[Wikipedia] 癌症(cancer)是醫學術語,其為最常見的惡性腫瘤,亦有人將癌症和惡性腫瘤混合使用;為由控製細胞分裂增殖機製失常而引起的疾病。癌細胞除了分裂失控外,還會局部侵入周遭正常組織甚至經由體內循環係統或淋巴係統轉移到身體其他部分。
癌細胞持續生長而不受外在訊息調控,可能是原本正常的原癌基因被激活,將細胞引入到癌變狀態,但主要還是因為一些與控製細胞分裂有關的蛋白質出現異常,如腫瘤抑製基因的功能失常。導致這種局麵,可能是為該蛋白編碼的DNA因突變而出現了損傷,轉譯而出的蛋白質因此也出現錯誤。要將一個正常細胞轉化成一個惡性腫瘤細胞通常需要許多次突變發生,或是基因轉譯為蛋白質的過程受到幹擾[2]。
引起基因突變的物質被稱為致癌物質,又以其造成基因損傷的方式可分為化學性致癌物與物理性致癌物。例如接觸放射性物質,或是一些環境因子,例如,香煙、輻射、酒精。還有一些病毒可將本身的基因插入細胞的基因裏,激活癌基因。但突變也會自然產生,所以即使避免接觸上述的致癌因子,仍然無法完全預防癌症的產生。發生在生殖細胞的突變有可能傳至下一代。
各個年齡層的人都有可能產生癌症,由於DNA的損傷會隨著年齡而累積增加,年紀越大得到癌症的機會也隨之增加。隨著人均壽命的增加,癌症在發達國家中已成為主要死亡原因之一。
Cancer genomics is the study of the human cancer genome. It is a search within "cancer families" and patients for the full collection of genes and mutations--both inherited and sporadic--that contribute to the development of a cancer cell and its progression from a localized cancer to one that grows uncontrolled and metastasizes (spreads throughout the body).
Slide 4
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Genes: Keepers of the Code
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The 25,000 genes scattered throughout the human chromosomes comprise only about 3 percent of the total genome. These genes hold information critical to all human life. While all the component bases in a gene are copied as information leaves the nucleus, not all this information is kept. This is because within a gene there are both coding and noncoding stretches of bases. For example, in split genes, coding sections called exons supply the genetic instructions that are copied to direct protein building. These sections are preserved, but other noncoding sections within the gene, called introns, are rapidly removed and degraded.
Close to each gene is a "regulatory" sequence of DNA, which is able to turn the gene "on" or "off." Farther away, there are enhancer regions, which can speed up a gene's activity.
The translation of base sequences from DNA to protein is dependent on the nucleotide triplet in mRNA. Each mRNA triplet of nucleotides, called a codon, codes for a single amino acid, and, ultimately, a string of amino acids makes up a protein. Since the complementary DNA that specifies a particular mRNA has only four nucleotide bases in a gene, 64 (4X4X4) possible combinations of codons are available to code for 20 amino acids. So there is great redundancy. There are 60 mRNA triplets for 19 amino acids, 3 triplets for "stop," and 1 triplet to call for methionine, the 20th amino acid that signals "start." Most amino acids are coded for by more than one triplet codon. However, each triplet is linked to only one amino acid. (For more information on how genes build proteins, please see Genetic Variation.)
All mutations are changes in the normal base sequence of DNA. These changes may occur in either coding or noncoding regions. Mutations may be silent and have no effect on the resulting protein. This is especially true if they occur in noncoding regions of the DNA. But even base pair changes in the coding region may be silent because of the redundancy of the code. For example, a mutation within a codon may occur, yet still call for the same amino acid as was called for earlier.
Mutations may involve a single base change--called a point mutation--or may involve larger sections of DNA through deletions, insertions, or translocations.
Slide 15
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Recombination: Crossing Over
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Early in meiosis, each chromosome pair copies itself. These homologs are all attached at the centromere and are wound very tightly around one another. Right before duplicate sets of homologs pull apart and move toward a different end of the cell to complete the first division, recombination can occur, as the intertwined genetic material separates. Then, later in meiosis, a second division occurs, and even the chromosomes within a homolog move apart, leaving only a haploid number (n) in each ovum or sperm. If mutations occur during meiosis, either in the ova or sperm, these will be germline mutations.
If mutated ova or sperm then go on to fertilization, their germline mutations will pass to every somatic cell in the new individual.
Point mutations, single base changes in DNA sequences, are the most common type of alteration in DNA. They can have varying effects on the resulting protein.
A missense point mutation substitutes one nucleotide for a different one, but leaves the rest of the code intact. The impact of these point mutations depends on the specific amino acid that is changed and the protein sequence that results. If the change is critical to the protein's catalytic site or to its folding, damage may be severe.
Nonsense mutations are point mutations that change an amino acid codon to one of the three stop codons, which results in premature termination of the protein. Nonsense mutations may be caused by single base pair substitutions or by frameshift mutations.
All genotypes are not created equal in their influence on phenotype. Genes come in many varieties called alleles, and some are more dominant than others. In a pair of alleles, the effect of a dominant allele prevails over the effect of a recessive allele. And the effects of a recessive allele become apparent only if the dominant allele becomes inactivated or lost.
Sometimes one person with a dominant allele will express a trait, yet that same genotype in another person will remain silent. This is an example of differences in penetrance. In classic Mendelian genetics, if an individual carries a dominant allele, the trait will be expressed (genotype = phenotype). However, if all carriers of a certain dominant allele in a population do not express the trait (same genotypes/different phenotypes), the gene is said to have incomplete penetrance.
Slide 49
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Normal Cell Growth: The Cell Cycle
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The cell cycle is a critical process that a cell undergoes in order to copy itself exactly. Most cancers have mutations in the signals that regulate the cell's cycle of growth and division. Normal cell division is required for the generation of new cells during development and for the replacement of old cells as they die.
Most cells remain in interphase, the period between cell divisions, for at least 90 percent of the cell cycle. The first part of the interphase is called G1 (for first gap), followed by the S phase (for DNA synthesis), then G2 (for second gap). During G1, there is rapid growth and metabolic activity, including synthesis of RNA and proteins. Cell growth continues during the S phase, and DNA is replicated. In G2, the cell continues to grow and prepares for cell division. Cell division (mitosis) is referred to as the M phase. Cells that do not divide for long periods do not replicate their DNA and are considered to be in G0.
In normal cells, tumor suppressor genes act as braking signals during G1 to stop or slow the cell cycle before S phase. DNA repair genes are active throughout the cell cycle, particularly during G2 after DNA replication and before the chromosomes prepare for mitosis.
Some mutations linked to cancer appear to involve a failure of one or many of the cell's repair systems. One example of such error involves DNA mismatch repair. After DNA copies itself, proteins from mismatch repair genes act as proofreaders to identify and correct mismatches. If a loss or mutation occurs in the mismatch repair genes, sporadic mutations will more likely accumulate. Other errors in repair may involve incorrect cutting out of bases--or whole nucleotides--as repair proteins try to fix DNA after bulky molecules, such as the carcinogens in cigarettes, have attached. This is faulty excision repair. Sometimes both strands of DNA suffer breaks at the same time, and faulty recombinational repair occurs. Any of these mistakes may enable mutations to persist, get copied, and eventually contribute to cancer's development.
Slide 57
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Cancer Susceptibility: Much Still Unknown
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Much remains elusive in our understanding of cancer susceptibility. Breast cancer is a good example of how incomplete a picture we have.
Most women with a family history of breast cancer DO NOT carry germline mutations in the single highly penetrant cancer susceptibility genes, yet familial clusters continue to appear with each new generation.
About 5 to 10 percent of breast cancer cases are linked to germline mutations in single, highly penetrant cancer susceptibility genes such as BRCA1 and BRCA2. Strong genetic predisposition and cancer susceptibility in these families is passed down in an autosomal dominant fashion.
Another 15 to 20 percent of breast cancers, however, are associated with some family history but no evidence of such autosomal dominant transmission. These cases are not well understood. Possibly environmental or multiple gene interactions contribute to very low penetrance of susceptibility genes, or possibly yet undiscovered mutations are involved.
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