Download 88208367 Office: A705, Research Building 2014/05 Learning

Genetics of
Gastrointestinal Neoplasia
张咸宁
[email protected]
Tel：13105819271; 88208367
Office: A705, Research Building
2014/05
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
World Cancer Report 2014, WHO Press.
• Cancer is a group of genetic diseases
affecting fundamental aspects of
cellular function, including DNA repair,
cell-cycle regulation, apoptosis, and
signal transduction.
特点
原癌基因
抑癌基因
基因功能
正常生长和增殖必
需
增殖负调控，分化
必需
突变（激活）方式
点突变、染色体重
排、基因扩增、病
毒插入
点突变、LOH等
致癌方式（They
behave as）
显性
隐性
突变蛋白的效应
功能失去突变
功能获得突变
遗传方式
体细胞突变，不遗
传
体细胞或生殖细胞
突变，可遗传
常见于哪些癌肿
白血病、淋巴瘤
实体瘤
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)
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
Women
270,100
31%
26%
Lung and bronchus
Colon and rectum
9%
15%
Breast
Prostate
9%
10%
Colon and rectum
Pancreas
6%
6%
Pancreas
Leukemia
4%
6%
Ovary
Esophagus
4%
4%
Leukemia
Liver/intrahepatic bile duct 4%
3%
Non-Hodgkin’s lymphoma
Non-Hodgkin’s lymphoma
3%
3%
Uterine corpus
Urinary bladder
3%
2%
Liver/intrahepatic bile duct
Kidney and renal pelvis
3%
2%
Brain/nervous system
Lung and bronchus
All other sites
24%
Jemal et al. CA Cancer J Clin. 2007;57:43.
25%
All other sites
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
Familial adenomatous polyposis (FAP)
• Or adenomatous polyposis coli (APC).
• An AD subtype of colon cancer that is characterized by
a large number of adenomatous polyps. Typically
develop during the 2nd 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%.
• > 700 different germline mutations of the APC gene
(5q21), most of which are nonsense or frameshift.
• 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.
• 100% chance of cancer if no surgery.
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 the affected, 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 APC 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).
• 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 6 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.
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.
CRC: Adenoma-Carcinoma Sequence
32-57%
K-Ras mutant
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
Epigenetics of CRC
• Epigenetics changes include: (1) altered
DNA methylation, (2) chromatin
remodeling and (3) non-coding small
RNA (miRNAs).
• Notable changes in epigenetics have been
reported for several age-related diseases,
including CRC.
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
•17p13 deletion/p53 mutation
Normal
•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)
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.