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育儿中要记住6个不能要


育儿知识 http://www.pangbaba.cc

Genetics of Gastrointestinal Neoplasia
张咸宁 zhangxianning@zju.edu.cn Tel:13105819271; 88208367 Office: A709, Research Building 2012/04

L

earning 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

Tumor Suppressor Genes Function of normal Regulates cell growth version and proliferation; some can induce apoptosis Mutation (at cell level) Recessive (both copies of gene inactivated)
Effect of mutation Loss of function

Feature

Oncogenes
Promotes cell growth and proliferation

Dominant (only one copy of gene mutated) 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.

Colorectal Cancer is a Major Cause of Cancer Deaths in the United States
Men 289,550 Lung and bronchus Colon and rectum Prostate Pancreas Leukemia Esophagus Non-Hodgkin’s lymphoma Urinary bladder Kidney and renal pelvis All other sites 31% 9% 9% 6% 4% 4% 3% 3% 3% 24% Women 270,100 26% 15% 10% Lung and bronchus Breast Colon and rectum

6%
6% 4% 3%

Pancreas
Ovary Leukemia Non-Hodgkin’s lymphoma

Liver/intrahepatic bile duct 4%

3%
2% 2% 25%

Uterine corpus
Liver/intrahepatic bile duct Brain/nervous system All other sites

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

Colorectal Cancer (CRC)
? Factors associated with increased risk
—Age (>90% diagnoses in individuals >50 years old) —Personal or first-degree family history of CRC, or adenomas, polyps or inflammatory bowel disease —Hereditary conditions
? Familial adenomatous polyposis (FAP) ? Lynch syndrome (Hereditary nonpolyposis colorectal cancer, HNPCC)

—Ulcerative colitis —Obesity, physical inactivity —High-fat or low-fiber diet, inadequate intake of fruits and vegetables
American Cancer Society. Cancer Facts & Figures 2005. National Cancer Institute. PDQ? 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 β-catenin and when APC is mutated, the complex accumulates in the cell leading to 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 polymorphic markers in normal (N) and tumor (T) samples from a patient with a 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 CRC

Genetics of Colon Cancer
? Mutations in tumor
– CIN: K-ras, APC, DCC, p53 (85%) – MIN: DNA MMR (15%)

? Mutations in patient
– FAP, HNPCC, methylating genes Approximately 5% of CRC case are caused by inherited 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-Ras
? First Biomarker in Colon Cancer ? Predictive, Possibly Prognostic ? Predicts response to anti-EGFR drugs ? Is an example of how we can “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
?7p12 amplification/EGFR overexpression ?8q24.1 amplification/c-myc overexpression ?11q13 amplification/cyclin D1 overexpression ?9p21 deletion/p16 inactivavtion ?chromosomal deletions (1p, 3p, 5q, 11q, 18q)

?17p13 deletion/p53 mutation

Normal

Squamous Dysplasia

Squamous Carcinoma

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, et al.


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