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肿瘤遗传学

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					Cancer Genetics

   肿瘤遗传学
Review the concepts of genetic
          disorders
   Genetic disorder or inherited disease:
  The diseases caused by human chromosomal
  aberration (畸变) or DNA mutation (突变)
 Classic genetic disorders:

    Chromosome disorder
    Monogenic disorder
    Polygenic disorder
 Non-classic genetic disorders
        Classic genetic disorders

   1. Mutation is transmitted from the germ cells
    of parents or occurred in the early stage of
    fertilized oocyte.
   2. Mutation exists in the whole tissues of the
    body and remains for the whole life time of the
    individual.
   3. Mutation will transmitted to the next
    generation.
      Non-classic genetic disorders

   Mitochondrial genetic disorder
    Mitochondrial DNA mutation (maternal
    original)
   Somatic cell genetic disorders “Tumor”
    A great number of chromosome aberrations
    and gene mutations, Marker chromosomes,
    Oncogenes
Neoplasia (肿瘤)




A group of diseases characterized by uncontrolled
cell proliferation and apoptosis leading to a mass
or tumor
Cancer: A malignant tumor, invading or/and
spreading
         Cancer is a genetic disease

   Sporadic cancer:99%,the abnormal
    phenotype of proliferated cells can be transmitted
    through cell generations by mitosis - Somatic cell
    genetic disorders.
   Hereditary cancer: 1%, the cancer occurs
    repeatedly in multiple individuals of a family as an
    hereditary trait. –Classic genetic disorders
     1. Genetic effects
          in cancer development

(1) Cancer family:
           G-family (Warthin, 1913)
    High incidences of adenocarcinoma in the family:
    1895-1976, 842 family members in 7 generations
    Cancer patients: 95,colorectal and endometrial cancer
    Multiple cancer: 13; Onset <40 ys: 19;
    One parent is the patient with cancer: 72
    Male : female:47:48
    Autosomal dominant
          (2) Breast cancer and
    carcinosarcoma family syndrome


   Li and Fraumeni (1969) reported
   Breast cancer and carcinosarcoma(骨肉瘤)
   Acute leukaemia, encephaloma, and cancers in
    pancreas, skin, adrenal gland
   50% cases with multiple cancers
   Onset <50ys: 25 times more than the general
   Autosomal dominant
     2. Genetic pre-cancerious lesion



   Monogenic disorders or syndromes
   Tendency to neoplasia formation and
    malignant
   Autosomal dominant
    Familial adenomatous polyposis, FAP
                (家族性腺瘤性息肉)


• Multiple polyposis
  in colon and rectum
• Bloody diarrhea or
   obstruction
 Autosomal dominant
 30~40 ys: 100% expressivity
 Nearly obligatory colorectal cancers
                APC gene

    Adenomatosis polyposis coli gene (腺瘤样结
    肠息肉基因)
   Cloning in 1991,locate on 5q21,15
    exons,mRNA: 9kb,coding 2843 AA.
   APC gene: signal transduction, cell
    adhesion, cell movement, cell apoptosis
    and transcription activation
   Functioned as cancer suppressor gene
   APC LOH + changes of oncogene K-RAS、
    suppressive gene DCC、P53:Colorectal
    cancer
            Neurofibromatosis I,NF1
                     (神经纤维瘤Ⅰ型)


 AD,incidence 1/3500
 Mutiple neurofibromatosis
  along peripheral nerves
 Malignant: 3%~15%

    NF1 gene:
    Cancer suppressor gene on 17q11.2,350kb, 60
    exons , mRNA with 12kb, coding for a protein with
    2818 aa, involving the control of cell cycling
          Basal cell nevus syndrome
                  (基底细胞痣综合征)


   AD,1/100, 000,Sex ratio 2:1
   Multiple basal cell nevus
   40 ys: 90% malignant
   Associated gene locate on 9q22.3-q31
   40% de-novo mutation
   Mutation related with advanced paternal age
      3. Genetic malignant tumor

(1)Retinoblastoma, RB (视网膜母细胞瘤)

   Only in infants and young child
   Leukocoria: 1st common sign
   Strabismus: 2nd common sign
   Othrer: poor vision, orbital swelling,
    mydriasis, glaucoma and so on
   Highly malignant, frequently metastatic
   Commonly invade to the brain
    A single gene disorder caused by
    mutation of the RB1 gene


             Retinoblastoma gene, RB1
   i. The first cancer-predisposition gene to be cloned
   ii. Chromosome map: 13q14
   iii. More than 100 different mutations reported to date
   a) Missense mutations
   b) Nonsense mutations
   c) Splice-site mutations
   d) Small and large deletions
     A single gene mutation from a mutation in
     somatic cell or germ cell

   Sporadic:
    a) Unilateral or unifocal
    b) A mutation occurred later in embryogenesis
   Hereditary:
    a) Bilateral or multifocal
    b) Autosomal dominant trait
    c) Mutations inherited from the parent: 25%
    d) New mutation: before early embryogenesis: 75%
    e) Penetrance of the trait: 85–95%
             (2) Neuroblastoma, NB
                  (神经母细胞瘤)

   Embryonic malignant tumor derived from neural crest
    cells
   Occur in sympathetic nervous system (交感神经) in
    medulla of adrenal gland, neck, vertebra and so on.
   The most frequently solid tumor in children: 8–10% of
    all cancers in children
   Sporadic: 80%
   Hereditary: 20%, autosomal dominant inheritance
    with early onset and multifocal tumours
   Geneitcs: The amplification of the oncogene MYCN (N-
    myc) in 2p24.1
    (3) Nephroblastoma
        (肾母细胞瘤)

   Renale embryoma
    ( Wilms tumor )
   Malignant, embryonic
    1/100,000, 3,5 ys (average)
   Sporadic: 62%
   Hereditary: 38%, bilateral, early onset, AD
   Genetics: Wilms tumor suppressor gene1 (WT1) on
    11p13, WT2 on 11p15 and p53 at 1p, 7p, 16q, 17p
    部分遗传性肿瘤综合征相关的原发癌、
      染色体定位及其肿瘤相关基因

                   原发癌     染色体定      相关基因       基因功能
肿瘤综合征                      位

视网膜母细胞瘤          视网膜母细胞瘤   13q14.3   RB     转录因子,细胞周期调控


Li-Fraumeni综合征   肉瘤、乳腺癌    17p13.1   P53    转录因子,DNA损伤应
                                            答,调节细胞周期调亡


家族性腺瘤性息肉         结肠直肠癌病    5q21      APC    β-链蛋白,基因表达,
                                            粘着信号,微管稳定性

神经纤维瘤I型          神经纤维瘤     17q11.2   NF1    激活RAS蛋白的GTP酶活
                                            胜

神经纤维瘤II型         听觉神经瘤     22q12.2   NF2    细胞骨架连接蛋白
         部分遗传性肿瘤综合征相关的原发癌、
           染色体定位及其肿瘤相关基因
肿瘤综合征                     原发癌   染色体定位      相关基因         基因功能

Wilms瘤               肾癌         11p13      WT1      转录衰减子和抑制子

家族性乳腺癌1型             乳腺癌        17q21      BRCA1    转录因子,DNA修复

家族性乳腺癌2型             乳腺癌        13q12      BRCA2    转录因子,DNA修复

家族性黑素瘤               恶性黑素瘤      9p21       CDKN2A   周期素依赖激酶2A

多发内分泌腺瘤I型            垂体、甲状旁腺和   11q13      MEN1     核蛋白,功能未知
(MENl)               胰岛细胞癌

多发内分泌腺瘤II型           甲状腺髓质癌     10q11.2    RET      酪氨酸蛋白激酶受体
(MEN2)
Von-Hippel-Lindau综   肾癌         3p25       VHL      转录延伸修复
合征
基底细胞痣综合征             基底细胞皮肤癌    9q22.3     NBCCS    转膜受体

遗传性乳头状肾癌             肾癌         7q31       MET      转膜受体

遗传性非息肉性 结肠           结直肠癌       2p22-p21   MSH2     DNA错配修复系统组分
直肠癌
4. Chromosome unstable syndromes



   Classic genetic disorders with
    defectiveness of DNA repair
   High incidence of tumors
         (1)Bloom syndrome

   1 in 100 Ashkenazi Jews, short stature, butterfly-
    shaped facial rash, sensitive to sunlight, often with
    infections and respiratory illness
   Various kinds of cancer, the mean age of death is 27 ys.
   Chromosome breakage, triradial, tetradial, SCEs 10
    times more than the normal
   Mutation of BLM gene on 15q26.1: coding for BLM,
    an enzyme for 3’-5’DNA uncoil, DNA repair,
    duplication.
         (2) Ataxia telangiectasia, AT
              (共济失调毛细血管扩张综合征)


   Ataxia: loss of muscle control, swaying head and trunk on
    standing; start at 2ys -
   Tiny red lesions, spider-veins-like: the corners of the
    eyes and the skin after exposure to sunlight
   Repeated infections
   Risk of cancer: 1200 times more than the some age
   High incidence of chromosome aberrration,
   ATM:AT mutated gene on 11q22-q23, coding for protein
    related with cell cycling and DNA repair
(3)Fanconi anemia, FA
   Hematological abnormalities
    progressing bone marrow failure and
    pancytopenia starting in child
   Growth retardation
    short stature, bone deformation
    and hypogonadism
   Skin pigmentation
   10% acute myeloid leukemia
   Frequent gaps and breakages of chromosomes
      Genetics

   Autosomal recessive
    Genetically and phenotypically heterogeneous
   FA genes complementation grouping:
    (1) FANCA, 16q24.3;   (2) FANCB, 13q12.3;
    (3) FANCC, 9q22.3;    (4) FANCD1, 13q12.3;
    (5) FANCD2, 3p25.3;   (6) FANCE, 6p21.22;
    (7) FANCF, 11p15;      (7) FANCG, 9p13
   Hypersensitive to cross-linking agents such as
    diepoxybutane (DEB)(only FA), nitrogen mustard (NTM)
    and mitomycin due to impairment DNA repair.
        (4 ) Xeroderma pigmentosum, XP
                       (着色性干皮病)

   Sensitive to ultraviolt, skin
    multiple rash, pigmentation
    and dryness and trophy
   Skin cancer, encephoma,
    sarcoma, fibroma and so on.
   High SCEs and chromosomal
    aberrations
   7 XP associated genes
    involving DNA repair.
       5. Chromosomal abnormality in
           tumor tissues -Somatic




   47, XX, Del (7) (q32q36), der(14)t(q12;p11),-22 in
                       meningioma
   Unrandomly change:
     Common: 8+/-、9+/-、12+/-、21+/-
     Uncommon: 7-、22-、Y-
  Structural abnormality: translocation,
deletion, duplication, ring chromosome and
so on
      Marker chromosome in cancer
               (肿瘤标记染色体)



   Nonspecific marker:only seen in
    some cancer cells
   Specific marker:frequently seen in
    some kinds of cancers
Del (11) (p13p15.1) in the patient with Wilms
                   tumor
Del (7) (q32q36), der(14)t(7;14)(q12;p11),-22
        in the patient with meningioma
    Specific markers in cancers
   病名      特异性标记染色体         病名     特异性标记染色
                                       体
慢 性 粒 细 胞 白 Ph染色体,t(9;22) 急性白血病    -7,+9
  血病
Burkitt淋巴瘤 t(8;14)(q24;q32) 黑色素瘤   +7,+22

视 网 膜 母 细 胞 del(13)(q14) 小细胞肺癌     del(3)(p14→p2
  瘤                                   3)
脑膜瘤        -22,22q-      结肠息肉      +8,+14

Wilms瘤     del ( 11 ) 鼻咽癌          t(1;3)(q41;p11)
              (p13→p14)
    二、Genes associated with cancer and
    mechanism of cancer development

   Oncogene: Normal activity promotes cell
    proliferation. Excessive or inappropriate activity
    cause the cancer development. The non-mutant
    version of oncogene: Proto-oncogene。
   Tumor suppressor gene:Gene products inhibit
    the events leading to cancer: prevent cell cycle
    progression, deviant cells into apoptosis and keep
    genome stable and low mutant rate.
         1. Oncogene (癌基因,onc)

   The genes stimulating cancer transformation and
    development.
   Normal genetic materials in whole genome.
   Regulating the normal functions of the cell cycle in
    the normal conditions.
   Transferring the cells to be malignant after
    activated by cancer induced factors or mutation
   Dominant gene, one mutation-activated
           Classification of 细胞-onc

   Growth factors:
    Stimulate G0 cells into mitosis and promote cell
    proliferation and differentiation. Plated-derived
    growth factor beta subunit, FGF2, FGF4
   Receptor of growth factors:
    Combine with GF to activate tyrosine kinase, initiate
    cell reaction. EGFR, TR and so on.
           Classification of c-onc
   Protein tyrosine kinase:Catalyze protein
    tyrosine radix phosphated, maintain the cell
    morphology, regulate cell differenitation: SRC、
    FGR、YES、FPS、FES、ABL1 and so on.
   Nucleus transcription factor: Specific DNA-
    binding protein,regulate gene transcription and
    cell proliferation: MYC、FOS、JUN and so on.
         Mechanism of c-onc activation
                      (1) Virus infection
      Over-express c-onc products by virus infection
   RV gene integrates with host genome near the c-onc
    Activation of RV gene enhances c-onc transcription
    Over-express lead to malignant changes of the host cells
   LTR, promoter of RV, integrates with host genome
    near the c-onc
    Initiate the c-onc or other gene transcription
    Over-express lead to malignant changes of the host cells
           Chicken myelocytomatosis virus DNA,

          LTR promote MYC to 30~100 times more.
            (2) Point mutation

 The alteration of the property of c-onc products

RAS gene family: c-onc mutaion:
HRAS、KRAS、NRAS on chromosome 11、12、1
Host mutation loci: 12, 13 and 61 codes

    Decrease GTP activation of P21 protein
    RAS protein maintain in a high activation
    Persistent signal transduction
    Over-duplication of cells, malignant
        (3) Chromosome translocation


    1. Alteration of onc expression
     Rearrangement of genes resulted from
    translocation
     C-onc is moved to the region near to the
    highly active promoter or enhancer and
    activated.
             Burkitt lymphoma




Translocations between chromosomes 8 and 2,14 and 22
Chromosome 2,14,22: Ig H gene clusters
       C-MYC FISH Probe Map




8q24: MYC:nuclear transcript factor
   Chr. 8:c-onc MYC
   Chr 14, 2 and 22: Ig H gene clusters
   Translocation: Highly active promoters of Ig H
    enhance the activity of MYC transcription
   Over-express MYC protein activates GF genes
    and leads cell malignant
IGH and C-MYC FISH results
         2.Gene fusion

c-onc is fused with other genes after
translocation and its abnormal expression
results in cell malignant changes




                            95% CML: Ph1 :
                            t(9;22)(q34;q11)
               t(9;22)(q34;q11)


   9q34.1: c-onc, ABL,
    coding for P145, a
    tyrosine kinase

   22q11.21: BCR
    (breakpoint cluster
    region)
After translocation, fused gene of BCR and ABL is
formed and produce a fused protein, P210, with higher
activation of tyrosine kinase and out of control of GFR
system. The cause of CML.
               BCR/ABL FISH Probe Map and
                     FISH in CLM




                           ABNORMAL
 NORMAL                     1 orange,
 2 of each                   1 green,
probe signal                 1 fusion
                              signal
(4) Proto-oncogene amplification

                    Increased number and
                     expression of proto-oncogenes
                    Over-express protein leads to
                     tumor.
                    Evidences of amplification:
                     Double minutes(双微体)
                     Homogenously staining region
                     (染色体均染区)
double minutes
Amplification of MYC in neuroblastoma
                              MYC might be amplified
                               from hundreds to
                               thousands times,RAS
                               protein increase from tens
                               to thousands.
                              The features of cancer at
                               developing stage,
                               suggesting more invasive,
                               metastasis and malignant.
Homogenously staining region
      人肿瘤中原癌基因的扩增
肿瘤          癌基因     扩增拷贝数
早幼粒细胞性白血病   MYC     ~20倍
小细胞肺癌       MYC     ~80倍
            MYCN    ~50倍
            MYCL    ~20倍
成神经细胞瘤      MYCN    ~250倍
急性粒细胞性白血病   MYB     ~10倍
结肠癌         MYB     ~10倍
表皮癌         EGFR    ~30倍
肺癌          KRAS    ~10倍
膀胱癌         KRAS    ~10倍
乳房肿瘤        NRAS    ~10倍
乳腺癌         HER2    ~30倍
            MYC     ~50倍
            CCND1   ~30倍
       2. Tumor suppressor gene, TSG
                           (肿瘤抑制基因)

   1969, Harris’s: The malignant potentials of mouse cancer
    cells were disappeared after they were hybridized with
    normal cells.
   Tumor suppressor gene or anti-oncogene: genes
    involving the negative control of cell proliferation.
   Recessive, loss of function of two alleles, homogenous
    inactivation, normal suppressive function of cell cycling is
    removed, tumorigenesis.
      TSG and development of cancer
(1) Deletion
     Loss of heterozygoteity (LoH)
          (肿瘤抑制基因杂合性丢失)
         Retinoblastoma (视网膜母细胞瘤)
   Smallest region of overlap of 13q14, SRO,
    (缺失重叠区)
   Heredity:100% with del(13)q14
   Sporadic : 10%~15% with del(13)q14.
In 1983, Cavenee found that the DNA marker in
13q14 might be lost due to disjunction and
recombination in mitosis.
 In 1985, the evidences from two RB families showed
that the patient lost the normal RB allele on 13q14.
RB gene: 13q14,200kb,27 exon,4.7 kb
mRNA, coding for protein of RB

Nuclear RB protein:de-phosphorylation RB
can combine with mitogen-reactive transcript
factor E2F, inhibit E2F activation, stop cell at
stage of G1 and suppress the cell proliferation.

Deficiency or inactivation of RB protein will
result in persistent high level of free-E2F,
continuously promote target gene to transcript
and keep in active cell division. Tumorigenesis
     DCC(Deleted in colorectal carcinoma) gene

   DCC : LOH in colorectal carcinoma
   DCC located on 18q21.3 with 29 exons, mRNA of
    4.3kb and protein of 1 447aa.
   Transmembrane phosphorylation protein
    associated with cell attachment and signal receptor
   Inactivation of DCC gene: disfunction of inhibit
    mechanism of cell contact and movement.
    Tumorigenesis
Other TSGs and LOH
               (2) Point Mutation

   P53 Gene: 17 p13.1,16~20kb,11 exons,
    mRNA of 2.8kb.
   P53 protein:53 000 phosphorylation protein
   Wide type of P53 gene: negatively regulate
    cell growth, important STG
   Involving DNA repair and cell apoptosis.
                      P53, TSG
related with tumorigenesis of >80% cancers


   Point mutaion: 393aa, 280 mutant types
   Mutation result in the changes of transcription
    activation and phosphorylation of P53 protein
   The function of suppressing tumor proliferation
    is disappeared and SGT is transfer as onc
   The complex of mutant and wide P53 proteins
    leads to failure of its DNA binding.
          Point mutation in other TSGs

   MCC(mutated in colorectal carcinoma)gene:
    5q21, 17 exons, mRNA 4.2kb,protein 929aa.
    10% colorectal carcinoma point mutation of MCC
   BRCA1 (Breast and ovarian cancer susceptibility)
    gene:17q21, 22 exons, mRNA7.8kb, protein 1
    863aa.
    Ovarian and breast cancers: BRCA1 mutation,
    including missense and nonsense mutation
            (3)Shift mutation

    APC gene
   Normal function: cell proliferation, cell
    movement, cell attachment, cell frame
    establishment and chromosomal stablity
   Shift mutation resulted from deletion of
    insertion
   APC protein “trunction”, its function of
    inhibiting cell proliferation is decreased.
   Mutation of APC gene and abnormal APC
    protein impaire the above functions and
    lead tumorigenesis.
         Other shift mutation of TSG



   MCC gene: Breast and ovarian
    cancer susceptibility gene
(4)Epigenetic modification
      Epigenetics (表遗传学):The expression of gene is
    regulated by modification of DNA or histone without
    alteration of DNA sequence.
     DNA methylation (DNA甲基化) is one of the most
    important epigenetic modification.
                 DNA methylation
                   (DNA甲基化)


   Predominantly occurs at the symmetrical
    dinucleotide CpG
   Dense methylation in promoter region is
    associated with a compacted chromatin
    structure, and transcriptional silencing of
    affiliated gene
                               Demethylation




                               Acetylation
Methylation
Acetylation
Transcription complex


                          Methylation



                        Deacetylation
                          Methylation
   Tumor:hypomethylation in global genomic DNA
            hypermethylation in certain loci, TSG
    promoter CpG island, is hypermethylation
             Gene silencing
   RB gene in RB patient: the promoters are shown to
    be DNA Hypermethylation
       三、Genetic hypothesis of
          cancer development

             1. Single clone original
   Exposure result in mutaion of somatic
    cells, gradually transfer to pre-
    carcinoma
   Evidence: Marker chromosomes, X
    inactivation, G6P expression.
    Some locus expression in all tumor cells
    2. “Two-hit hypothesis”
            Knudson’s tumorigenesis

 i. In the unaffected individual, both RB1 genes are
 intact and serve as guardians of the retina
 ii. Retinoblastoma develops as a result of two

  separate mutations
 iii. Sporadic tumors: two separate mutations

  occurring, somatically in the same retinal cell
 iv. Heritable retinoblastoma: The first mutation is

  germinal and the second somatic cells
   Hereditary RB genotype: rb/RB,
    1 time mutaion resut in “rb/rb” or “rb/-”, LOH
   Sporadic RB genotype: RB/RB,2 times of
    mutation result in “rb/rb” or “rb/-”, LOH.
      3. Multi-step carcinogenesis theory


Land and his colleagues:
 The transfection of ras onc to the fibroblasts
  leads to cell proliferation.
 Co-transfection of Ras onc and MYC onc
  leads to cell proliferation and carcinogenesis.
 The malignant transfer needs at least two

  oncs co-operation.
               Colorectal carcinoma
   LOH of APC on 5q21:cell over-proliferation,
    gradually develop to adenoma. (FAP)
   Mutation of KRAS on 12q :adenoma at
    early stage develop into midstage.
   LOH of DCC on 18q:adenoma develop to
    late stage.
   LOH of P53 on 17q:adenoma at late stage
    develop to carcinoma.
   Alteration of genes related with metastasis:
    metastasis of carcinoma
     Multi-step carcinogenesis theory

   Carcinogenesis is a process with multi-
    steps involving multiple genetic mutation,
    a series of changes of gene structure and
    function and co-operation of several
    genes.
   The process is influenced by both genetic
    and environmental factors
              5. Development of Cancer
                      Genetics

   Lane (1979): found p53, 53 000 phosphorylation protein
   1984 P53-cDNA cloning: unlimited proliferation, P53 was
    considered as an onc.
   Finley (1989):proto-onc P53 inhibit malignant, TSG?
   Jenkins isolated P53 from tumor tissue, mutant P53, onc;
    wide type of P53 negatively regulate cell proliferation, TSG
   P53 an important TSG,maintain normal growth and inhibit
    malignant proliferation of cells.
  Cancer family      Genetic precan-cerious
  肿瘤家族聚集、                     lesion
  多发、早发                  单基因遗传病
                     伴肿瘤形成和恶变倾向


1. G家族(腺癌)            1.家族性腺瘤性息
2. Li and Fraumeni    2.Neurofibromatosis I
 Syndrome (乳腺癌癌肉      3.Basal cell nevus
 瘤家族综合征 )             syndrome
 Genetic malignant   Chromosomal   Chromosomal
        tumor          unstable     Abnormality
                       syndrome      in Cancer



1.Retinoblastoma 1. Bloom S
2.Neuroblastoma  2. AT               Marker
3.Nephroblastoma 3. FA              Chromosome
    基因突变         4. XP              畸变克隆
                 DNA损伤修复
                             癌基因
  Normal genetic      Transferring the cells
     materials,           to be malignant
normal functions in      after activated by    Dominant
     the normal           cancer induced
     conditions                factors


c-onc:Proto-oncogene            v-onc:c-onc编码序列拼接
1.生长因子                          3.蛋白激酶类
2.生长因子受体                        4.核内转录因子
                   细胞癌基因激活
 Virus induction    Point mutation   Chromosomal
                                      translocation
1. 直接引起肿瘤的
   增量               RAS族c-on的点       改变基因调节
                                      Burkitt淋巴瘤
2. 基因整合              突变               融合基因:CML


              肿瘤抑制基因失活
杂合性丢失:隐性纯合                    表遗传学改变
  子和半合子致癌
                   名词解释和思考
   Positional cloning approach (steps)
   candidate gene approach (confirm disease causing gene)
   Position-dependent candidate gene approach
   SNP
   DNA-based genetic testing
   Anticipation
   dominant-negative effect
   haploinsufficiency
   Lost-of-function
   gain-of-function
   genomic imprinting
   Epigenetics
   Genetic Principles for prevention and treatment of genetic
    disorders

				
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