Hereditary Stomach Cancer Syndromes Melyssa Aronson, MS, (C)CGC Senior Genetic Counsellor Zane Cohen Centre Mount Sinai Hospital

Overview • • • •

Different types of gastric (stomach) cancer Features of a hereditary syndrome Hereditary Diffuse Gastric Cancer syndrome (CDH1) Other hereditary conditions • Lynch syndrome • Polyposis conditions • And more..

• Common Q&A about genetic testing

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Not all stomach cancer is the same…

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Types of Stomach cancer

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Types of Stomach cancer

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Ann Surg Oncol 1999;6:290-7

Intestinal adenocarcinoma (54%) • High incidence geographically • Decreasing incidence world-wide • Male predominance (2:1) • Diagnosed ~60-80 yrs old • H. pylori bacteria • Inflammation -> Metaplasia (Ulcer)

Diffuse-type adenocarcinomas (32%) • Increasing incidence? • No gender preference • Younger age of onset • Poorer prognosis • More common in proximal stomach • Lower association with H. pylori • Signet-ring cell 6 US Gastroenterol Hepatol Rev. 2011 Jun; 7(1): 59–64.

Signet ring cell Cancer (seen in diffuse gastric cancer)

Diffuse Gastric Cancer

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http://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/esophagus_stomach/gastric_cancer.pdf

Risk factors for gastric cancer • • • • •

Aging Geographic location Smoking Diet? Gastritis (Helicobacter pylori)

http://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/esophagus_stomach/gastric_cancer.pdf

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Helicobacter Pylori • Nearly 50% of the world population is infected with H. pylori • In Ontario: 29.4% in men, 14.9% women • Increased risk based on: • Age • # sibs • Being non-white (First Nation) • Immigrated to Canada at > age 20 • Higher incidence in Japan, Korea, China

Naja et al. Can J Gastroenterol. 2007 Aug;21(8):501-6.

Risk factors for gastric cancer • • • • • • • • • •

Aging Geographic location Smoking Diet? Gastritis (Helicobacter pylori) Intestinal metaplasia Gastric polyps (adenoma) Chronic gastric ulcer Pernicious anemia Blood group – Type A 11

A quick lesson in genetics!

All cancer is genetic, but NOT all cancer is hereditary.

Ulcer/metaplasia Or look normal!

Malignant tumour

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Most Cancer is Sporadic!

An example of a sporadic gene mutation: HER2/neu • Makes HER2/neu protein – growth promoting protein • Is tumour HER2 positive, i.e. gene mutation turning on HER2 gene? • If so, drugs like Herceptin can be used to treat that cancer (block HER2 receptors) • NOT hereditary cause of the cancer

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Sporadic cancer

Hereditary cancer

Features of Hereditary Cancer  Families • • • •

Younger ages at diagnosis  than the general population Multiple generations affected Multiple cancers in one  person Similar types of cancers in  one family (or clustering of  cancers ie. Breast and ovarian  cancer

What is the most common hereditary condition causing stomach cancer? Hereditary Diffuse Gastric Cancer Syndrome (CDH1)

Hereditary Diffuse Gastric Cancer Syndrome

• CDH1 gene • E-cadherin protein • Cell to cell adhesion Inheritance: 50/50 to 1st degree relatives

Diffuse gastric cancer risk in men with CDH1 = 70% to age 80 (95%CI, 59%-80%)

Hansford, S et al. JAMA Oncol. 2015;1(1):23-32.

Diffuse gastric cancer in women with CDH1 = 56% to age 80 (95%CI, 44%-69%).

Hansford, S et al. JAMA Oncol. 2015;1(1):23-32.

Breast cancer (lobular) in women with CDH1 = 42% to age 80 (95%CI, 23%-68%).

Hansford, S et al. JAMA Oncol. 2015;1(1):23-32.

Can gastroscopy find diffuse-type gastric cancer?

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Cambridge protocol screening • 5 biopsies from 6 sites (30 biopsies min)

Transitional zone

van der Post RS, et al. J Med Genet 2015;52:361–374

Prophylactic total gastrectomy

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• Most patients do very well • Mild physical symptoms may persist • Need longer term follow-up studies

Screening for HDGC carriers • Prophylactic gastrectomy recommended after age 20 • Annual endoscopy by age 20 • random biopsies x6 of each of the following zones: antrum, transitional zone, body, fundus, cardia. Miniumum of 30 biospies recommended

• MRI and mammography beginning at age 25 (mammogram only after age 69) • Prophylactic mastectomy may be an option • CRC screening based on family history

International criteria (IGCLC) for HDGC (2015) ** Testing offered to individual with cancer Established criteria: • 2 GC regardless of age, at least one confirmed DGC • One case of DGC <40 • Personal or family history of DGC and LBC, one diagnosed <50

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Families in whom testing could be considered: Bilateral LBC or family history of 2 or more cases of LBC <50 A personal or family history of cleft lip/palate in patient with DGC In situ signet ring cells and/or pagetoid spread of signet ring cells

van der Post RS, et al. J Med Genet 2015;52:361–374

How common is CDH1 in diffuse  gastric cancer?

34 of 183 cases meeting 2010 criteria  had CDH1 mutation (19%) JAMA Oncol. 2015;1(1):23‐32.

J Med Genet August 2015 Vol 52 No 8

Index Case

CDH1 mutation Detection rate

Increase in genetic testing (Zane Cohen Centre) Starting doing panels New diagnosis Family member

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Mutation identified in individuals with gastric ca (by age of onset) 30

Pick-up of CDH1 = 8-12%

other mutation 25

CDH1 mutation no mutation

20 # of patients

15 10 5 0 <20

20‐29

30‐39

40‐49 age

50‐59

60‐69

70+

Zane Cohen Centre, 2015

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What are the other syndromes that cause hereditary stomach cancer?

Brain and childhood cancer • Li-Fraumeni (TP53) Breast/ovarian cancer • BRCA2 (?BRCA1)

Colon cancer/polyps • FAP (APC) • Juvenile Polyposis (SMAD4) • Peutz Jeghers Syndrome (STK11)

Diffuse Stomach cancer • CDH1 • CTNNA1

Colon and Uterine • Lynch syndrome (5 genes – MSH2, MLH1)

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What mutations are seen(Zane Cohen Centre)? • Diffuse gastric cancer (n=49) • 42 (86%) no mutation identified • 4 (8%) CDH1 mutations + 2 variants [HDGC] • 2 (4%) STK11 [Peutz-Jeghers Syndrome] • 2 (4%) MSH2, MLH1 [Lynch syndrome] • 1 (2%) BRCA2 [Hereditary Breast-Ovarian Cancer]

• Intestinal gastric cancer + family history (n=4) • 2 (50%) no mutation • 2 (50%) MSH2 [Lynch syndrome]

• Other (mixed, not specified) + family history/young (n=16) • 6 (38%) no mutation • 8 (50%) MSH2, MLH1 [Lynch syndrome] • 2 (12%) APC [Familial Adenomatous Polyposis]

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Gastric cancer – hereditary causes

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Oncology, review article, May 15 2012, Schrader et al

JAMA Oncol. 2015;1(1):23‐32

CTNNA1-Associated Diffuse gastric cancer

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CTNNA1 (α-catenin) • CTNNA1 role in cell adhesion (intercellular) interacts with CDH1 • Seen in a few unrelated families

JAMA Oncol. 2015;1(1):23‐32. JAMA Oncol. 2015;1(1):23‐32.

Lynch syndrome Colorectum + Endometrium

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MSH2 MSH6 EPCAM

PMS2

MLH1

Cancer in LS

Huge range – depends on gene/study/gender

Higher in Asia > in MSH2 (~12%)

<5%

Clinical Gastroenterology and Hepatology (2014) Vol. 12, No. 5

Lynch syndrome family

• MSH2 • MLH1

Colon @ 49 Gastric @ 54

Colon @ 42 Endometrial @ 49

• EPCAM • MSH6 • PMS2 Colon @ 38

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Other GI cancers Ovarian Urinary cancers < Brain Skin (sebaceous)

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Estimated penetrance and age of  onset of neoplasms in BMMRD  Organ

Estimated  penetrance (%)

Brain cancer Colorectal cancer adenomas Small bowel cancer adenomas Lymphoma Leukemia Endometrial cancer Urinary tract cancer Other sites#

70 70 >90 10 50 20‐40 10‐40 <10 <10 <10

Age at diagnosis:  median, range  (yrs) 9    (2‐40) 16  (8‐48) 9    (6‐15) 28 (11‐42) 12 (10‐20) 5    (0.4‐30) 8     (2‐21) (19‐44) (10‐22) (1‐35)

Immunohistochemistry (IHC) Instability (MSI)by AGA, US Multitask Force of CRC, CGA Ref:Microsatellite In Review - Position paper endorsed

Immunohistochemistry (IHC)

Blood

Tumour

MSH2 gene

MSH2 protein

MLH1 gene

MLH1 protein

MSH6 gene

MSH6 protein

PMS2 gene

PMS2 protein

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Polyposis conditions Familial Adenomatous Polyposis Juvenile Polyposis Peutz-Jeghers Polyposis

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Polyposis Syndromes Syndrome

Features

Gastric Cancer risk

Gene

Familial Adenomatous Polyposis

10 to 100s of colon polyps in adolescent

Rare (but FG polyps very common)

APC

Juvenile Polyposis

5 to hundreds of juvenile polyps in digestive tract

20% (and polyps very common)

SMAD4

Peutz-Jeghers Syndrome

Polyps in colon, freckling in mouth and around fingers, cancer risk

30%

STK11

50

Peutz-Jeghers Syndrome (PJS) Cancers risk: >90% lifetime risk Organ

Cancer Risk

Ovarian

Usually benign (rare tumour: ovarian sex cord tumour)

5%

Cervical

Adenoma Malignum (rare cancer)

10%

Testicular

Sertoli cell -> gynecomastia

9%

Breast

Infiltrating ductal and papillary

54%

Uterine

CRC

39%

Small bowel

13%

Stomach

29%

Lung

13%

Pancreas

36%

Hereditary Breast and Ovarian Cancer Syndrome Breast + Ovarian cancer

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Hereditary Breast-Ovarian Cancer syndrome

• BRCA2 • BRCA1

Breast @ 42 Ovarian @ 51

Prostate @ 55

Breast @ 49

• Pancreas • Melanoma • ? Colon or gastric

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JAMA Oncol. 2015;1(1):23‐32.

Li-Fraumeni Syndrome Childhood brain, sarcoma and early onset breast cancer

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Li‐Fraumeni Syndrome

TP53 mutation Stomach cancer

Breast @ 32

Brain @ 6 Sarcoma @ 10 56

Common Questions for me…. • Why aren’t high‐risk gastric patients being referred to genetics? • Why does genetic testing begin on individuals with gastric cancer? • If you have stomach cancer: – How do I get referred for genetic testing? – What is involved with genetic testing? – If I was tested years ago and had a normal result, can I be re‐ tested for newer genes?   • What if I am unaffected – can I still have genetic testing?

Take home messages • Most stomach cancer is sporadic • Flags for hereditary syndromes: early‐onset cancer, multiple  related cancer, multiple relatives affected over generations • The TYPE of stomach cancer (diffuse vs intestinal type) impacts  how genetic testing is done • Most common stomach cancer syndrome  – HDGC:  caused by mutation in CDH1  (lobular breast +DGC)

• Other syndromes can explain diffuse and intestinal cancer  (Lynch syndrome, PJS, etc) • Majority of high‐risk looking families have no gene identified!

Thank you!