GENETICS A Conceptual Approach Benjamin A. Pierce GENETICS A Conceptual Approach FIFTH EDITION CHAPTER 23 Cancer Genetics © 2014 W. H. Freeman and Company

Villa designed by Renaissance architect Andrea Palladio, for whom the palladin gene is named. Palladin encodes an essential component of a cell’s cytoskeleton; when mutated, palladin contributes to the spread of pancreatic cancer. [La Rotunda a Vicenzo by Giovanni Giaconi.]

Figure 23.1 Pancreatic cancer is inherited as an autosomal dominant trait in a family that possesses a mutant palladin gene. [After K. L. Pogue et al., Plos Medicine 3:2216–2228, 2006.]

23.1 Cancer Is a Group of Diseases Characterized by Cell Proliferation Tumor Formation Cancer as a Genetic Disease The Role of Environmental Factors in Cancer

Figure 23.2 Abnormal proliferation of cancer cells produces a tumor that crowds out normal cells. (a) Metastatic lung-tumor masses (white protrusions) growing on a human liver. (b) A light micrograph of the section in part (a) showing areas of small, dark tumor cells invading a region of larger, lighter normal liver cells.

****Hallmarks of Pathways to Malignant Cancer Cancer cells acquire self-sufficiency in the signaling processes that stimulate division and growth. Cancer cells are abnormally insensitive to signals that inhibit growth. Cancer cells can evade programmed cell death. Cancer cells acquire limitless replicate potential. Cancer cells develop ways to nourish themselves by stimulating angiogenesis. Cancer cells acquire the ability to invade other tissues and colonize them (metastasize).

Tumor Formation: A Distinct Mass of Abnormal Cells Benign tumor: the tumor remains localized. Malignant tumor: tumor cells invade other tissues. Metastasis: the tumor cells induce secondary tumors.

Cancer as a Genetic Disease Genetic evidence for cancer Carcinogens, chromosomal abnormalities, inheritance Knudson’s multistep model of cancer Requires several mutations The clonal evolution of tumors Tumor cells acquire more mutations that allow them to become increasingly more aggressive in their proliferate properties.

Figure 23.3 Alfred Knudson proposed that retinoblastoma results from two separate genetic defects, both of which are necessary for cancer to develop.

Figure 23.4 Through clonal evolution, tumor cells acquire multiple mutations that allow them to become increasingly aggressive and proliferative. To conserve space, a dashed arrow is used to represent a second cell of the same type in each case.

Role of Environmental Factors in Cancer Cancer is a genetic disease, but most are not inherited Different cancer incidence in different parts of the world (Table 23.2) Factors contributing to cancer (Table 23.3): Tobacco use Obesity Alcohol UV radiation

23.2 Mutations in a Number of Different Types of Genes Contribute to Cancer Oncogenes and Tumor-Suppressor Genes Genes That Control the Cycle of Cell Division DNA-Repair Genes Genes That Regulate Telomerase Genes That Promote Vascularization and the Spread of Tumors MicroRNAs and Cancer The Cancer Genome Project

Oncogenes and Tumor-Suppressor Genes Oncogenes: mutated, dominant-acting stimulatory genes that cause cancer Proto-oncogenes: responsible for basic cellular functions in normal cells; when mutated, they become oncogenes Tumor-suppressor genes: mutated recessive-acting inhibitory genes that are inactive Loss of heterozygosity

Figure 23.5 Both oncogenes and tumor-suppressor genes contribute to cancer but differ in their modes of action and dominance.

Figure 23.6 Loss of heterozygosity often leads to cancer in a person heterozygous for a tumor-suppressor gene.

Mutations in Genes That Control the Cycle of Cell Division Control of the cell cycle Cyclin-dependent kinases (CDKs), cyclins G1-to-S transition Retinoblastoma protein (RB) G2-to-M transition Mitosis-promoting factor (MPF) Spindle assembly checkpoint Mutations in cell-cycle control and cancer

Figure 23.7 The RB protein helps control the progression through the G1/S checkpoint by binding transcription factor E2F. RB name comes from a protein mutated in a genetically inherited cancer of the retina. RB is a tumor suppressor gene that controls the progression of the cell cycle to move past the S phase.

P53 and RB have critical roles in the regulation of the cell cycle http://www.tankonyvtar.hu/hu/tartalom/tamop425/0011_1A_Molekularis_terapiak_en_book/ch11.html

Figure 23.8 Progression through the G2/M checkpoint is regulated by cyclin B.

Figure 1. Cytosolic and mitochondrial p53 apoptotic pathways Figure 1. Cytosolic and mitochondrial p53 apoptotic pathways. In the cytosolic p53 apoptotic pathway, nuclear p53 induces Puma expression, which in turn releases cytosolic p53 held inactive in the cytoplasm through binding to Bcl-XL. Then, cytosolic p53 induces Bax oligomerization and mitochondrial translocation. Accumulation of p53 in the cytosol as a consequence of normal intracellular transport or stable monoubiquitination is the major source for mitochondrial p53. In the mitochondria, p53 induces Bax and Bak oligomerization, antagonizes the Bcl-2 and Bcl-XL antiapoptotic effect, and forms a complex with cyclophilin D in the mitochondrial inner membrane. These changes result in marked disruption of mitochondrial membranes and subsequent release of both soluble and insoluble apoptogenic factors. MPT, mitochondrial permeability transition; U, ubiquitin. http://www.discoverymedicine.com/Joana-D-Amaral/2010/02/20/the-role-of-p53-in-apoptosis/

Concept Check 1 What would be the most likely effect of a mutation that caused cyclin B to be unable to bind to CDK? Cells pass through the G2/M checkpoint and enter mitosis even when DNA has not been replicated. Cells never pass through the G1/S checkpoint. Cells pass through mitosis more quickly than unmutated cells do. Cells fail to pass through the G2/M checkpoint and do not enter into mitosis.

Concept Check 1 What would be the most likely effect of a mutation that caused cyclin B to be unable to bind to CDK? Cells pass through the G2/M checkpoint and enter mitosis even when DNA has not been replicated. Cells never pass through the G1/S checkpoint. Cells pass through mitosis more quickly than unmutated cells do. Cells fail to pass through the G2/M checkpoint and do not enter into mitosis.

Mutations in Genes That Control the Cycle of Cell Division Signal-transduction pathways Signals trigger a cascade of intracellular reactions producing a specific response Ras protein Receptors

Figure 23.9 The Ras signal-transduction pathway conducts signals from growth factors and hormones to the nucleus and stimulates the cell cycle. Mutations in this pathway often contribute to cancer.

Ras proteins are activated when they . Concept Check 2 Ras proteins are activated when they . bind GTP release GTP bind GDP undergo acetylation

Ras proteins are activated when they . Concept Check 2 Ras proteins are activated when they . bind GTP release GTP bind GDP undergo acetylation

Mutations in Genes That Control the Cycle of Cell Division DNA-Repair Genes Genes That Regulate Telomerase Genes That Promote Vascularization and the Spread of Tumors MicroRNAs and Cancer The Cancer Genome Project

Concept Check 3 Which type of mutation in telomerase could be associated with cancer cells? mutations that produce an inactive form of telomerase mutations that decrease the expression of telomerase mutations that increase the expression of telomerase All of the above.

Concept Check 3 Which type of mutation in telomerase could be associated with cancer cells? mutations that produce an inactive form of telomerase mutations that decrease the expression of telomerase mutations that increase the expression of telomerase All of the above.

23.3 Epigenetic Changes Are Often Associated with Cancer Alterations to DNA methylation or chromatin structure are seen in many cancers Hypermethylation or hypomethylation Reversible and not a mutation

23.4 Colorectal Cancer Arises Through the Sequential Mutation of a Number of Genes Excellent example of sequential mutation Led to tumor progression model

Figure 23.10 Mutations in multiple genes contribute to the progression of colorectal cancer.

Chromosomal instability is a general feature of cancer cells 23.5 Changes in Chromosome Number and Structure Are Often Associated with Cancer Chromosomal instability is a general feature of cancer cells Deletions, inversions and translocations Example: a reciprocal translocation between chromosome 9 and 22 causes chronic myelogenous leukemia. Aneuploidy

Figure 23.11 A reciprocal translocation between chromosomes 9 and 22 causes chronic myelogenous leukemia.

Figure 23.12 A reciprocal translocation between chromosomes 8 and 14 causes Burkitt lymphoma.

Figure 23.13 Cancer cells often possess chromosome abnormalities, including extra chromosomes, missing chromosomes, and chromosome rearrangements. Shown here are chromosomes from a colon-cancer cell, which has numerous chromosome abnormalities. [Courtesy of Dr. Peter Duesberg, University of California at Berkeley.]

23.6 Viruses Are Associated with Some Cancers Retroviruses cause cancer by mutating and rearranging proto-oncogenes inserting strong promoters near proto-oncogenes Human papilloma virus and cervical cancer

Figure 23.14 Retroviruses cause cancer by (a) mutating and rearranging proto-oncogenes or (b) inserting strong promoters near proto-oncogenes.