Cancer Genomics Overview

Cancer: A Genetic Disease

• Cancer is a genetic disease caused by mutations in genes, primarily somatic rather than heritable.
• These mutations affect genes responsible for crucial cellular functions, including DNA repair, cell growth regulation (oncogenes), and cell growth inhibition (TSGs).
• The Human Genome Project has significantly advanced cancer genomics research.

Cancer Genomics

• Cancer genomics aims to identify differences in genes between normal and cancer cells.
• Techniques include:
  • Sequencing Analysis: Exome and whole-genome sequencing analyze genetic variations.
  • Gene Expression Analysis: Examines how genes are utilized in normal and cancer cells.
  • Copy Number Analysis: Identifies changes in gene copies between normal and cancerous cells.
  • Epigenetic Modifications: Studies alterations in DNA methylation and histone modification patterns.
• Data Integration: Combining different analyses into unified datasets reveals correlations between genomic features and cancer development.
• Linking genomic data to clinical outcomes offers a comprehensive view of the cancer's molecular profile.
• Identifying cancer pathways through multiple tissue samples improves targeted therapy development.

Human Karyotype and Cancer

• Human Normal Karyotype: Studies chromosomal abnormalities in cancer.
  • Visualizes missing chromosomes, fragments, and abnormal connections using techniques like Spectral Karyotyping (SKY).
• Genomic techniques enhance cancer diagnosis accuracy.
• Gene Expression Analysis: Monitoring gene expression (e.g., via transcriptomics) determines over- or under-expression of genes.
• Exemplary application: Diffuse Large B Cell Lymphoma (DLBCL) classification:
  • ABC (Activated B Cell-like): Poor prognosis
  • GCB (Germinal Center B Cell-like): Better prognosis, linked to higher survival rates due to differing gene expression profiles.

Diagnosis of Breast Cancer

• Breast cancer is categorized into various molecular groups.
• Traditionally, diagnosis didn't involve genetic studies; contemporary methods focus on transcriptomics to assess gene expression profiles.
• This allows for more precise and personalized treatments for patients, utilizing personalized genetic profiles.
• Breast cancers subtypes are categorized by ER (Estrogen Receptor), PR (Progesterone Receptor), HER2 status.
• ER-, PR-, HER2- cancers resemble healthy cells without overexpressed receptors.
• HER2+ cancers exhibit increased HER2 gene expression, which promotes cell growth.
• Tamoxifen blocks estrogen receptors, inhibiting growth in ER-positive breast cancers.

Cellular Fitness & Mutations

• Normal cells maintain genetic stability.
• Barriers prevent tumor growth, including processes that limit growth and initiate cell death.
• Genetic instability (mutations in DNA repair genes) enables cells to overcome these barriers, causing more mutations and tumor growth.
• Cancer cell mutations accumulate throughout life, from conception through tumor development, leading to chemotherapy resistance.
• Intrinsic Mutations: Occur during normal replication.
• Environmental Factors: Outside influences (chemicals, radiation, lifestyle) can cause mutations.
• Genetic Instability: Contributes to accumulating mutations.

Mutations in Solid Tumors

• Solid tumors may require only a small number (4-10) of mutations to fully exhibit cancer traits. Others may have hundreds to thousands.
• Not all mutations in cancer cells contribute to their transformation.

Founder vs. Driver vs. Passenger Mutations

• Founder Mutations: Occur in the first cancer cell, contributing to genetic instability. Often inherited; however, sufficient by themselves to fully transform a normal cell into a cancer cell, usually not.
• Driver Mutations: Needed for the full expression of the cancerous phenotype (fully transformed cell). Typically 3-7. Can sometimes be reversed/addressed in treatment.
• Passenger Mutations: Accumulate due to genetic instability but don't directly drive cancer progression; they do not affect the cell birth/death ratio.
• Numerous cancer-related genes (oncogenes and TSGs) are identified as driver mutations ( approximately 3% of our genome and 80 oncogenes and 140 TSGs)

Cancer Treatment & Genomics

• Surgery and radiation are effective when the tumor is localized.
• Chemotherapy can target cancer throughout the body.
• Understanding dominant drivers of cancer provides new targeted therapies.

Copy Number Variation (CNV) in Pancreatic Cancers

• Extra gene copies (amplification) often indicate oncogenes, promoting cancer.
• Gene deletions are associated with tumor suppressor gene loss.
• Amplifications are often driver mutations, but amplified genes may also have passenger mutations.

Breast Cancer Genomics

• Breast cancers are highly heterogeneous (genetically diverse).
• Sequencing of breast cancers reveals a unique combination of mutated genes.
• Genes involved in core pathways and functions contribute to breast cancer development (approx 12 pathways, 8 are major pathways).
• Major functions: DNA Repair, Cell Adhesion, Cell Cycle Control, and Cell Fate (Differentiation and Death).

Gene Mutations in Cancer

• Common mutated genes include BRAF, JAK, RAS, p53, FLT3, EGFR.

Receptor Tyrosine Kinases and Ras Activation

• Receptor tyrosine kinases activate Ras, initiating a cell signaling cascade affecting growth, differentiation, and survival.

Constitutively Activated Pathways

• Oncogenic mutations make signaling pathways constantly active, regardless of normal control mechanisms.
• Inhibiting molecules within these pathways disrupts cancerous signaling.
• Genomic approaches, including mutation identification, are crucial for targeted cancer treatments.

Explore the intricate relationship between genetics and cancer in this quiz. Understand how mutations affect critical cellular functions and the role of the Human Genome Project in cancer research. Test your knowledge on genomic analysis techniques used to differentiate between normal and cancer cells.