Genetics of Cancer PDF

12/2/2024 Cancer & What are the cancer risks for the Genetics general population? 1 in 3 people will develop cancer at some point in their lives...

12/2/2024 Cancer & What are the cancer risks for the Genetics general population? 1 in 3 people will develop cancer at some point in their lives Oncogenesis That is cancer development, is a multistage process during which a cell accumulates damage in several critical genes related to mitosis and/or cell differentiation Cancer as a Genetic Disease Hereditary vs. Sporadic Cancer Cancer is a disease caused by Hereditary cancers are caused by genetic mutations in cells that lead inherited mutations in germline to uncontrolled growth. cells, whereas sporadic cancers arise from somatic mutations These mutations can be inherited acquired during a person’s lifetime (germline) or acquired (somatic). 1  12/2/2024 How Many Cancers are Genetic? Sporadic (~85%) Familial (~10%) Hereditary (~5%) Familial cancer and hereditary cancer are both terms used to describe It is important to remember that cancers that occur in families more The vast majority of cancers occur often than expected, but they have sporadically due to non-genetic different definitions factors such as lifestyle, environment, hormones and an Familial cancer element of chance, only about 5- Cancer that occurs in a family more 10% are due to an inherited often than by chance, but may not be predisposition linked to a known gene mutation. Sporadic Cancer Hereditary cancer As cancer is common, many patients have a family history of A narrower definition of familial cancer cancer that occurs when there is a … having one or two family known genetic cause. Hereditary members diagnosed with cancer in cancers are caused by a gene 60’s or 70’s does not increase risk mutation that is passed down from as is most likely to be sporadic a parent to a child occurrence…. 2  12/2/2024 Genetic Cancers Types of Genetic Changes: Breast and ovarian Multiple endocrine Colon cancers neoplasia (MEN) These include point mutations, Gastric cancer Neurofibromatosis deletions, insertions, amplifications, Phaeochromocytoma and chromosomal translocations. Li-Fraumeni Retinoblastoma Wilm’s tumour These changes affect oncogenes, tumor suppressor genes, and DNA repair mechanisms. Knudson’s Two-hit Hypothesis was an early explanation correlating familial and sporadic incidences of similar cancers. A more recent concept is the Gatekeeper Hypothesis (1996), a theory that proposes that genes in which one particular gene plays called gatekeepers must be a pivotal role in maintaining a inactivated before a cell can constant cell number in a given become cancerous tissue type. 3  12/2/2024 Indicators of inherited cancer 4. unusually early age of onset; Familial disease clusters can be caused by shared environments; the following are pointers to genetic 5. bilateral tumours in paired causation of cancer. organs; 1.several close relatives with the same or genetically associated 6. non-clonal tumours that are cancers; multifocal, or in different organ 2.two family members with the systems of the same individual. same rare cancer; Oncogenes: Mutations in proto- DNA Repair Genes and Cancer oncogenes (e.g., Ras, Myc) lead to the development of oncogenes that promote excessive cell division. Mismatch Repair (MMR) Genes: Tumor Suppressor Genes: These Mutations in MMR genes (e.g., genes (e.g., p53, BRCA1, BRCA2) MLH1, MSH2) lead to Lynch prevent cell division or induce syndrome (HNPCC) increasing the apoptosis when DNA is damaged. risk for colorectal and other Mutations can impair their function, cancers. allowing uncontrolled cell growth. Homologous Recombination Deficiency: Mutations in genes like BRCA1 and BRCA2 impair DNA repair, leading to genomic instability in cancers such as breast and ovarian cancer. 4  12/2/2024 Cancer Syndromes with Inherited Genetic Mutations Familial Adenomatous Polyposis (FAP): leading to the Li-Fraumeni Syndrome: development of hundreds to leading to a predisposition to thousands of polyps in the colon, multiple cancers, including breast, which can progress to colon sarcoma, and brain tumors. cancer Hereditary Breast and Ovarian Breast Cancer Genetics Cancer (HBOC) BRCA1 and BRCA2 Mutations Mutations in the BRCA1 and BRCA2 BRCA1 and BRCA2: Mutations genes are the most common inherited in these genes are associated with causes of breast cancer. increased risks of breast and ovarian cancers. These genes normally help repair DNA damage, and mutations impair this function, increasing the risk of cancer development. HER2 Amplification HER2 (human epidermal growth factor receptor 2) is a proto-oncogene, and its amplification leads to aggressive breast cancer 5  12/2/2024 BRCA Mutations in Male Breast Hereditary Breast and Ovarian Cancer Cancer Other genes Men with BRCA1 or BRCA2 BRCA1 BRCA2 mutations are at a higher risk of 5-10% developing breast cancer, though Sporadic the incidence is much lower than in Hereditary Most cases caused by a mutation in BRCA1 women. or BRCA2 gene BRCA1 / 2 are tumour suppressor genes, which are involved in the repair of DNA Accounts for about 5% of breast cancer cases and about 12% of ovarian cancer cases Ovarian Cancer Genetics Lynch Syndrome and Ovarian BRCA1 and BRCA2 in Ovarian Cancer Cancer Lynch syndrome, also known as hereditary non-polyposis colorectal Similar to breast cancer, mutations in cancer (HNPCC), is caused by BRCA1 and BRCA2 significantly mutations in mismatch repair increase the risk of ovarian cancer. genes increases the risk of ovarian cancer, along with colorectal and other cancers. Lung Cancer Genetics KRAS Mutations and Lung Cancer KRAS (oncogene) mutations, EGFR Mutations in Lung Cancer common in smokers, drive the Epidermal growth factor receptor development of lung cancer by (EGFR) mutations are common in lung cancer, particularly in never- activating oncogenic signaling smokers or Asian populations. pathways. These mutations make the tumor more susceptible to EGFR-targeted therapies (e.g., erlotinib). 6  12/2/2024 p53 Mutations and Lung Cancer p53 mutations are found in a significant number of lung cancer cases and are associated with poor prognosis. HER2 Mutations in Lung Cancer Environmental Factors and Genetic Interactions in Lung Cancer While HER2 is typically associated with breast cancer, mutations in the HER2 gene are also found in a Smoking is the most significant subset of lung cancers, particularly environmental risk factor for lung in those who are never-smokers cancer, but genetic susceptibility also plays a role. Familial Lung Cancer Syndromes Colorectal Cancer A small percentage of lung cancer cases are familial, with inherited genetic mutations in genes like Sporadic EGFR, TP53, and LKB1 (~60%) contributing to the development of Familial (~30%) lung cancer in multiple family members. Rare HNPCC Syndromes FAP (~1%) (3-5%) (~4%) MAP (~1%) 7  12/2/2024 Familial Adenomatous Polyposis HNPCC or Lynch syndrome (FAP) 3-5% of all colorectal cancer cases FAP is caused by mutations in the Autosomal dominant – multiple APC gene, which normally generations affected regulates cell division. High penetrance Typical age of cancer onset is 40-50 yrs These mutations lead to the development of numerous polyps Polyps may be present, multiple primaries common. in the colon, which eventually progress to cancer if not managed. 8