Cancer Genetics: Mechanisms, Genes, and Environmental Factors

Cancer Genetics

Introduction to Cancer Genetics

Cancer genetics explores the genetic and molecular basis of cancer development, progression, and inheritance. Cancer arises from abnormal cell proliferation due to genetic mutations and environmental influences.

• p53 protein: Known as the "guardian of the genome," p53 regulates cell cycle, DNA repair, and apoptosis to prevent tumor formation.

• Pedigrees and Inheritance: Familial cancer syndromes, such as Li-Fraumeni syndrome, demonstrate inherited mutations in tumor-suppressor genes.

Tumor Formation and Types

Tumors are masses of abnormal cells resulting from uncontrolled cell division. Tumors can be classified based on their behavior and ability to spread.

• Benign tumor: Remains localized and does not invade surrounding tissues.

• Malignant tumor: Invades other tissues and can spread throughout the body.

• Metastasis: Formation of secondary tumors at distant sites.

• Example: Metastatic lung-tumor masses growing on a human liver, with tumor cells crowding out normal cells.

Incidence and Mortality of Cancer

Cancer incidence and mortality rates vary by type and geographic location.

Type of Cancer	New Cases per Year	Deaths per Year
Breast	246,660	40,450
Lung and Bronchus	224,390	158,080
Prostate	180,890	26,120
Colon and Rectum	135,430	50,260
Lymphoma	81,090	21,270
Leukemia	60,140	24,400
All sites	1,685,210	595,690

Cancer as a Genetic Disease

Cancer is fundamentally a genetic disease, though most cases are not inherited. Genetic evidence includes carcinogens, chromosomal abnormalities, and inheritance patterns.

• Knudson's Multistep Model: Multiple mutations are required for cancer to develop, as shown in retinoblastoma.

• Clonal Evolution: Tumor cells acquire additional mutations, becoming more aggressive and proliferative.

Role of Environmental Factors

Environmental factors significantly influence cancer risk and incidence.

• Major factors: Tobacco use, obesity, alcohol consumption, UV radiation.

• Geographic variation: Cancer rates differ by region due to environmental and lifestyle factors.

Factor	Percentage of Cancer Cases (UK)
Tobacco	19.4
Diet	9.2
Overweight and obesity	5.5
Alcohol	4.0
Radiation (UV)	3.5
All environmental factors	42.7

Oncogenes and Tumor-Suppressor Genes

Genetic mutations in specific classes of genes drive cancer development.

• Oncogenes: Mutated, dominant-acting genes that stimulate cell proliferation. Derived from proto-oncogenes, which normally regulate cell growth.

• Tumor-suppressor genes: Mutated, recessive-acting genes that lose their inhibitory function, allowing uncontrolled cell division.

• Loss of heterozygosity: Loss of the normal allele in a heterozygous individual predisposes to cancer.

Gene	Normal Function	Cancer in Which Gene Is Mutated
erbB	Growth factor receptor	Many types
fos	Transcription factor	Osteosarcoma, endometrial carcinoma
jun	Transcription factor, cell cycle control	Lung, breast cancer
myc	Transcription factor	Lymphoma, leukemia, neuroblastoma
ras	GTP binding, GTPase	Many types
sis	Growth factor	Glioblastomas, other cancers
src	Protein tyrosine kinase	Many types

Gene	Normal Function	Cancer in Which Gene Is Mutated
APC	Scaffold protein, interacts with microtubules	Colorectal
BRCA1	DNA repair, transcription factor	Breast, ovarian
CDKN2A	Regulates cell division	Melanomas
NF1	GTPase activator	Neurofibromatosis
p53	Regulates cell division, apoptosis, DNA repair	Many types
RB1	Regulates cell division	Retinoblastoma, many other cancers

Mutations in Genes That Control the Cell Cycle

Cell cycle regulation is critical for normal cell division. Mutations in these regulatory genes can lead to cancer.

• Cyclin-dependent kinases (CDKs) and cyclins: Control progression through cell cycle phases.

• G1-to-S transition: Regulated by retinoblastoma protein (RB).

• G2-to-M transition: Regulated by mitosis-promoting factor (MPF) and cyclin B.

• Spindle assembly checkpoint: Ensures proper chromosome segregation.

• Mutations: Disrupt cell cycle control, leading to uncontrolled proliferation.

Signal-Transduction Pathways

Signal-transduction pathways transmit signals from growth factors and hormones to the nucleus, stimulating cell division. Mutations in these pathways, such as in the Ras protein, are common in cancer.

• Ras pathway: Conducts signals to promote cell cycle progression; mutations can result in continuous cell division.

Epigenetic Changes in Cancer

Epigenetic modifications, such as DNA methylation and chromatin structure changes, are frequently observed in cancer cells. These changes are reversible and do not involve DNA sequence mutations.

• Hypermethylation: Can silence tumor-suppressor genes.

• Hypomethylation: Can activate oncogenes.

Sequential Mutation Model in Colorectal Cancer

Colorectal cancer exemplifies the sequential accumulation of mutations in multiple genes, leading to tumor progression.

• Tumor progression model: Stepwise mutations in genes such as APC, KRAS, and p53 drive the development from benign growths to malignant cancer.

Chromosomal Changes in Cancer

Cancer cells often exhibit chromosomal instability, including deletions, inversions, translocations, and aneuploidy.

• Translocations: Example: Reciprocal translocation between chromosomes 9 and 22 (Philadelphia chromosome) causes chronic myelogenous leukemia.

• Burkitt lymphoma: Caused by translocation between chromosomes 8 and 14.

• Chromosome abnormalities: Extra, missing, or rearranged chromosomes are common in cancer cells.

Viruses and Cancer

Certain viruses are associated with cancer development, often by affecting proto-oncogenes.

• Retroviruses: Cause cancer by mutating/rearranging proto-oncogenes or inserting strong promoters near them.

• Human papillomavirus (HPV): Linked to cervical, penile, and vulvar cancers.

Virus	Cancer
Human papillomavirus (HPV)	Cervical, penile, vulvar cancers
Hepatitis B virus	Liver cancer
HTLV-1	Adult T-cell leukemia
HTLV-2	Hairy-cell leukemia
Epstein-Barr virus	Burkitt lymphoma, nasopharyngeal cancer, Hodgkin lymphoma
Human herpesvirus	Kaposi sarcoma
Merkel cell polyomavirus	Merkel cell carcinoma

Additional info:

• Knudson's two-hit hypothesis for retinoblastoma is a foundational concept in cancer genetics, explaining why both alleles of a tumor-suppressor gene must be inactivated for cancer to develop.

• Clonal evolution describes how cancer cells accumulate mutations over time, leading to heterogeneity within tumors and increased malignancy.

• Epigenetic changes are increasingly recognized as important contributors to cancer, offering potential targets for therapy.