Genetics of Cancer: Oncogenes, Tumor Suppressors, and Hereditary Syndromes

Cancer

Disease caused by uncontrolled division of abnormal cells in a part of the body; fundamentally a genetic disease

Causes of Cancer

Inherited mutations, environmental exposure to mutagens and carcinogens, or viruses

Carcinogen

Environmental agent that causes cancer

Cancel cell characteristics

Ability to divide without growth factor stimulation, immortality, and loss of contact inhibition

Oncogene

A gene that can transform cells into cancer cells; a cancer causing gene. Usually from gain-of-function mutation which are dominant

Proto-oncogene

The normal version of an oncogene. Usually positive regulators of the cell cycle with promote cell division in a controlled fashion

Mechanism of Activation for oncogenes

Mutations that prevent silencing, increase number of copies, and increased transcription (Ex. is translocation leading to Philadelphia chromosome)

Tumor Supressor Gene

A gene that prevents uncontrolled cell division; act as brake pedals in their ability to stop the cell cycle at checkpoints, repair DNA damage, and direct apoptosis. Usually loss of function mutations which are recessive occur (ex. TP53)

Two-hit hypothesis

Alfred Knudson, two alleles of tumor suppressor gene are inactivated to develop cancer

TSG and Hereditary Cancer

An individual inherits one mutated allele and a later somatic mutation causes loss of function and initiates cacer

Inheritance Pattern of TSG

TSG mutations are recessive at the cellular level, the predisposition is transmitted as autosomal dominant as inheriting the first hit increases the the risk

Loss of heterozygosity

Usually the second hit, results in the loss of the normal allele or normal chromosome

Hereditary Breast and Ovarian Cancer (HBOC)

Associated with pathogenic variants in BRCA1 and BRCA2; autosomal dominant inheritance which significantly increases the risk of female breast cancer, contralateral breast, ovarian, prostate, and pancreatic cancer

BRCA 1+2

TSG which function to repair double-stranded DNA breaks

Lynch Syndrome (Hereditary Non-polyposis Colon Cancer)

Most common cause of hereditary colorectal cancer, caused by germline mutation in DNA mismatch-rapair genes, causing genomic instability and accumulation of mutations

Familial Adenomatous Polyposis

Caused by germline heterozygous pathogenic variants in the APC tumor suppressor gene

Li-Fraumeni Syndrome

Germline heterozygous mutations in the TP53 tumor suppressor gene causing increased risk of multiple cancer; commonly soft tissue sarcomes, osteosarcoma, breast cancer, and CNS tumors

Importance of Molecular Diagnosis

Identifies the specific genetic syndrome, influences cancer treatment, direct types and timing of screening and surveillance, and allows for pre-symptomatic identification of affected relatives

Current Testing Standard

Targeted whole exome sequencing of panels of genes associated with hereditary cancer susceptibility syndromes

Possible Test Outcomes

Positive: A deleterious variant is identified

True Negative: No deleterious gene variant is found, and a deleterious variant was previously found in an affected family member

Negative: No deleterious variant is found, but no family member has been tested

VUS: Not actionable

Presymptomatic Testing for Relatives

Maximize management for carriers and eliminate unnecessary invasive or expensive surveillance for those who test true negative

Hematopoiesis

The process where pluripotent hematopoietic stem cells differentiate into all red and white blood cells

Innate Immunity

Non-specifc, involves recognition of pathogenic patterns via toll-like receptors

Adaptive Immunity

Specific, characterized by clonal selection of lymphocytes, generating receptor diversity, and creating immunologic memory

B Lymphocytes

Develop from the common lymphoid progenitor; produce antibodies which function as a B cell receptor on the membrane

Diversity of Antibodies

Generated by rearranging gene segments using recombination

T Lymphocytes

Develops from the common lymphoid progenitor; only recognizes antigen when complexed with MHC molecules

Antigen Presentation

APCs (macrophages, dendritic cells, B Cells) angulf pathogens and break them down, presenting pieces on their surface via MHC molecules

Major Histocompatibility Complex

Highly conserved, tightly linked cluster of genes whose products play roles in intercellular recognition and discrimination between self and non-self

Are polygenic and polymorphic

Polygenic

High variability means no two individuals have the exact same set of MHC molecules (besides identical twins)

Codominant Expression

Protein products of both alleles at a locus are expressed, allowing a much larger set of peptides to be presented

Metagenomics

The study of genetic material recovered directly from environmental or clinical samples without prior cultivation

Benefits of Metagenomics

Allows access to the "unculturable" majority of microorganisms. Provides both taxonomic composition and functional capabilities

16sRNA Amplicon Sequencing

In metagenomics, targets conserved marker genes for cost-effective analysis and better strain-level resolution

Application of metagenomics

Human microbiomes studies, environmental monitoring, and clinical diagnosis

Alpha Diversity

Richness within a metagenomic samples

Beta Diversity

Differences between samples in metagenomics