L2 | Cancer & Genomic Medicine Notes

Learning Objectives

• Ability to identify the characteristics of cancer and carcinogenesis.
• Understanding of the role of genes and common abnormalities involved in carcinogenesis.
• Knowledge of the role of epigenetics and microbiome in carcinogenesis.
• Recognition of common types of cancer.
• Understanding of the potential of genomic medicine in cancer
• Knowledge of the applications of genomic medicine in breast cancer

What is Cancer?

• Cancer involves abnormal cell division that spreads throughout the body.
• Aggregates of cells invade tissues, causing metastasis.
• This is typically driven by genetic and environmental factors (carcinogens), and is the 2nd leading cause of death worldwide

Terminology

• Intertumoral heterogeneity refers to differences between different tumors, while intratumoral heterogeneity refers to differences within the same tumor.
• Driver mutations promote the development or progression of cancer and occur at higher frequencies in specific cancer types such as the TP53 gene.
• Passenger mutations develop as neoplasia progresses, are majority of mutations in cancer, not common in particular cancer types.

Types of Cancer

• Carcinoma: epithelial cells (solid tumors)
• Sarcoma: connective or muscle cells
• Leukemias, Lymphomas, myelomas: blood cells
• Neuroblastoma & gliomas: nerve cells

Tumor Nomenclature

• Carcinoma implies an epithelial origin, while sarcoma indicates a mesenchymal origin; both generally imply malignancy.
• Benign tumors are usually well-differentiated, well-demarcated, with low mitotic activity, no metastases, and no necrosis.
• Malignant tumors (cancers) may show poor differentiation, erratic growth, local invasion, metastasis, and apoptosis.
• Hamartoma is a term for non-neoplastic malformations including disorganized overgrowth of tissues in their native location. An example is Peutz-Jeghers polyps.
• Choristoma: normal tissue in a foreign location, e.g., gastric tissue located in the distal ileum in Meckel diverticulum.

The Origin of Cancer

• Carcinogenesis involves genetic material mutations, division at a higher rate, clonal division, new mutations, impact on tumor immunovigilance, and results in neoplasia.

Genetic vs Microbiome Mutations

• Sporadic mutations: caused by environmental exposure and/or somatic mutations.
• Germline mutations occur in 10% of cases, show a higher frequency than expected, no pattern of inheritance, and can be inherited, affecting younger individuals
• Proto-oncogenes promote uncontrolled growth and cell division through transcription factors like K-ras, Cyclins, CDK, c-myc, c-erbB.
• Tumor suppressor genes limit cell growth and slow down cell division (G1 arrest) or cause apoptosis (BAK & BAX)
• RB (governor of cell cycle): negative regulator of G1/S cell cycle transition.
• TP53 (guardian of the genome): regulates cell cycle progression (p21-CDK inhibitor causing G1 arrest), senescence, DNA repair (GADD45), apoptosis (BAX).

Microbiome

• Dysbiosis or bacterium infections trigger inflammation involving inflammasomes and TLRs.
• Myofibroblasts leads to EREG/AREG ERK cascade contributing to cell proliferation.
• Macrophages release inflammatory cytokines (IL-1, TNF, IL-23) → NF-kB→ antiapoptotic.
• IL-23→ Th17 development→ STAT3→ anti-apoptosis

Chromosomal Changes

• Translocation: fusion of genes activates proto-oncogenes (promoter or enhancer substitution).
• Deletions: not all lead to cancer just a few.
• Amplification: reduplication and amplification of DNA sequences involves multiple small extrachromosomal structures called double minutes and homogenous staining regions.

Genomic Medicine Applications

• Genomic medicine can be applied to areas of diagnostics, classification, prognosis, surveillance, and treatment selection.
• Expression profiling provides insights into recurrence risk and metastatic potential to guide better decision-making for surgery and/or chemotherapy for breast, ovarian, and colon cancer treatment
• Molecular profiling identifies genomic alterations, and tumor boards with specialists determine treatments.

Breast Cancer: Epidemiology

• 1.5 million new cases of breast cancer.
• 16% of cancer deaths are due to breast cancer.
• 80-85% of breast cancers are Ductal carcinomas.
• 10-15% of breast cancers are Lobular carcinomas.
• Risks: early menarche, late pregnancy, late menopause, obesity & dietary factors, high dose radiation early in life & nulliparity

Breast Cancer: Etiology

• BCRA1 and BCRA2 genes are implicated.
• Immunohistochemical analyses are used for the expression of ER, PR, and HER2.
• 70-80% of cases are immunohistochemical analyses positive for expression of ER, PR, HER2.
• 10-15% of cases are HER2+ and treated with anti-HER2 therapy.
• 15-25% are TNBC, which fail to respond to chemotherapy (antihormone).
• Basal-like cancers lack expression of ER, PR, and HER2 receptors.
• Lum A cancers have better prognosis and sensitivity to endocrine therapy.
• Lum B cancers are resistant to endocrine therapy, but have greater sensitivity to chemotherapy and Luminal B(Luminal A)

Breast Cancer: Epigenetics

• Hypermethylation of BRCA1, metastasis-Inhibitory genes (CDH1, TIMP-3), hormone receptor genes (ER-a, PR) and cell cycle control genes (p16INK4a, CDKN2A).

Breast Cancer and Genomic Medicine

• Gene expression profiling helps predict patient survival, risk of recurrence, treatment response, and metastasis.
• HER2+ tumors are clinically challenging, showing variable responses to therapy, which highlights the complexity of these tumors.
• TNBC fail to respond to hormone therapy so chemotherapy is the normal course of treatment