 MSH6 PMS2

10 Guidelines for Mutation Carriers (MLH1, MSH2, MSH6, PMS2, EPCAM) Colonoscopy at age 20 to 25 or 2 to 5 years before earliest colon cancer in family; repeat every 1 to 2 years Consider upper endoscopy with visualization of the duodenum, age Consider treatment for H. pylori Annual urinalysis, age 30, especially men

11 Guidelines for Mutation Carriers (cont.) (MLH1, MSH2, MSH6, PMS2, EPCAM) Endometrial biopsy for symptoms Consider hysterectomy after childbearing

12 Audience Response Question Which skin growth is characteristic of Lynch syndrome (HNPCC)? A) Trichilemmoma B) Trichofolliculoma C) Sebaceous neoplasm D) Myxoma E) Basal cell carcinoma

13 Audience Response Question Which skin growth is characteristic of Lynch syndrome (HNPCC)? A) Trichilemmoma B) Trichofolliculoma C) Sebaceous neoplasm D) Myxoma E) Basal cell carcinoma

14 Muir-Torre is not a syndrome: Lynch syndrome, Muir-Torre Variant

15 I. Age, 50 Stomach Cancer II. Endometrial III. Brain Colon Endometrial Increased cancer of colon (40-70%), endometrium (25-60%), ovary (8-11%), GI tract, urinary tract, brain

16 Lynch Syndrome: Muir-Torre Variant I. Age, 50 Stomach Cancer II. Endometrial III. Colon Brain Endometrial = Skin Sebaceous Neoplasm or Keratoacanthoma

17 Sebaceous Adenomas

18 Keratoacanthoma

19 Sebaceous Carcinoma in Muir-Torre Variant May appear similar to epidermoid cyst

20 Muir-Torre Variant Occur before internal malignancy or concurrently in about 30% Sebaceous Adenoma Sebaceous Epithelioma Sebaceous Carcinoma Keratoacanthoma

21 Skin Tumors in Muir-Torre Variant Sebaceous Differentiation Seborrheic Keratosis Basal Cell

22 Non-profit Alliance of 27 cancer centers most designated comprehensive cancer centers by NCI National Comprehensive Care Network

23 Audience Response Question Where are updated guidelines for high-risk cancer syndromes? A) National Comprehensive Cancer Network ( B) Foundation for Ichthyosis and Related Skin Types (FIRST) C) Gene Cards ( D) Online Mendelian Inheritance in Man (OMIM)

24 Mismatch Repair Genes MLH1, MSH2, MSH6, PMS2 Microsatellites: repetitive DNA sequences e.g. AAAAAAA Microsatellite instability (MSI) creates mutations, tumors Lynch Syndrome Testing recommended in stepwise fashion Used with permission. Modern Pathology (2006) 19, S93 S126 Sebaceous Adenoma

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

27 Muir-Torre Variant Immunohistochemical Staining MSH2 most common mutation Also MLH1 and MSH6 Normal MSH1 uptake Decreased MSH2 uptake Confirms Somatic Mutation in tumor Blood test needed to confirm germ-line mutation

28 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%

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

30 A 65-year-old man has a diagnosis of sebaceous carcinoma on his right back. Immunohistochemical staining showed MSH 2 and MSH6 loss Detailed pedigree showed no endometrial cancer, colon cancer, brain cancer. Personally, few adenomatous polyps. Blood test for hot spots mutation in MSH2 and MSH6, negative. Decided to proceed with testing for MLH1 and PMS2 mutations. Also negative.

31 A 65-year-old man has a diagnosis of sebaceous carcinoma on his right back. Immunohistochemical staining showed MSH 2 and MSH6 loss No fam hx of endometrial cancer, colon cancer, brain cancer. Personally, few adenomatous polyps. Blood test for hot spot mutation in MSH2, MSH6, MLH1, PMS2, all negative. Does our patient have Lynch syndrome?

32 Practice Gap A negative genetic test does not rule out a disease or diagnosis It lessens the chances the person has the disease a mutation may be undetectable based on current technology Advise follow-up if new features of the condition appear in the patient or family, or recommend periodic reassessment.

33 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

34 Audience Response Question Which inherited cancer syndrome is most likely? A) Neurofibromatosis 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):

35 Constitutional Mismatch Repair Syndrome. 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

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37 Autosomal Recessive Inheritance Family history is often negative. New dominant mutation indistinguishable from AR AR inheritance has 25% risk New AD has very low risk of recurrence

38 Constitutional Mismatch Repair Syndrome (CMMR) Associated cancers: high-grade glioma, acute myeloid leukemia childhood hematologic malignancies. medulloblastoma Possible that rare cancers associated with NF1 occurred in misdiagnosed children that had CMMR

39 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 Associated with pilomatricomas Wimmer K, Rosenbaum T, Messian L. Connections between CMMRD and NF1. Clin gen doi: /cge.12904

40 I. Autosomal Dominant Inheritance II. III.

41 I. Autosomal Recessive Inheritance II. III.

42 Audience Response Question Is the MSH2 mutation Autosomal Dominant or Recessive? A) Autosomal Dominant B) Autosomal Recessive C) It depends.

43 Practice Gap Autosomal Dominant or Autosomal Recessive describes the inheritance pattern Some mutations behave both ways (i.e. cause a different phenotype depending whether one or two copies are present.

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46 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

47 Thank You!

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