WEEK 13 - Oncology and molecular pathology

Adenocarcinoma

= A type of non-small cell lung cancer (NSCLC) that harbours activating mutations or fusions in oncogenes like KRAS, EGFR, ALK, and ERBB2, making them potentially targetable

Arrayed Screening

= A type of functional genetic screen where RNAi molecules are placed in known map positions, and changes in phenotype are analyzed in many parallel cell cultures

• It is highly reproducible and suitable for complex phenotypes

Chromosomal Copy Number Aberrations (CNAs)

= Somatic alterations in the cancer genome characterized by extra or missing pieces of a chromosome, ranging from a few bases to an entire chromosome

• CNAs are a major class of mutation in cancer

Clonal Hematopoiesis

 = The presence of non-tumoral mutations in blood cells, which can be a confounding factor in liquid biopsy analysis

Clonality

= The state of cells being derived from a single common ancestor

• In oncology, determining if multiple tumors are clonal (metastasis) or non-clonal (separate primary cancers) is critical for treatment decisions

Cytology

= A diagnostic modality in pathology that examines loose cells, for example from a smear, to make a diagnosis

Epigenetics

= The study of heritable phenotype changes that do not involve alterations in the DNA sequence. These mechanisms, such as DNA methylation and histone modifications, regulate gene expression and are involved in cancer development

Feedback System Control (FSC)

= An optimization strategy to rapidly identify optimal, low-dose, synergistic drug combinations

• Uses a learning algorithm (like differential evolution) to navigate through a large parametric space

Functional Genomics

= The direct analysis of the relationship between gene expression and a cellular phenotype

• Aims to determine the function of genes and whether their expression drives biological behaviour

Gene Expression Signature

= A list of genes that are differentially expressed in a specific biological distinction, which can be used to predict a patient's prognosis or likelihood of responding to a particular treatment

HER2 (Human Epidermal Growth Factor Receptor 2)

= A protein involved in cell growth

• In about 15% of breast cancers, the HER2 gene is amplified, leading to protein overexpression, tumor proliferation, and providing a target for therapies like trastuzumab (Herceptin)

Histology

= A diagnostic modality in pathology that examines tissue sections fixed in formalin (preserves tissue structure) to make a diagnosis, with an accuracy of 95-97%

Immunohistochemistry (IHC)

 = An in situ technique used on histologic tissue slides to detect the presence and location of specific proteins (antigens) by using antibodies that bind to them

• In situ refers to detecting molecules within their original location in intact tissue, preserving cellular and architectural context, as in immunohistochemistry

Kinase

= An enzyme that catalyzes phosphorylation (the addition of a phosphate group to a protein)

• Aberrant kinase activity is a hallmark of cancer, making kinases a major class of drug targets

Knockdown (KD)

= A gene expression modulation technique that decreases the expression of a gene, for instance by RNA interference

• This can mimic the effect of a pharmaceutical inhibitor

Knockout (KO)

 = A gene expression modulation technique that results in the complete loss of a gene's expression, for example by using CRISPR/Cas9

KRAS

= An oncogene that is frequently mutated in cancers like adenocarcinoma of the lung and colorectal cancer.

• KRAS = gene that encodes a protein involved in cell growth signalling

• In CRC: KRAS is a negative predictive biomarker for response to anti-EGFR antibody therapy

  • EGFR is a receptor upstream of KRAS in the growth pathway: 

    • EGFR → KRAS → cell growth 

    • Anti-EGFR antibody therapy (e.g. cetuximab) works by: 

      • Blocking EGFR at the cell surface 

      • Preventing growth signals from being sent

  • If KRAS is mutated: 

    • KRAS sends growth signals without needing EGFR 

    • Blocking EGFR does nothing

Liquid Biopsy

= A minimally invasive test done on a sample of blood to look for cancer cells or for pieces of DNA from tumor cells (cfDNA)

• Used to identify targetable alterations, especially when tissue is unavailable

  • Detect mutations (e.g. EGFR, KRAS) 

  • Helps choose targeted therapies

Microsatellite Instability (MSI)

= A type of genomic instability resulting from a deficient mismatch repair (dMMR) system

• Key biomarker in colorectal cancer, indicating potential hereditary 

• Lynch syndrome and predicting a positive response to immunotherapy.

  • MSI = The length of these repeat DNA sequences becomes unstable because DNA repair is not working properly

Mutation

= A somatic or acquired alteration in the DNA of a tumor cell that is not a polymorphism. 

• Examples include point mutations and CNAs

Next-Generation Sequencing (NGS)

= High-throughput DNA sequencing technology used in molecular pathology to analyze DNA and RNA

• It can detect chromosomal copy number aberrations, mutations, and other genetic alterations for research and diagnostic purposes

Pharmacogenetics

= The study or clinical testing of specific genetic variations that give rise to differing drug responses, including metabolism, disposition, tolerability, and efficacy

Pharmacogenomics

= The study of the role of the whole genome in drug response, representing a broader application of genomic technologies to aid in new drug discovery and development

Phosphoproteomics

= The large-scale analysis of proteins that are post-translationally modified by phosphorylation

• Provides direct insight into cell signalling pathways and aberrant kinase activity in cancer

Polymorphism

= A DNA variation in which a possible sequence is present in at least 1% of the population

• Single Nucleotide Polymorphisms (SNPs) are the most common type

Pooled Screening

= A type of functional genetic screen where a library of RNAi molecules is introduced into a single pool of cells, which are then cultured and selected for a particular phenotype

• RNAi = Process that turns off (silences) specific genes by destroying or blocking their mRNA

Precision Medicine

= An approach to patient care that allows doctors to select treatments that are most likely to help patients based on a genetic, environmental, and lifestyle understanding of their disease

Predictive Biomarker

= A marker used to identify which patients are most likely to benefit from a particular treatment

• Example: KRAS mutations for anti-EGFR therapy or MSI status for immunotherapy

  • MSI-high tumors predict a good response to immunotherapy because they have many mutations that create abnormal proteins the immune system can easily recognize

Prognostic Biomarker

= A marker that provides information about the likely course of a disease in an untreated individual

• An example is the 1p/19q co-deletion in lower-grade gliomas, which is associated with better survival

Proteomics

= The large-scale analysis of proteins, including their expression, post-translational modifications, and interactions

• Provides a direct link between the information encoded by the genome and biological function

Single Nucleotide Polymorphism (SNP)

 = A type of DNA variation in which only one nucleotide differs between a reference sequence and a variant

Squamous Cell Carcinoma

= A subtype of non-small cell lung cancer (NSCLC) characterized primarily by mutations in tumor suppressor genes, with no currently identified targetable driver mutations

Synthetic Lethality

= A type of interaction where a combination of deficiencies in two or more genes leads to cell death, whereas a deficiency in only one of these genes does not

• Concept used in functional genetic screens to find cancer-specific therapeutic target

• Example: 

  • Cancer cells often have: A broken DNA repair gene (e.g. BRCA) 

  • They survive only because: A backup repair pathway (e.g. PARP) is still working

  • Use drug to inhibit PARP: 

    • No repair left → cell dies

    • Removing all DNA repair pathways in cancer cells is intentional and beneficial, because it selectively kills cancer cells while leaving normal cells largely unharmed