1、Cancer Genetics and Genomics,ZHANG Xian-Ning, PhD E-mail: Tel：13105819271; 88208367Office: A713,Reseach Building 2008/10,Cancer,After more than three decades, the “War on Cancer,“ declared by President Nixon in 1971 with the enactment of the National Cancer Act, is still going on in this country. Th
2、e Question is: “Are we winning the war?“,We Fought CancerAnd Cancer Won. After billions spent on research and decades of hit-or-miss treatments, its time to rethink the war on cancer.,In 2008, cancer will take the lives of about 230,000 more Americans69 percent morethan it did in 1971 Four decades i
3、nto the war on cancer, conquest is not on the horizon. As a somber statement on the NCI Web site says, “the biology of the more than 100 types of cancers has proven far more complex than imagined at that time.“ Oncologists resort to a gallows-humor explanation: “One tumor,“ says Otis Brawley of the
4、ACS, “is smarter than 100 brilliant cancer scientists.“-From Newsweek Sep. 15, 2008,http:/cgap.nci.nih.gov/,Useful internet,MGH Cancer Center: http:/www.cancer.mgh.harvard.edu/Links.htm National Cancer Institute Information:http:/cancer.gov/cancerinformation,Rudiments of oncology “Cancer” is a colle
5、ction of disorders that share the common feature of uncontrolled cell death. Cancer is a disease of genes gone awry. Genes that control the orderly replication of cells become damaged, allowing the cell to reproduce without restraint and eventually to spread into neighboring tissues and set up growt
6、hs throughout the body., All cancer is genetic just a small portion of cancer is inherited, Cancer usually arises in a single cellThe location and type of that cell is the site of the primary cancer.,Proto-oncogene: a class of normal cellular protein-codinggenes that promote growth and survival of c
7、ells. Gatekeeper TSGs control cell growth. Caretaker TSGs protect the integrity of the genome.,microRNAs (miRNAs),The catalogue of genes involved in cancer also includes genes that are transcribed into noncoding RNAs from which regulatory microRNAs (miRNAs) are generated. There are at least 250 miRN
8、As in the human genome that carry out RNA-mediated inhibition of the expression of their target protein-coding genes, either by inducing the degradation of their targets mRNAs or by blocking their translation. Approximately 10% of miRNAs have been found to be either greatly overexpressed or down-reg
9、ulated in various tumors, sometimes strikingly so, and are referred to as oncomirs.One example is the 100-fold overexpression of the miRNA miR-21 in glioblastoma multiforme.,The original clone of neoplastic cells serves as a reservoir of genetically unstable cells, referred to as cancer stem cells,T
10、he major features of cellular regulation, Tumor can be classified as benign and malignant,BASIC CONCEPTS,Neoplasia: A group of diseases characterized by uncontrolled cell proliferation leading to a mass or tumor (neoplasm). Cancer: A malignant tumor that is capable of invading or spreading (metastas
11、izing) or both. ( sarcoma: mesenchymal tissuescarcinoma: epithelial tissuesleukemia/lymphoma: hematopoietic/lymphatic)hereditary cancer syndrome vs. sporadic Apoptosis (Programmed cell death, PCD): A normal process of DNA fragmentation and cellularsuicide.,Oncogenesis,Oncogenes Oncogenes are genes t
12、hat are associated with the development of cancers These genes are often bad alterations of normal genes that are concerned with normal cell identity, cell growth, and cell division during embryogenesis included Viral oncogenes and cellular oncogenes,v-oncare named “V-whatever“ when they were identi
13、fied in viruses; e.g. V-ras, V-src, V-fos,c-onc The normal versions of key developmental control genes are called celluler oncogenes. The celluler oncogene are named “C-whatever”.e.g. c-src EGFR(epidermal growth factorreceptor)BRCA1(breast cancer),The relationship of v-onc and c-onc: viral oncogenes
14、 come from cellular oncogenes,Mechanisms of Activation of Proto-oncogenes,Mechanisms of tumorigenesis by oncogenes of various classes. Unregulated growth factor signaling may be due to mutations in genes encoding growth factors themselves (1), their receptors (2), or intracellular signaling pathways
15、 (3). Downstream targets of growth factors include transcription factors (4), whose expression may become unregulated. Both telomerase (5) and antiapoptotic proteins that act at the mitochondria (6) may interfere with cell death and lead to tumorigenesis.,Function of oncogenes,The activation of a pr
16、oto-oncogene to express its oncogenic potential can occur in several ways: point mutation chromosome rearrangement(translocation, fusion gene,etc.)gene amplificationviral insertion,Chronic Myelogenous Leukemia (CML),Chronic Myelogenous Leukemia (CML),The Ph cs translocation,t(9;22)(q34;q11),Chronic
17、Myelogenous Leukemia (CML),The Ph cs, t(9;22)(q34;q11),Tumor Suppressor Genes There are genes whose products suppress tumors. They behave as recessives (Oncogenes: dominant!) Common in solid tumors (Oncogenes: leukemia repairing DNA damage and maintaining genomic integrity.,RB - the retinoblastoma g
18、ene,RB,The gene is about 180 kb in length with 27 exons which code for a transcript of only 4.7 kb,RB,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 retinobla
19、stoma,breast cancer,and other tumors due to mutation in a TSG.,LOH (loss of heterozygosity),Gel electrophoresis of three different microsatellite polymorphic markers in normal (N) and tumor (T) samples from a patient with a mutation in MSH2 and microsatellite instability. Although marker#2 shows no
20、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 MECHANISMS LEADING TO LOH,“Two-hit” hypothesis:In the hereditary form of retinoblastoma,“Two-hit” hypoth
21、esis:In the non-hereditary (sporadic) form of retinoblastoma,“Two-hit” hypothesis:In the non-hereditary (sporadic) form of retinoblastoma,Epigenetics,The second hit is most often a somatic mutation, although loss of function without mutation, such as occurs with transcriptional silencing, has also b
22、een observed in some cancer cells. Silencing due to epigenetic changes such as DNA methylation, associated with a closed chromatin configuration and loss of accessibility of the DNA to transcription factors, is another important, alternative molecular mechanism for loss of function of a TSG.,“Two-hi
23、t” 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.,Tp53:another important TSG! .17p13 .contains 393 codons .has four “hot spots“ for mutation: codons 129
24、-146, codons 171-179, codons 234-260, and codons 270-287. . codes for a protein that acts as a transcription factor and serves as a key regulator of the cell cycle.,Recent research suggests that cancers originate by a multi-hit, multi-step processs,The dev of colon cancer,Figure legend,Schematic of
25、an idealized gene expression profiling experiment of eight samples and 100 genes. Left: Individual arrays of gene sequences spotted on glass or silicon chips are used for comparative hybridization of eight different samples relative to a common standard. Dark blue indicates decreased expression comp
26、ared with control, white indicates increased expression, and light blue is unchanged expression. (In this schematic, blue and white represent decreased or increased expression, whereas a real experiment would be quantitative with shades of blue and white.) Center: All 800 expression measurements are
27、 organized so that the relative expression for each gene, 1 through 100, is put in order vertically in a column under the number of each sample. Right: Clustering into signatures involves only those 13 genes that showed correlation across subsets of samples. Some genes have reciprocal (high versus low) expression in the two tumors; others show correlated increase or decrease in one tumor and not the other.,Breast cancer,BRCA1,BRCA2,The best prescription is knowledge !,Former US SurgeonGeneral Everett Koop,
