Hereditary GI tumor syndromes ACG guidelines of genetic testing and management. Dr. med. Henrik Csaba Horváth PhD

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1 Hereditary GI tumor syndromes ACG guidelines of genetic testing and management Dr. med. Henrik Csaba Horváth PhD

2 Genetic testing and management of hereditary GI tumor syndromes June 29,

3 Clinical relevance of hereditary GI tumor syndromes 1. Increased life-time risk for malignancy (synchronous/ metachronous syndrome-specific tumors) 2. Extragastrointestinal manifestations 3. Specific guidelines (diagnosis, screening, surveillance) 4. Genetic abnormalities (testing of index patients and family members) 5. Identify those at significantly increased risk and offer options to prevent and diagnose earlier cancer in these individuals Genetic testing and management of hereditary GI tumor syndromes June 29,

4 Major entities of hereditary GI tumor syndromes 1. Lynch syndrome 2. Polyposis syndromes Adenomatous 1. Familial adenomatous polyposis (FAP) 2. Attenuated familial adenomatous polyposis (AFAP) 3. MUTYH-associated adenomatous polyposis (MAP) 4. Colonic adenomatous polyposis syndrome of unknown etiology (CPUE) Hamartomatous 1. Peutz-Jeghers syndrome (PJS) 2. Juvenile polyposis (JP) 3. Cowden syndrome (CS, PTEN hamartoma tumour syndrome) Serrated polyposis syndrome (SPS) Mixed polyposis syndromes (HMPS) 3. Hereditary pancreatic cancer 4. Hereditary gastric cancer Genetic testing and management of hereditary GI tumor syndromes June 29,

% of patients with carcinoma Universitätsklinik für Viszerale Chirurgie und Medizin Lynch syndrome Autosomal dominant mutation of the mismatch-repair /EPCAM-gen(s) 100 80 60 Colon 78% MLH1 (3p21)

5 % of patients with carcinoma Universitätsklinik für Viszerale Chirurgie und Medizin Lynch syndrome Autosomal dominant mutation of the mismatch-repair /EPCAM-gen(s) Colon 78% MLH1 (3p21) MSH2 (2p16) MSH6 (2p16) PMS2 (7p22) Endometrium 43% Stomach 19% Bile duct 18% Urinary tract 10% Ovary 9% Small bowel 1-4% Brain/ CNS 1-4% EPCAM (2p21) Age (yr) German HNPCC-Consortium 2013 mod. Aarnio et al: Int J Cancer : Genetic testing and management of hereditary GI tumor syndromes June 29,

age 50 years; Diagnosis One family member should be a first-degree relative of the other 2 members FAP excluded Clinical suspicion

6 Identification of patients with Lynch syndrome Criteria Modified Amsterdam criteria (all of them are required to Dx) - 3 or more relatives with a Lynch syndrome associated cancer; - 2 or more successive generations affected; - 1 or more relatives diagnosed before age 50 years; Diagnosis One family member should be a first-degree relative of the other 2 members FAP excluded Clinical suspicion Hoffmann R et al Gastroenterology & Endoscopy News 2010;61[5]:1,19-20,22 Genetic testing and management of hereditary GI tumor syndromes June 29,

7 Genotype-phenotype associations in Lynch syndrome Carcinoma MLH1 MSH2 MSH6 Males Females Males Females Males Females Cumulative risk 76% 80% 73% CRC 58-65% 50-53% 54-63% 36-68% 36-69% 18-30% Endometrium n.a. 27% n.a. 40% n.a. 71% Ovary n.a. 6% n.a. 12% n.a.? Upper GI tract 2,1% 0,4% 20% 9%? Stomach 6% 5%? Small bowel 3% 6% 3% 6%? Hepatobiliary tract 4%? CNS 1,7% 2,5%? Sebaceous neoplasms 42% 44% 0% Hampel H et al: Gastroenterology :415 Watson P et al: Int J Cancer : 444 Koessler T et al: Gut :1097 Hendriks YM et al: J Natl Cancer Inst :277 Barrow E et al: Clin Genet :233 Genetic testing and management of hereditary GI tumor syndromes June 29,

8 Screening modality and schedule Colonoscopy EGD gynecology Start Interval Start interval MLH y or 2-5y prior to the MSH2 earliest CRC (25y) annual (mut. carriers) 2y (Pt at risk) MSH y 2(-3y) (1y) 30- after age 40y 1-2y PMS y 2(-3y) after age 50y 1-2y 35y (35y) Treat H. pylori 3-5y Prophylactic hysterectomy and bilateral salpingooophorectomy if childbearing completed Annual transvaginal US and endometrial biopsy from 30-35y (from 35y annual) CA-125 and/or transvaginal US optional - ACG guidelines 2016 S3- German guidelines 2013 Genetic testing and management of hereditary GI tumor syndromes June 29,

9 Adenomatous polyposis syndromes AD mutation of the APC gen (5q21-22) FAP: >100 adenomas throughout the colon Risk of CRC 7% at age of 21y, 93% at age of 50y 100% no treatment AFAP: less adenomas (10-100) prox. colon late manifestation decreased risk of CRC (70%) AR mutation of the MutYH Gen (1p34) MAP: adenomas after age of 40y Lifte-time risk of CRC at 70-80% extracolonic manifestations infrequent Extracolonic malignancies similar to Lynch Extracolonic tumors adenomas in the duodenum (periampullar)/small bowel (10%) fundic glang polyps in the stomach (low malignant potential) pancreatic carcinoma (1-2%) Extragastrointestinal tumors congenital hypertrophy of the retinal pigment epithel (CHRPE) desmoid tumors thyroid gland carcinoma hepatoblastoma in infants, CNS tumors Genetic testing and management of hereditary GI tumor syndromes June 29,

10 Making a correct diagnosis Personal history of classical/attenuated FAP 1. To confirm the diagnosis 2. To allow for mutation-specific testing in other family members 3. To predict the severity of polyposis, rectal involvement and desmoid tumours APC positive APC negative Family history of classical/attenuated FAP FAP/AFAP regard as FAP/AFAP Affected: see above Unaffected (no symptoms/findings), 1st degree relative of an affected individual, known family mutation APC genetic testing for familial mutation is recommended APC positive APC negative FAP/AFAP not affected (average risk) Genetic testing and management of hereditary GI tumor syndromes June 29,

11 Making a correct diagnosis Personal history of colorectal polyposis 1. Patients with multiple (>10) adenomatous or serrated GI polyps (Pt with MAP may also meet the criteria for serrated polyposis syndrome!) 2. Have FH of adenomatous polyps or CRC compatible with an AR inheritence 3. No APC-mutation is detected 4. Young onset CRC diagnosis w/o MMR-mutations (MSS, no change in IHC) 5. Siblings of biallelic mutation carriers Family history of MAP Unaffected (no symptoms/findings), 1st degree relative/sibling of an affected individual, known family mutation MUTYH genetic testing for familial mutation is recommended Genetic testing and management of hereditary GI tumor syndromes June 29,

12 Making a correct treatment Personal history of classical FAP/AFAP/MAP (phenotype+genotype) Absolute indication for proctocolectomy with end ileostomy or ileal pouch-anal anastomosis: - Documented or suspected carcinoma - Significant symptoms (bleeding, ileus/subileus) Relative indication for surgery: - Multiple adenomas 6mm of size - Significant increase in adenoma number - Inability to adequately survey because of multiple diminutive polyps Making a correct surveillance colonoscopy EGD + side-viewing duodenoscopy Postsurgical endoscopy of the rectum/ileal pouch Abdominal US with AFP Thyroid gland US Start interval Start interval Start interval Start interval Start interval FAP AFAP MAP 10-15y* After colectomy 12 mo Rectoscopy 6-12mo Ileoscopy 1-3y 25-30y Spiegelman`s Stage 0 Stage I Stage II Stage III Stage IV 4y 2-3y 1-3y 6-12mo 3-6mo** After colectomy Consider CT/MRI If symptoms/ palpation for desmoid 1y 1-3y if negative 5-10y Dx (6 mo) 2y until the age of 7y Late teenage 1-2y *consider prophylactic colectomy when >20 adenomas, >1 cm of size or advanced histology ** Surgical evaluation Genetic testing and management of hereditary GI tumor syndromes June 29,

Making the genetic testing of hamartomatous polyposis

polyps 2 hamartomatous polyps - mucocutanous

colorectal polyps - multiple juvenile polyps in the

- multiple hamartomatous polyps in the GI tract -

Juvenile polyposis syndrome? Cowden syndrome?

for SMAD4/BMPR1 gene germline mutation (~60%) Search

13 Making the genetic testing of hamartomatous polyposis syndromes Clinical characteristics of hamartomatous polyps 2 hamartomatous polyps - mucocutanous hyperpigmentation - family history of PJS 3 juvenile colorectal polyps - multiple juvenile polyps in the stomach/small intestine/colon - family history of FJP - multiple hamartomatous polyps in the GI tract - mucocutanous lesions - personal/family history of breast, thyroid gland or endometr. cancer Peutz-Jeghers syndrome? Juvenile polyposis syndrome? Cowden syndrome? Search for STK1 gene germline mutation (~90%) Search for SMAD4/BMPR1 gene germline mutation (~60%) Search for PTEN gene germline mutation (~80%) Genetic testing and management of hereditary GI tumor syndromes June 29,

14 Peutz-Jeghers syndrome Making the diagnosis (diagnostic criteria): Any of the followings: 1. 3 histologically confirmed Peutz-Jeghers polyps 2. any number of Peutz-Jeghers polyps and a family history of PJS 3. 1 Peutz-Jeghers polyp and characteristic, prominent, mucocutaneous pigmentation 4. characteristic, prominent mucocutaneous pigmentation and family history of PJS Genetic testing and management of hereditary GI tumor syndromes June 29,

15 Familial juvenile polyposis Prevalence: 1: Making the diagnosis (diagnostic criteria): Any of the followings: 1. 3 juvenile polyps of the colorectum 2. Multiple juvenile polyps throughout the GI-tract (at least one in the upper, one in the lower GItract) 3. 1 juvenile polyp in an individual with a family history of JPS Genetic testing and management of hereditary GI tumor syndromes June 29,

16 PTEN-associated hamartomatous polyposis syndrome(s) Prevalence: 1: Clinical characteristics GI hamartomas + 1. Multiple polyps of different types/ mixed phenotype in the colon/stomach: inflammatory, adenomatous, hyperplastic, sessile serrated, lymphoid hyperplasia 2. Glycogenic acanthosis in the esophagus 3. Mucocutaneous lesions: hamartomas of the face (appear typically by late 20s), abnormal skin/mucous membranes (gingiva, bucca), pigmented maculas of glans penis Genetic testing and management of hereditary GI tumor syndromes June 29,

Cowden syndrome Making the diagnosis (diagnostic criteria): Major criteria: 1. Multiple hamartomas 2. Nonmedullary thyroid cancer 3. Breast cancer 4. Endometrial cancer 5. Mucocutaneous lesions 6.

17 Cowden syndrome Making the diagnosis (diagnostic criteria): Major criteria: 1. Multiple hamartomas 2. Nonmedullary thyroid cancer 3. Breast cancer 4. Endometrial cancer 5. Mucocutaneous lesions 6. Macrocephaly Minor criteria: 1. Single GI hamartoma/ganglineurinoma 2. Thyroid adenoma/multinodular goiter 3. Fibrocystic disease of the breast 4. Mental retardation/autism 5. Fibromas 6. Renal cell carcinoma 7. Uterine fibroids 8. lipomas Any of the following: 1. 2 major criteria (including macrocephaly) 2. 3 major criteria (w/o macrocephaly) 3. 1 major and 3 minor criteria 4. 4 minor criteria Genetic testing and management of hereditary GI tumor syndromes June 29,

Serrated polyposis syndrome Multiple/large serrated polyps throughout the colon Frequent co-occurence with adenomatous polyps Number of hyperplastic/serrated polyps positively correlates with CRC

000 Making the diagnosis (diagnostic criteria): Any of the following: 1. 20 cumulative serrated polyps of any size distributed throughout the colon 2.

18 Serrated polyposis syndrome Multiple/large serrated polyps throughout the colon Frequent co-occurence with adenomatous polyps Number of hyperplastic/serrated polyps positively correlates with CRC incidence Less is known about genetic factors («serrated pathway» predominates over WNT pathway, sporadic CIMP-H CRC, epigenetic silencing of hmlh1 gene w/ or w/o BRAF mutation) Prevalence: 1: Making the diagnosis (diagnostic criteria): Any of the following: cumulative serrated polyps of any size distributed throughout the colon 2. 5 serrated polyps proximal to the sigmoid colon with 2 being >10 mm 3. 1 serrated colonic polyp with a 1 st -degree relative with SPS Langner et al: Dig Dis :28-37 Consider searching for MutYH germline mutation Genetic testing and management of hereditary GI tumor syndromes June 29,

19 Hereditary pancreatic cancer Up to 10% of PC may arise from a hereditary susceptibility 1. Pt with known genetic syndrome - Hereditary breast-ovarian syndrome - FAMM (familial atypical melanome and mole syndrome) - PJS - Lynch syndrome 2. History of hereditary pancreatitis 3. Familial pancreatic cancer 2 relatives with pancreatic cancer, one is FDR 3 relatives with pancreatic cancer Genetic testing and management of hereditary GI tumor syndromes June 29,

20 Genetic testing and management of hereditary GI tumor syndromes June 29,

21 Familial gastric cancer 2 histological types of gastric cancer: 1. Intestinal 2. Diffuse FAP, PJS, Lynch Hereditary diffuse gastric cancer HDGC criteria: - 2 cases of DGC at least one diagnosed at <50y - 3 cases of DGC - DGC diagnosed at <40y - Lobular breast cancer+dgc diagnosed at <50y Surveillance and management of patients at risk CDH1- mutation Prophylactic gastrectomy after age>20y (life-time risk 80%) Annual mammography and breast MRI every 6 mo after age>35y (life-time risk 60%) Colonoscopy beginning at age 40y Genetic testing and management of hereditary GI tumor syndromes June 29,

ACG Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes

ACG Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes Sapna Syngal, MD, MPH, FACG, 1,2,3 Randall E. Brand, MD, FACG, 4 James M. Church, MD, FACG, 5,6,7