2022 HCI Molecular Basis of Cancer

HWA CHONG INSTITUTION / 2022-2023 H2 BIOLOGY / Core Idea 2 / Molecular Basis of Cancer 1 Molecular Basis of Cancer The development of cancer is a multi -step process that comprises gene mutations caused by environmental factors, biological agents or hereditary predispositions. These mutations might cause cells to bypass cell cycle checkpoints. Normally, two groups of genes are involved in regulating cell division: tumour suppressor genes and proto-oncogenes. Mutations in either or both of these groups of genes may lead to the development of cancer. Cancer has a much higher incidence in Singapore compared to other diseas es and accounts for as much as 30 per cent of the deaths in this country. The recorded incidence of cancer is on the rise and this could be due to the accumulation of mutations from one generation to the next, although other reasons have also been proposed: increased exposure to carcinogens and increased detection rates as a result of effective cancer screening programmes. As such, an understanding of how cancer develops is important as this would set the platform for discussion of developing anti-cancer drugs. Learning Outcomes Candidates should be able to: 2(p) identify the causative factors, including genetic, chemical carcinogens, ionising radiation and loss of immunity, which may increase the chances of cancerous growth 2(q) explain how the loss of function mutation of tumour suppressor genes, including p53, and gain in function mutation of proto-oncogenes, including ras, results in uncontrolled cell division 2(r) describe the development of cancer as a multi -step process that includes accumulation of mutations, angiogenesis and metastasis Use the knowledge gained in this section in new situations or to solve related problems Learning Experiences 2.5.1 Uncontrolled Cell Division This SLS lesson explains how dysregulation of the cell cycle can result in uncontrolled cell division. In addition, it explains how mutation of two groups of genes (tumour suppressor gene and proto-oncogene) can result in uncontrolled cell division. 2.5.2 Cancer This SLS lesson describes the factors that increase the chance of cancer development, and explains that cancer development is a multi-step process.

HWA CHONG INSTITUTION / 2022-2023 H2 BIOLOGY / Core Idea 2 / Molecular Basis of Cancer 2 2.5.3 Useful information about Cancer About 30 percent of deaths in Singapore are related to cancer (the principal cause of death in 2011). Through studies on families with high incidence of cancer, certain cancer genes such as BRCA have been elucidated. The following websites provide useful information about cancer: The following websites provide useful information about cancer: i. General cancer information – Singapore cancer statistics ii. Principal causes of death

HWA CHONG INSTITUTION / 2022-2023 H2 BIOLOGY / Core Idea 2 / Molecular Basis of Cancer 3 CONCEPT MAP Under normal circumstances Codes for proteins that inhibits the uncontrolled cell division (when DNA damage/mutations occur during cell division). Codes for proteins that promotes normal cell division Proto-oncogene Eg: ras Tumour Suppressor Gene Eg: p53 Gain in function mutation in ras proto-oncogene to form oncogene, which codes for protein that stimulates excessive cell division in the absence of growth factor. Loss of function mutation in p53 tumour suppressor gene, which does not produce functional p53 proteins. Cell division is unchecked and DNA mutations accumulate if cell division proceeds. Uncontrolled Cell Division (Rate of Cell Division >>> Rate of Cell Death) Mutations in these cancer-critical genes can disrupt the cell cycle 2 classes of cancer-critical genes Under normal circumstances For malignancy to occur, several processes must occur in a single cell lineage in addition to accumulation of mutations. This is known as the multi-step model of cancer progression. Case Studies: Colorectal Cancer & Breast Cancer SUSTAINED ANGIOGENESIS 1. Cancer cells produce angiogenesis-activating proteins 2. Formation of new blood vessels to supply tumour with oxygen & nutrients METASTASIS 1. Invasion of surrounding tissues 2. Cancer cells are transported by the circulatory system to distant sites 3. Establish new secondary tumours at these sites by by Results in Allows for Accumulation of other kinds of mutations that allow it to escape normal growth restrain ts e.g. anchorage dependence, contact and density inhibition, replicative senescence in a single cell lineage. Occurrence of processes such as Results in MALIGNANT TUMOUR Causative Factors of Cancer Characteristics of Cancer Cells can be caused by recognised by

HWA CHONG INSTITUTION / 2022-2023 H2 BIOLOGY / Core Idea 2 / Molecular Basis of Cancer 4 CONTENT PAGE 1. Introduction to Cancer 1.1 Cancer terminology 5 1.2 Important characteristics of cancer 6 1.3 Tumours can be benign or malignant 8 2. Uncontrolled cell division could result in cancer 2.1 Cell cycle 10 2.2 Cell cycle checkpoints 10 2.3 Role of cyclins & cyclin-dependent protein kinase in cell cycle 11 2.4 Mutations in genes controlling cell cycle 13 2.4.1 Tumour Suppressor Gene 13 2.4.1.1 Loss of function mutation of tumour suppressor gene 14 2.4.1.2 p53, a tumour suppressor gene 14 2.4.1.3 p53 protein is involved in the cell cycle-inhibiting pathway 15 2.4.2 Proto-oncogene & Oncogene 16 2.4.2.1 Gain in function mutation of proto-oncogene 16 2.4.2.2 ras, a proto-oncogene 17 2.4.2.3 ras protein is involved in the cell cycle-stimulating pathway 17 2.4.2.4 Consequences of conversion of proto-oncogene to oncogenes 18 3. Multi-step Model of Cancer Progression 3.1 Accumulation of mutations 21 3.2 Activation of telomerase 22 3.3 Angiogenesis 23 3.4 Metastasis 24 3.5 Case Study – Hereditary Colorectal Cancer 3.5.1 Sequence of mutation accumulation in colorectal cancer 26 3.6 Case Study – Breast Cancer 3.6.1 Development of breast cancer 28 30 4. Causative Factors of Cancer 32 4.

HWA CHONG INSTITUTION / 2022-2023 H2 BIOLOGY / Core Idea 2 / Molecular Basis of Cancer 5 1. INTRODUCTION TO CANCER During normal development of healthy cells, there is intricate balance between the rate of cell division and rate of cell death in response to various growth signals, growth-inhibiting signals and death signals. Cancer is a disease that results from uncontrolled cell division. Mutations in the genes that control cell division may result in a dysregulation of cellular checkpoints , such that a cell divides uncontrollably. Two important classes of genes, proto -oncogenes and tumour suppressor genes are involved in controlling cell division. In cancer cells, the rate of cell division far exceeds the rate of cell death, resulting in a net uncontrolled proliferation of new cells. As this cell divides, it will pass on the damaged genes to the daughter cells, giving rise to a clone of altered cells. This uncontrolled proliferation of the cell allows the cell to possess an unstable genome and accumulate more mutations that allow it to escape normal growth restraints e.g. anchorage dependence, contact and density inhibition, replicative senescence. These mutations occur at various stages and cancer is considered to develop via a multi-step model with accumulation of important mutations at each step. These mutations would eventually allow cancerous cells to invade tissues and metastasise (spread destructively) to distant sites, and causing death of the host organism. The death of