Chapter 23 Study Guide

Explain how it is that you interpret Kaplan-Meier graphs to discuss risk and prognosis.

-Risk is the mutation that you have, and the odds of the cancer progressing o Observe the mutation presence vs cancer incidence -The prognosis is determined by observing: o Normal karyotype vs abnormal karyotype o Percentage of normal vs abnormal cells o Exact aberrations present, ploidy of cells o Complexity of karyotype in main clone o Presence and extent of clonal evolution o Finding of double minutes/ HSRs which indicate gene amplification o Abnormal karyotype finding after successive normal studies -Kaplan-Meier Survival Curves o Anytime the curve drops, a percentage of the population observed has died o Can be read to estimate the likelihood of survival of the patient with that specific type of cancer

Tumor Suppressor Gene

A gene whose protein products inhibit cell division, thereby preventing uncontrolled cell growth (cancer).

Cancer

A genetic disorder arising from somatic mutations in multiple genes that affect cell division and proliferation.

Cyclins

A group of proteins whose function is to regulate the progression of a cell through the cell cycle and whose concentrations rise and fall throughout the cell cycle. -When bound to CDKs, they specify which protein the CDK will phosphorylate.

Clone

An cell that is genetically identical to the cell from which it was produced

Familial cancer

Cancer that occurs in families more often than would be expected by chance. These cancers often occur at an early age, and may indicate the presence of a gene mutation that increases the risk of cancer. -They may also be a sign of shared environmental or lifestyle factors. -Not always the same type of cancer for everyone in the family

Sub-Clone

Cells that contain the primary and additional secondary aberrations, related to the main-line clone.

List the different types of cancer origins and discuss how each type can lead to cancer.

Chromosome Rearrangements: o Deletions: Results in the loss of one or more tumor suppressor genes which can lead to cancer and tumor growth o Inversions: Can bring together sequences from two different genes, generating a fused protein that stimulates some aspect of the cancer process. o Translocations: Transfer of a potential cancer-causing gene to a new location where it is activated by different regulatory sequences. o Duplications: Increases aneuploidy and may accelerate cancer progression. o Amplifications: Only in cancer cells, enhances proliferation. Exogenous sequences: Sequences of DNA originating outside of the organism o Can cause cancer by mutating and rearranging proto-oncogenes or by inserting strong promoters near proto-oncogenes.

Primary Aberration

Cytogenetic abnormality that is either by itself or common to all cells examined, even in the presence of other aberrations.

Discuss how problems in repair mechanisms express themselves differently when it comes to cancer.

Defects in DNA repair genes often increase the overall mutation rate of other genes, leading to defects in proto-oncogenes and tumor suppressor genes that can contribute to cancer progression. -DNA repair gene mutation o Inactivation § Increased standing mutation load · More mutations and probability of mutations in proto-oncogenes and tumor suppressant genes. o Mutation accumulation § Cancer progression is accelerated § Progression of mutation pathways that progress cancer to the next stage.

Oncogene

Dominant mutated copies of normal genes (proto-oncogenes) that stimulate cell division.

Cyclin Dependent Kinases

Enzymes that activate or inactivate other proteins by phosphorylating them -To be active they must be attached to a cyclin

Amplifications

Extra copies of particular genes

Explain the two hit hypothesis and discuss why two hits are needed in tumor suppressor genes but NOT in Oncogenes.

For retinoblastoma, two mutations are required for cancer to occur. Each of these mutations is considered a "hit", and this is the basis of the two-hit hypothesis. -Not all cancers require two hits, most require more. Oncogenes are different because they are dominant acting mutations, meaning they only require one hit rather than two for excessive cell proliferation because they would dominate over the other allele regardless of what gene it codes for.

Secondary Aberration

Found usually in a subset of cells, indicative of clonal evolution and disease progression.

Discuss the concept of progressions pathways related to specific cancers.

If one or more mutations are inherited, then fewer additional mutations are required for cancer to develop. A mutation that allows the cell to divide rapidly gives an advantage, as it can give rise to clones with the same mutation and advantage and increase the growth of the cancer. o Colo rectal cancer starts by mutations that stimulate cell division, which leads to a small, benign tumor. Mutations cause this to enlarge, invade, and spread to other parts of the body.

Explain the concept of clonal expansion and how it is that we can determine the number of clones in a particular tumor.

In clonal expansion we see a healthy cell that divides, and during that division, one of the two cells that is created has a mutation. Since this one cell has a mutation, when it divides it will make 2 cells that also have mutations. This will continue and we will see first, second, third, and fourth mutations until we come to a malignant cell.

Explain why mutation accumulation is faster in cancer cells.

Mutation accumulation is faster in cancer cells because it gives rise to more cancer cells that have mutations than if a regular cell were to divide until it came to a mutation. Within the clones of these cancer cells, other mutations occur that provide additional advantages to growth, and these mutated cells become dominant in the clone, and the clone evolves and replicates.

Clonal Evolution

Process by which mutations that enhance the ability of cells to proliferate predominate in a clone of cells, allowing the clone to become increasingly rapid in growth and increasingly aggressive in proliferation properties.

Mutation Accumulation

Progression of cancer causing pathways that accelerate its progression. -Having multiple mutations in the same cell leads to a higher increase in its cancer causing properties.

Exogenous Sequences

Sequences of DNA originating outside of the cell that can cause mutations by rearranging proto-oncogenes or by inserting strong promoters near proto-oncogenes. -Cancer-causing

Translocation

The process in which a segment of a chromosome breaks off and attaches to another chromosome.