patho 2 test 1 both ppts combined

Biology of Cancer

• Cancer is a disease caused by uncontrolled division of abnormal cells in a part of the body.
• It is a collection of more than 100 different diseases, each caused by a specific and often unique age-related accumulation of genetic and epigenetic alterations.
• Environment, heredity, and behavior interact to modify the risk of developing cancer and the response to treatment.

Hallmarks of Cancer

• There are 8 hallmarks and 2 traits that enable cancer progression.
• The hallmarks of cancer include:
  • Sustaining proliferative signaling
  • Evading growth suppressors
  • Resisting cell death
  • Inducing angiogenesis
  • Activating invasion and metastasis
  • Tumor-promoting inflammation
  • Enabling replicative immortality
  • Deregulating cellular energetics
  • Genomic instability and mutation
  • Avoiding immune destruction

Cell Cycle and Cell Division

• Checkpoints are found at G1, S, and M (in Metaphase of M) phases of the cell cycle.
• G1 checkpoint: cell checks for DNA damage and resources availability.
• S checkpoint: cell checks for DNA errors.
• M checkpoint: cell checks for sister chromatid attachment to mitotic spindles.
• Proto-oncogenes: normally ensure that checkpoints are followed.
• Mutated proto-oncogenes are called oncogenes, which can cause checkpoint dysfunction.

Oncogenes and Tumor-Suppressor Genes

• Oncogenes: genes that encode components of pathways that regulate normal cell proliferation.
• Her2/neu: a gene that encodes for a growth factor receptor, often overexpressed in breast cancer.
• Tumor-suppressor genes: genes that regulate the cell cycle and inhibit proliferation.
• Examples of tumor-suppressor genes: Rb, p53, BRCA1.
• Rb: contributes to the control of cell division, regulates antigrowth signals.
• p53: detects genomic damage, halts the cell cycle, and initiates DNA repair.

Inheritance and Cancer

• Inactivation of tumor-suppressor genes requires at least two mutations (one in each allele).
• A single mutation in the germline cells (sperm or egg) results in the transmission of cancer-causing genes from one generation to the next.
• Familial cancer syndromes: caused by loss of tumor-suppressor gene function, examples include Retinoblastoma, Li-Fraumeni syndrome, and Familial melanoma.

Angiogenesis

• Angiogenesis: the process of establishing new blood vessels.
• Hypoxia-inducible factor 1alpha (HIF-1⍺): a major regulator of angiogenesis in normal tissue.
• In cancer, HIF-1⍺ is increased, leading to increased angiogenic factors and vascularization.

Apoptosis

• Apoptosis: programmed cell death.
• Intrinsic pathway: monitors for abnormal physiology (cellular stress) and triggers apoptosis.
• Extrinsic pathway: relatively dormant until the death receptor is activated.
• In cancer, p53 suppression messes up the intrinsic pathway for apoptosis.

Cancer Treatments

• Surgery: allows for tissue diagnosis and staging, often definitive treatment for localized cancers.
• Radiation therapy: used to kill cancer cells, produces slow changes in most cancers.
• Chemotherapy: attacks rapidly dividing cells, often given in combinations to limit toxicity.
• Immunotherapy: targets unique antigens on cancer cells, aims to induce an immune response.

Tissue Pathology of Cancer

• Neoplasm/Tumor: formation or presence of a new, abnormal growth of tissue.
• Malignant: a tumor tending to invade normal tissue or recur after removal.
• Benign: a slow-growing tumor that is non-invasive and does not metastasize.
• Cancer: a malignant tumor.

Cancer Classification

• Based on: tissue and organ of origin, extent of distribution (stages), microscopic appearance of the malignant tumor, and critical genetic changes in the cancer cells.
• Benign tumors: usually encapsulated, well-demarcated, and do not invade beyond their capsule.
• Malignant tumors: characterized by rapid cell growth, loss of differentiation, and absence of normal tissue organization.

Progression to Malignancy

• Cancers develop incrementally as they accumulate genetic mutations.

• Dysplasia: a premalignant condition, can range from mild to severe.

• Carcinoma In Situ (CIS): preinvasive epithelial tumors of glandular or squamous cell origin.

• Invasive carcinoma: histologic features of malignancy that invade past the basement membrane.### Genomics and Cancer

• Genomics involves the study of germ cell mutations and somatic cell mutations, as well as the interactions between genes, environment, and viral or bacterial genes.

• Cancer is driven by genetic alterations and changes in epigenetic regulation.

Types of Cancer

• Sporadic Cancers: involve genetic changes in somatic cells, are the majority of cancer cases, occur at older ages (60s, 70s, 80s), and have no family history.
• Hereditary Cancers: involve a strong cancer gene inherited through a germ cell line, have high risks to other family members and usually risks for other types of cancer too.
• Familial Cancers: involve multiple family members with the same cancer, with an unknown cause, and share similar genes and lifestyle, environment, and exposures.

Identifying Hereditary Cancers

• Family history and pedigree are used to identify hereditary cancers.
• Genetic counseling and testing are also used to determine hereditary cancer risks.
• "Clues" for hereditary cancers include: young ages of diagnosis, multiple family members with cancer, multiple generations with cancer, multiple cancers in the same person, and related cancers.

Family Pedigree

• A family pedigree allows for a larger picture of the family's cancer history.
• It helps to narrow down which gene to test for and whom to consider testing.
• It also helps with test interpretation.

Interpreting a Pedigree Chart

• Remember the Mendelian modes of inheritance.
• Determine if the pedigree chart shows an autosomal or X-linked disease.
• Determine whether the disorder is dominant or recessive.

Breast Cancer

• Breast cancer is the most common cancer in women, affecting ~12% of American women who live to 85 years or older.
• 5-10% of breast cancer cases in the US are inherited.
• BRCA1 and BRCA2 are autosomal dominant mutations that increase the risk of breast cancer.

Hereditary Breast Cancer

• Women with BRCA1 or BRCA2 mutations have a 50-80% lifetime risk of developing breast cancer.
• BRCA1 also increases the risk of ovarian cancer and moderate risk of colon and prostate cancer.
• BRCA2 increases the risk of ovarian cancer.

BRCA1 and BRCA2

• Both genes are tumor suppressor genes that code for proteins important in DNA damage repair.
• Both genes "put the brakes" on DNA replication until DNA repair is completed.
• With a BRCA1 or BRCA2 mutation, one of the "sets of brakes" is broken, leading to impaired DNA repair.

Colorectal Cancer

• ~1 in 21 Americans will develop colorectal cancer.
• Family history increases the risk of colorectal cancer.
• Hereditary syndromes that increase the risk of colorectal cancer include Familial Adenomatous Polyposis (FAP) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch syndrome.

Hereditary Colorectal Cancer Syndromes

• Familial Adenomatous Polyposis (FAP): caused by a mutation in the APC gene, which encodes a tumor suppressor.
• Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch syndrome: caused by mutations in genes involved in DNA repair, with an 80% lifetime risk of colorectal cancer.

Cancer Risks and Genetic Testing

• When DNA repair is affected, cancer-causing mutations can persist in cells, leading to tumor growth.

Autosomal Dominant Inheritance

• Increases risk of colon cancer (80%), endometrial cancer (60%), ovarian, stomach, small intestine, biliary tract, renal, and skin cancers.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

• Identified using Bethesda and Amsterdam Criteria.

Genetic Testing for Cancer Risk

• Predictive Genetic Testing looks for inherited gene mutations that increase the risk of certain cancers.
• Suggested for:
  • Individuals with a strong family history of certain cancers.
  • Those already diagnosed with cancer.
  • Family members of individuals with an inherited gene mutation.

Genetic Counseling

• A genetic counselor evaluates family history and creates a family pedigree.
• Counsels patients on risk of inherited cancer and management if at high risk.