Cancer Genetics

Cancer

genetics

what is cancer genetics?

Genetic factors attribute to cancer 1 、 incidence of cancer and race 2 、 familial aggregation

Jew

Leukaemia

American

breast cancer

cancer family: the family with high incidence of certain cancer which has a early outset age and follow a AD inheritance

G family

in 1913,Warthin reported a G family for the first time. Hauser （ 1936 ）、 Lynch （ 1971 ） ob served the same family constantly. among the 7 generations, 842 family members, 95 patients were found. The total number of tumors was 113. The affected included 47 males and 48

Li – fraumeni syndrome 50% patients were diagnosed before 30

familial carcinoma Common carcinoma which affected more than 1 member in a family, the incidence of the first degree relative of the patient is higher than the general population. No mendelian pattern can be observed in most cases. 遗传性前列腺癌

Chromosome and cancer

1 the chromosomal abnormality in cancer cell origin 46

mutate

85

85

85

85

109

85 49

stem line modal line 69

45

side line

1.The numerical abnormality aneuploidy

euploidy

2.Structural abnormality ring cell

breakag e deletion

marker chromosome

isochromosome

duplication translocatio n

Chromosome changes in colorectal cancer

Cancer karyotype

Stable karyotype

Marker chromosome The structurally abnormal chromosome which appear frequently in certain cancer cell.

Nonspecific marker chromosome specific marker chromosome

95% CML, Ph chromosome

Burkitt lymphoma

Lung cancer

chromosomal fragile site and cancer Certain locus at which the chromosome is easily to break, which always leads to chromosomal rearrangement.

Kidney cancer del(11)(p13p14) 11p13 Malignant lymphomat (12;14)(q13;q23) 12q13 AML inv(16)(p13q22) 16q22

Chromosomal instability syndrome and cancer chromosomal instability syndrome

the diseases or syndromes with instable chromosome which frequently lead to chromosome breakage or rearrangement. susceptible to Leukaemia and other malignant cancer

1.Bloom syndrome (AR) Symptom: short stature, chronic infection, immunological deficiency, susceptible to leukaemia and other cacer. The offspring of Jew from susceptibles eastern Europe

Characteristics chromosomal instability, or genome instability micronucleus 、 SCE

metaphase: SCE=50~100

Micronucleus test The chemical or physical factor can destroy the chromosome or spindle which will lead to breakage of chromosome, the fragment can form micronucleus. Exclusion from the cell

The residual

micronucleus

Genetic foundation Some enzyme responsible for the DNA repair was wrong, which lead to chromosome instability. Chromosome 15q26.1

diagnosi s

cytogenetics

SCEs: 50 - 100

Molecular genetics SSCP

2. Fancone anemia （ FA ）

symptoms:

AR

congenital malformation including: bone, brain, small eyeball ， hypocytosis.

The probability for the patients to suffer leukaemia is 20 times higher than the general population.

Cytogenetics spontaneous chromosomal breakage is common ， especially for chromatid, bicenchromosome can be formed.

Molecular genetics FA gene encode the enzyme that can repair the DNA mutation, especially for T-T caused by explosion under ultraviolet.

diagnosi s

cytogenetics

SCEs: normal

Molecular genetics SSCP

Chromosomal disease and cancer Down syndrome tend to suffer leukaemia. The incidence is 1/95 while the general population incidence is 1/3 000. Klinefelter syndrome: breast cancer Turner syndrome: ovarian

Gene and cancer

proto-oncogenes 1 、 discovery 2 、 characteristics 3 、 classification 4 、 activation

discovery

Retroviruses

in 1910 ， P. Rous noticed that the sarcoma can be caused by filtrate without any cell (filtrate is made from chicken sarcoma)

In 1911, Rous sarcoma virus, RSV was named.

In 1963 ， two mutants were screened out from the RSV. One was sensitive to temperature and called tsRSV. Another contain deletion and was called tdRSV.

In 1972, it was confirmed that protooncogene exist in almost any animal cells.

Virus-oncogene,V-onc the DNA sequence exist in the virus genome that can cause cancer. cellular oncogene, c-onc) proto oncogene refer to a kind of normal gene that exist in human or animal cell. It is usually unexpressed or only express at a low level but play an important role in the cell proliferation, cell differentiation and fetation.

Oncogene: the nucleotide sequence that can cause cancer. It derives from the proto-oncogene and is a result of activation of the proto-oncogene.

the relationship between the oncogene and proto-oncogene

2 、 characteristics  Be universal among the creature  Maintain the cell function, cell growth, and cell differentiation.  Conservative evolutionally, single  sequence Unexpressed or only express strictly     

Express according to cell type, tissue, stage of differentiation and period of cell cycle. have negative regulatory sequence at 5’ primer. Become into oncogene when numerical or structural change take place Lead to cancer with a mode of dominance. Mutation can happen to the somatic cell.

3 、 classification Growth factor nucleus protein

sis

myc 类

erb 类 Proto-oncogene

ras 类 G protein

src 类 tyrosine protein kinase

The old way of classification

Growth factor recepto r

Sis gene

Growth factor

transcription translation Growth factor

receptor

ly e v i ss e c x e s s e r p Ex

cellcellcell cellcellcell cellcellcell cellcell Out off control

cell cell Stimulate cell to proliferate

Growth factor receptor Erb gene normal

mutate Abnormal receptor

cell

Proliferation without growth factor

abnormal Normal proliferation

Protein kinase

Src gene PP60 protein Tyrosine kinase Excessive activity

P

P

cell

P

The excessive activity can change the function of the cell

The amount of kinase increase in cancer

Ras gene

G protein

Active RAS cAMP increase lead to cell proliferatio n Normal way

GTP

GDP 失活的 RAS

cAMP decrease lead to cell stop proliferation

Ras gene Mutation lead

to abnormal

active RAS cAMP keep a high level, which stimulate cell to proliferate

GTP ck o l b

GDP Inactive RAS

Reduce the cAMP which baffle the cell proliferate

Transcription factor in the nucleus Myc gene

Express continuousl y

encode

Transcription factor

stimulate gene

CELL CELL CELL CELL CELL CELL CELL

Proto-oncogene and their function

细胞癌基因编码蛋 蛋白质酪氨酸激酶 生长因子 生长因子受体

Growth factor

Protein kinase Proto-oncogene Nuclear protein factor

Communication factor The new way of classification

4 、 activation mechanism （ 1 ） point mutation missense mutation lead to abnormal function Bladder cancer: ras mutation Normal cell the 12th amino acid

GGC

gly

Cancer cell the 12th amino acid

GTC

val

（ 2 ） chromosomal translocation and gene new protein canrearrangement be produced by fusion gene

95% CML ： t(9 ； 22) (q34,q11) ， fusin gene: bcrabl

例 BCR1

C-ABL

BCR-ABL produce a fusin protein, 210kD with excessive tyrosine kinase activity

BCR1 C-ABL

BCR-ABL fusion protein

（ 3 ） LTR insertion Strong promot er

LTR

retrovirus

LTR:long terminal repeat,

genome

LTR

Insert randomly into the genome LTR

Proto-oncogene

proto-oncogene can be activated by the strong promoter.

（ 4）

gene amplification

homologous stained region HSR, double minutes, DMs, separate from the chromosome

Examples Breast cancer Liver cancer

ERBB2 HRAS

Common in development stage

30 30-60

tumor suppressor gene Restrain the excessive proliferation, prevent the cell from growing abnormally. lead to cancer with a mode of recessive. qualification 1.Express in the normal cell but not in the cancer cell. 2.The cancer cell can be suppressed by introduce of it.

In 1985 ， Cavence found the Rb gene on chromosome 13q14.

Difference between gene inhertiance

proto-oncogene dominant

function Increase proliferation mode be activated mutate point, amplification, cell type somatic cell

example

RB P53 P16 ……

suppressor recessive

decrease proliferation be intivated or lost rearrangement point, deletion somatic and genital cell

1 、Ｐ５３ function P53 protein Act on P21 protein which influence the cell cycle P21 protein DNA unrepairable

apopto sis

DNA damage

Stop at G1/S phase

2 、 Rb function RB protein phosphorylation lead to cell proliferate

RB protein dephosphorylation stop the cell cycle at G1 phase

G2 期

M期

S期

G1 期

Phosphorylation and dephosphorylation regulate the cell growth

3. P16 function P16 locates on 9p21 ， suppress many kinds of cancer. The first protein discovered to control cell cycle. P16 protein

CDK4

CDK4 can not act on RB protein which inactivate the regulatory transcription factor

CDK ： cyclic dependent kinase

Cancer following the monogenic pattern Retinoblastoma Rb:incidence 1/210001/10000, outset age of less than 4,20% of which before 2 hereditary and nonhereditary type can be divided. The former account for 20%-25% among the total which is always diagnosed before 1 and is proved to follow a pattern of autosome dominance (AD). AD)

At early stage, no conscious symptom, white bump can be found in the bottom of the eye

stage

Cancer cell transfer into 1.Inside eye vitreous body which reflect yellow light accordingly called cat 2. glaucoma eye

3.Spread outside the eye 4.Transfer anywhere

RB pedigrees

treatment Ablate the eyes as early as possible, assisted with chemical thrapy

Guard against By genetic counseling and prenatal diagnosis

two-hit theory in 1970 ， Kundson put forward this theory, two mutation are required during the cancer formation Genital cell: hereditary, early, multiple bilateral, severe Somatic cell: to the opposite

hereditary

nonheredita ry

Monogenic disease and cancer precancerious lesion Some single disease patients are susceptible to certain cancer. Most of them follow AD pattern

1. familial polyposis coli, FPC

APC,5q21-q22 APC + 癌基因（ KRAS2 ） + 抑癌基因 （ DCC 、 Tp53 ）

FPC

adenocarcinoma

2.neurofibromatosis NF1

NF,17q11.2 fibrosarcoma 3%-15% turn into

squama 鳞癌 Neural fibrosarcoma

Ploygenic cancer Incidence, 2-3 times than general population, environmental factors.

肿瘤的多步骤遗传损伤学说 癌症发生的多阶段性

癌 发 生 的 多 因 素 性

导

致 机 死 亡

体

加速进 展过程 , 免疫监视机能的 丧失和恶性程度的 加深构成促进 癌基因的激活 , 抑癌基因的失活 , 构成始动而形成恶性细胞

肿瘤基因解剖计划 (Cancer Genome Anatomy Project, CGAP)

http://www.ncbi.nlm.nih.gov/ncicgap/

http://cgap.nci.nih.gov/Chromosomes/ CCAP

小

结

癌家族 , 肿瘤的干系 , 旁系 , 众数 , 标记 染色体 , 特异标记染色体， 癌基因 , 原 癌基因，抑癌基因，染色体的脆性部位 ，染色体不稳定综合征等概念 .  癌基因的特点 , 分类 , 激活机制 .  抑癌基因的种类与机理  二次突变学说  肿瘤的多步骤遗传损伤学说

21 三体综合征 (Down syndrom)

核型： 47,XX(XY),+21

Klinefelter 综合 征 47, xxy

Tuner 综合 征

45, x

非整倍体的形

核内复制（ endoreduplication ） —— 形成四倍体

新的细胞

第一次复制

含 46 条 染色单体

含 46 条染色 体

第二次复制 含 92 条染色 体

细胞分裂 每个细胞含 92 条染色单 体