Genetics of Gastrointestinal Neoplasia

张咸宁zhangxianning@zju.edu.cn

Tel ： 13105819271; 88208367 Office: A709, Research Building

2012/04

Learning Objectives

1.掌握结直肠癌为模型的恶性肿瘤的多步骤发生模式。

2.了解 APC等相关癌基因。

Required Reading

Thompson &Thompson Genetics in Medicine, 7th Ed （双语版， 2009）

● pp.396-401； ● Clinical Case Studies-19

Hereditary Nonpolyposis Colon Cancer

Feature Tumor Suppressor Genes

Oncogenes

Function of normal version

Regulates cell growth and proliferation; some can induce apoptosis

Promotes cell growth and proliferation

Mutation (at cell level)

Recessive (both copies of gene inactivated)

Dominant (only one copy of gene mutated)

Effect of mutation Loss of function Gain of function

Germline mutations resulting in inherited cancer syndromes

Seen in most tumor suppressor genes

Seen in only a few oncogenes

Tumour suppressor gene (TSG)

• Caretaker genes: TSGs that are indirectly involved in controlling cellular proliferation by repairing DNA damage and maintaining genomic integrity, thereby protecting proto-oncogenes and gatekeeper TSGs from mutations that could lead to cancer. E.g., ATM, BRCA1/2, MLH1, MSH2, XPA.

• Gatekeeper genes: Tumor-suppressor genes that directly regulate cell proliferation. E.g., APC, CDKN2A, RB, TP53, VHL.

“Two-hit” hypothesis: Knudson,1971. This explains why hereditary retinoblastoma usually has an earlier age of

onset and exhibits bilateral or multifocal occurrence more often than sporadic retinoblastoma.

Men289,550

Women270,100

26% Lung and bronchus

15% Breast

10% Colon and rectum

6%Pancreas

6%Ovary

4%Leukemia

3% Non-Hodgkin’s lymphoma

3%Uterine corpus

2%Liver/intrahepatic bile duct

2%Brain/nervous system

25% All other sites

Lung and bronchus 31%

Colon and rectum 9%

Prostate 9%

Pancreas 6%

Leukemia 4%

Esophagus 4%

Liver/intrahepatic bile duct 4%

Non-Hodgkin’s lymphoma 3%

Urinary bladder 3%

Kidney and renal pelvis 3%

All other sites 24%

Colorectal Cancer is a Major Causeof Cancer Deaths in the United States

Jemal et al. CA Cancer J Clin. 2007;57:43.

Colorectal Cancer (CRC)Colorectal Cancer (CRC)• Factors associated with increased riskFactors associated with increased risk—Age (>90% diagnoses in individuals >50 years old)Age (>90% diagnoses in individuals >50 years old)

—Personal or first-degree family history of CRC, or Personal or first-degree family history of CRC, or adenomas, polyps or inflammatory bowel diseaseadenomas, polyps or inflammatory bowel disease

—Hereditary conditionsHereditary conditions• Familial adenomatous polyposis (FAP)Familial adenomatous polyposis (FAP)

• Lynch syndromeLynch syndrome (Hereditary nonpolyposis colorectal cancer, (Hereditary nonpolyposis colorectal cancer, HNPCC)HNPCC)

—Ulcerative colitis Ulcerative colitis

—Obesity, physical inactivityObesity, physical inactivity

—High-fat or low-fiber diet, inadequate intake of fruits High-fat or low-fiber diet, inadequate intake of fruits and vegetablesand vegetables

American Cancer Society. American Cancer Society. Cancer Facts & Figures 2005Cancer Facts & Figures 2005. . National Cancer Institute. National Cancer Institute. PDQPDQ®® Physician Statement Physician Statement..

Genetic predisposition to CRC

CRC• Familial adenomatous polyposis (FAP): also called adenomatous polyposis coli (APC). an AD subtype of colon cancer that is characterized by a large

number of adenomatous polyps. These polyps typically develop during the second decade of life and number in the hundreds or more (polyposis itself is defined as the presence of >100 polyps). FAP accounts for ~1% of all CRC.

• Penetrance of FAP is virtually 100%. • More than 700 different mutations of the APC gene (5q21)

have been reported, most of which are nonsense or frameshift mutations.

• APC: Adhesion molecule. Interacts with Adhesion molecule. Interacts with ββ-catenin and when -catenin and when APC is mutated, the complex accumulates in the cell leading APC is mutated, the complex accumulates in the cell leading to transcriptional activation of other tumor promoting genesto transcriptional activation of other tumor promoting genes

In late childhood and early adulthood, up to 1000 and more polyps develop in the mucous membrane of the colon (1). Each polyp can develop into a carcinoma (2). In about 85% of affected persons, small hypertrophic areas not affecting vision are present in the retina (congenital hypertrophy of the retinal pigment epithelium, CHRPE, 3).

FAP• Persons with FAP have increased risks of other

cancers, including gastric cancer (<1% lifetime risk), duodenal adenocarcinoma (5%-10% lifetime risk), hepatoblastoma (1% risk), and thyroid cancer.

• Mutations in the APC gene can also produce a related syndrome, termed attenuated familial adenomatous polyposis. This syndrome differs from FAP in that patients have fewer than 100 polyps (typically 10-20).

• FAP can also result from recessive mutations in MUTYH, a gene that encodes a DNA repair protein.

CRC

• Lynch syndrome or Hereditary nonpolyposis colorectal cancer (HNPCC) comprises 1–3% of CRC and is characterized by early-onset proximal CRC exhibiting MSI (microsatellite instability).

• Inherited as an AD, high-penetrance cancer syndrome, HNPCC individuals face a 50–70% lifetime risk of developing CRC, in addition to other malignancies.

• HNPCC is caused by mutations in any of six genes (MSH2, MLH1, MSH6, MLH3, PMS1/2) involved in DNA mismatch repair.

Gel electrophoresis of 3 different microsatellite polymorphicmarkers in normal (N) and tumor (T) samples from a patient witha mutation in MSH2 and microsatellite instability (MSI, MIN). Although marker #2 shows no difference between normal and tumor tissues, genotyping at markers #1 and #3 reveals extra alleles (blue arrows), some smaller, some larger, than the alleles present in normal tissue.

chromosomal instability (CIN); mismatch repair pathway (MMR)

Two Pathways to CRCTwo Pathways to CRC

Genetics of Colon CancerGenetics of Colon Cancer

• Mutations in tumorMutations in tumor– CIN: K-ras, APC, DCC, p53 (85%)CIN: K-ras, APC, DCC, p53 (85%)– MIN: DNA MMR (15%)MIN: DNA MMR (15%)

• Mutations in patientMutations in patient– FAP, HNPCC, methylating genesFAP, HNPCC, methylating genes

Approximately 5% of CRC case are caused by Approximately 5% of CRC case are caused by inherited genetic mutationsinherited genetic mutations

CIN = chromosome instable; APC = adenomatous polyposis coli; DCC = deleted in colon cancer [gene]; MIN = multiple intestinal neoplasia; MMR = mismatch repair; FAP = familial adenomatous polyposis; HNPCC = hereditary nonpolyposis colorectal cancer.

K-RasK-Ras

• First Biomarker in Colon CancerFirst Biomarker in Colon Cancer

• Predictive, Possibly PrognosticPredictive, Possibly Prognostic

• Predicts response to anti-EGFR Predicts response to anti-EGFR drugsdrugs

• Is an example of how we can Is an example of how we can “personalize” cancer therapy“personalize” cancer therapy

CRC: Adenoma-Carcinoma Sequence

32-57%K-Ras mutant

LOH (loss of heterozygosity)

• Loss of a normal allele from a region of one cs of a pair,allowing a defective allele on the homologous cs to be clinically manifest.

• A feature of many cases of retinoblastoma,breast cancer,and other tumors due to mutation in a TSG.

LOH (loss of heterozygosity)

A and B represent two microsatellite polymorphisms that have been assayed using DNA from a cancer

patient's normal cells (N) and tumor cells (T)

Risk Factors of Pancreatic Cancer• Family history (10 %)

• familial atypical multiple mole melanoma syndrome• familial breast cancer (BRCA2)• Peutz-Jeghers syndrome• hereditary pancreatitis

• Diet• Meat/fats

• Advancing age• Male gender• Diabetes• Environmental factors

• smoking• alcohol• coffee (?)• asbestos, pesticides, dyes

Hereditary Pancreatitis

• trypsin

• autosomal dominant

• early progressive fibrosis

• 40 x risk pancreatic cancer

Progression Model of Pancreatic Cancer

Bardeesy et al., Nature Rev Cancer 2002

Gastric Cancer

•Diffuse type – linitis plastica•Intestinal type

Genetic Progression in Esophageal Squamous Neoplasia

NormalSquamousDysplasia

SquamousCarcinoma

•7p12 amplification/EGFR overexpression

•8q24.1 amplification/c-mycoverexpression

•11q13 amplification/cyclin D1overexpression

•9p21 deletion/p16 inactivavtion•chromosomal deletions (1p, 3p,

5q, 11q, 18q)•17p13 deletion/p53 mutation

Acknowledge （ PPT特别鸣谢！）

• UCLA David Geffen School of Medicine

• www.medsch.ucla.edu/ANGEL/

• Prof.s Wainberg ZA, Hines J, Hart S, Prof.s Wainberg ZA, Hines J, Hart S,

et al.et al.