Tumour biology

BI108 Mechanisms of Human Disease

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Examining Cancer Statistics

Frequency of Invasive Cancers by Gender

• Invasive cancers have varying frequencies based on gender:

  • Females: Breast, lung, and bowel cancers are more frequent.

  • Males: Prostate, lung, and bowel cancers are more common.

Prognosis of Cancers

• Certain cancers exhibit more aggressive characteristics, leading to poorer prognoses.

• Reasons for poor prognosis in some cancers include:

  • Patients may not notice changes, such as in ovarian cancer (females) or pancreatic cancer (both genders).

  • Patients can ignore changes, such as symptoms of colon cancer, leading to late diagnosis.

• These high-risk cancers are associated with high mortality rates.

Limitations of Current Treatments

• Treatment options for some cancers are limited, particularly when diagnosed late.

• Suggested improvements include:

  • Better Screening Programs:

  • Mammogram screenings are recommended starting at age 50 for breast cancer detection.

  • Pap smears for cervical cancer screening.

  • Bowel screening for colorectal cancer between the ages of 58 to 70 every two years.

  • BowelScreen will eventually be offered to individuals aged 55 to 74.

  • Awareness Programs: Launched through various media (e.g., television) to promote awareness of male cancers and early diagnosis.

  • Introduction of Screening Tests: Exploration of screening tests for other high-risk cancers.

  • Biomarker Identification: Researching noninvasive biomarker approaches for cancer detection and treatment options.

  • Combined Therapies and Personalized Medicine: Research is ongoing to bring hope for new treatment regimens through personalized medicine approaches.

Incidence of Cancer in Ireland (2020-2022)

Average Cancer Diagnoses

• On average, 41,654 cancer or related tumors were diagnosed each year from 2020 to 2022.

• International comparisons indicate that, excluding non-melanoma skin cancers (NMSC), there were 24,207 cases diagnosed annually (12,925 males and 11,282 females). This accounts for 58% of all registered tumors, which are classified as life-changing invasive cancers often requiring extensive treatments.

Breakdown of Cancer Registrations

• 24% of all registered cancers are non-melanoma skin cancers (NMSC).

• Approximately 18% of the total diagnoses were non-invasive neoplasms (including in situ carcinomas, uncertain behavior tumors, and benign tumors of the brain and central nervous system).

Common Incident Cancers (2020-2022)

Most Common Cancers Diagnosed

• Excluding non-melanoma skin cancers (NMSC):

  • Prostate and female breast cancer were the most frequently diagnosed invasive cancers, each accounting for approximately one-third of all invasive cancers in men and women, respectively.

  • Other common cancers by gender:

  • Males:

    • Colorectal (11.2%)

    • Lung (10.4%)

    • Melanoma (5.1%)

    • Head and neck cancer (4.6%)

  • Females:

    • Lung (10.9%)

    • Colorectal (9.3%)

    • Melanoma (5.6%)

    • Uterine cancer (5.1%)

Annual Cancer Deaths

• On average, there were 9,797 deaths per year from invasive cancer (5,246 males and 4,551 females) from 2020 to 2022, and 10,041 deaths per year was observed across all tumor types.

Top Causes of Cancer Death (2020-2022)

Common Causes of Cancer Death by Gender

• Lung cancer is the leading cause of cancer death in both sexes, constituting 1 in 5 of all cancer-related deaths during this period.

• Common causes of cancer deaths by gender after lung cancer:

  • Males:

  1. Prostate (12.0%)

  2. Colorectal (11.2%)

  3. Pancreas (6.0%)

  4. Oesophagus (6.0%)

  • Females:

  1. Breast (16.7%)

  2. Colorectal (9.6%)

  3. Ovary (6.8%)

  4. Pancreas (6.5%)

Sex-Specific Differences in Cancer Incidence and Mortality

• Lopes-Ramos et al. presents sex differences in cancer incidence and mortality rates across various cancers, showing disparities in occurrence.

• Cancer types included in the analysis are represented in a figure comparing incidence and mortality rates per 100,000 individuals in the US.

Understanding Tumor Biology

Definitions and Concepts

• Tumor (Neoplasm): A cluster of cells showing unregulated proliferation,

  • Benign: Not capable of indefinite growth or invasion of healthy tissue.

  • Malignant: Continues to grow and becomes progressively invasive, referred to simply as cancer.

• Metastasis: The ability of malignant tumors to form secondary tumors (metastases) at other body sites. This involves dislodged cancerous cells invading blood or lymphatic vessels, migrating to distant sites, and proliferating there.

• The term Metastatic potential refers to the ability of a tumor to metastasize.

Tumor Types

• A majority of human tumors originate from epithelial tissue.

• Carcinomas (80-90% of all cancers) arise from epithelial cells, affecting organs like skin, the gut, and the lining of various internal organs.

  • Example cancers: Breast, colon, prostate, lung, stomach, skin, oesophagus, liver, ovary, gallbladder, and urinary bladder.

• Non-epithelial cancers:

  • Leukemia, Lymphoma, and Multiple Myeloma (9% of cancers): Malignant tumors of hematopoietic cells from the bone marrow.

  • Sarcomas (1% of cancers): Derived from mesenchymal cell types, including osteoblasts, adipocytes, and fibroblasts.

  • Cancers of the central and peripheral nervous systems include glioblastomas, neuroblastomas, and medulloblastomas, representing 1.3% of diagnosed cancers but 2.5% of cancer deaths.

Genes Associated with Cancer

Overview of Cancer-Related Genes

• Oncogenes: Involved in cell growth-promoting processes.

• Tumor-Suppressor Genes: When these genes fail, cancer cells can survive and proliferate abnormally.

• Apoptosis: Faults in this process can lead to abnormal cell survival, contributing to cancer development.

Functional Classification of Cancer-Associated Genes

1. Genes That Induce Cellular Proliferation:

   • Growth Factors: E.g., SIS (PDGF), FMS, ERBB.

   • Signal Transducers: E.g., ABL, RAS.

   • Transcription Factors: E.g., JUN, MYC.

2. Tumor-Suppressor Genes (Inhibitors):

   • E.g., Rb, APC, NF1 (suppressors for various cancers).

3. Genes Regulating Programmed Cell Death:

   • Examples include BCL-2, BCL-x, which suppress apoptosis, and BAX, BIM, PUMA, which induce it.

Oncogenes and Proto-Oncogenes

• Proto-Oncogenes: Normal genes that can become oncogenes if altered to lose expression control.

• More than 100 proto-oncogenes are conserved through evolution, contributing to cancer development if mutated or overexpressed.

• Oncogenes can be activated via:

  1. Mutations

  2. Gene amplification

  3. Chromosomal translocations

Mechanisms of Oncogene Activation

Point Mutations:

• An example includes a point mutation in the H-ras gene associated with bladder carcinoma that results in a glycine to valine substitution impacting the H-Ras protein's structure and function, causing constitutive activation.

• Point mutations are prevalent in various cancers, especially in H-RAS, K-RAS, and N-RAS genes, affecting oncogenic functions.

Gene Amplification and Cancer

• In breast cancers, HER2 is often amplified, leading to higher HER2 protein expression.

• FISH (Fluorescence In Situ Hybridization) analysis can identify effects of HER2 gene amplification. In breast cancer cells, multiple spots would show the amplified HER2 gene under a fluorescence-labeled probe.

Chromosomal Translocations in Cancer

• An example is Burkitt’s Lymphoma, common in Africa, where chromosomal translocations involving the c-myc gene lead to its overproduction because it comes under the control of highly active transcription regulators due to translocations.

Causes of Cancer

Multifactorial Nature of Cancer

• The causative factors for cancer are multifactorial, encompassing a complex interplay of genetic and environmental triggers, with only 10% attributed to infectious agents.

Specific Causes and Risk Factors

• Smoking: Particularly associated with lung cancer.

• Environmental Factors: Such as radon gas contributing to lung cancer, as well as ionizing radiation increasing risks for leukemia and thyroid cancer.

• Infectious Agents:

  • HPV linked to cervical cancer

  • Hepatitis C associated with liver cancer

  • H. pylori’s contribution to gastric cancer and MALT lymphoma.

• Lifestyle Factors: Dietary influences leading to obesity and low-grade inflammation, notably linked to colon cancer.

• UV Exposure: Contributing to melanoma rates.

• Reproductive History: Affects cancer prevalence in females.

• Genetic Background: Inherited predispositions such as Li-Fraumeni syndrome and retinoblastoma increase cancer risks.

Inherited Single Gene Defects and Cancer Susceptibility

Overview

• Inherited gene defects contribute to 5-10% of all cancers.

• Examples:

  • Retinoblastoma: A childhood eye cancer linked to RB tumor suppressor gene.

  • Li-Fraumeni Syndrome: Related to the p53 gene, causing multiple cancer types in young individuals.

  • BRCA1 and BRCA2: Increase susceptibility to breast and ovarian cancer.

  • APC Gene Mutations: Linked to inherited forms of precancerous polyps, leading to colon cancer.

Learning Outcomes

1. Identify the most common cancers among females and males, and understand which are the most aggressive.

2. Understand the causes and risks associated with cancer development.

3. Describe inherited single-gene defects and their implications in cancer susceptibility with given examples.

4. Classify cancers into epithelial and non-epithelial categories.

5. List at least two examples each of oncogenes, tumor-suppressor genes (TSGs), and genes involved in programmed cell death that can become deregulated in cancers.