L-24 Carcinogenesis and Oncogene Activation

• Neoplasia means "new growth" in scientific terminology.

Carcinogenesis

• Carcinogenesis involves non-lethal genetic damage and often affects four regulatory genes.
• cMyc is a growth-promoting oncogene and is associated with Burkitt's lymphoma.
• Ras protein is another growth-promoting oncogene.
• p53 is a growth-inhibiting tumor suppressor gene.
• Genes regulating apoptosis are affected, such as in t(8:14) Burkitt lymphoma.
• Xeroderma pigmentosa impacts genes involved in DNA repair.
• Carcinogenesis typically needs multiple steps. CML and melanoma are exceptions.
• Tumors come from the clonal expansion of a single, genetically damaged precursor cell.

Mechanisms of Oncogene Activation

• Point mutations and chromosomal translocations can activate oncogenes.
• The translocation 8:14 moves C-myc to IgH in Burkitt lymphomas.
• Gene amplification is another mechanism.
• N-myc amplification occurs in neuroblastoma.

Adenoma to Carcinoma Sequence

• The first hit involves inheriting a gene mutation in APC at 5q21, a tumor suppressor gene; the colon is initially normal.
• The second hit involves CH3+ and methylation abnormalities, inactivating normal genes and affecting beta catenin; the mucosa is now at risk.
• Proto-oncogene mutations such as Kras at 12p12 appear next.
• Homozygous loss of additional tumor suppressor genes, such as overexpression of COX2 and p53 loss at 17p13 LOH, occurs.
• Later mutations, gross chromosomal alterations, telomerase activation, and many gene changes lead to carcinoma.

Neoplasms

• Neoplasia means new growth that isn't reversible.
• Dysplasia involves disordered growth that is reversible and can result in neoplasia.
• Benign neoplasms are small, slow-growing, encapsulated/demarcated, and well-differentiated (resemble normal tissue).
• Malignant neoplasms exhibit large, rapid growth, necrosis and hemorrhage, poor demarcation, poor differentiation, pleomorphism, nuclear hyperchromasia, and high mitotic activity.
• Tumor cells can undergo clonal expansion, growth and diversification, and angiogenesis, leading to a metastatic clone.
• Adhesion and invasion of the basement membrane allow the passage through the extracellular matrix by intravasation.
• The tumor cell forms an embolus with platelets and adheres to the basement membrane via extravasation.
• Angiogenesis supports growth of metastatic tumors.
• Well-differentiated lesions show prominent keratinization.
• Poorly differentiated lesions show significant number of keratin pearls and perineural invasion.

Cancer Statistics

• Cancer incidence is declining by about 2% each year since 1992.
• Overall, the most significant risk factor for cancer is age.
• From birth to age 49, the chance of developing cancer is 1 in 29 for men and 1 in 19 for women.
• Between ages 50 and 59, the odds are 1 in 15 for men and 1 in 17 for women.
• For ages 60 to 69, cancer risk is 1 in 6 for men and 1 in 10 for women.
• For those aged 70 and older, the risk is 1 in 3 for men and 1 in 4 for women.
• Men have a 44% lifetime risk of developing cancer, while women have a 38% lifetime risk.

Modifiable Risk Factors

• Nine modifiable risk factors are responsible for more than one-third of cancers worldwide:
  • Smoking
  • Alcohol consumption
  • Obesity
  • Physical inactivity
  • Low fruit and vegetable consumption
  • Unsafe sex
  • Air pollution
  • Indoor smoke from household fuels
  • Contaminated injections

Incidence of Cancers in the US (2020 Estimates)

• Prostate cancer is the most incident cancer in men, representing 21.5% of new cancer cases or 191,930.
• Breast cancer is the most incident cancer in women, representing 30.3% of new cancer cases or 276,480.
• Lung & bronchus cancers account for 8.8% of cancers in men (116,300 new cases) and 12.3% in women (112,520 new cases).
• Colon & rectum cancers account for 9.0% of cancers in men (78,300 new cases) and 7.6% in women (69,650 new cases).

Classification Systems

• Diagnosis is based on tissue biopsy.
• Fine-needle aspiration can be used for thyroid diagnosis.
• Tissue samples determine tumor histology, grade, invasiveness, and molecular diagnostic information (cell-surface markers, intracellular proteins).
• In cases involving an unknown primary: the patient presents with metastatic disease, and the primary is unknown.
• Identification of the primary involves age, sex, sites of involvement, histology, tumor markers, and personal and family history.

Concepts in Cancer

• Patient history and physical examination are important, including the duration of symptoms and any past medical and social history
• Social History: includes any occupational exposures and smoking and alcohol habits.
• Family history helps assess cancer risk in the family.
• ROS (review of systems) can identify early metaplastic disease or paraneoplastic syndrome
• Multidisciplinary Management: includes primary care, medical oncologist, radiation oncologist, oncology nurse specialist, pharmacist, social worker, rehabilitation specialist.

Methods of Staging Neoplasms

• The initial step involves determining the extent of the disease.
• Ideal Diagnosis: tumors are diagnosed with screening efforts.
• Patients often present with symptoms related to the cancer by mass effects or production of cytokines or hormones by the tumor.
• Assessment involves assessing the Extent of disease: can be invasive and noninvasive.
• Clinical Staging: involves physical examination, radiographs, isotopic scans, and CT scans.
• Pathologic Staging: involves intraoperative palpation, resection of regional lymph nodes and/or tissue, inspection and biopsy of organs commonly involved in disease spread, including histological examination of all tissues removed.
• Staging information helps to define the extent of disease.
• TNM (tumor, node, metastasis): This staging system is defined by the International Union Against Cancer and American Joint Committee on Cancer.
• Size of tumor lesion: ranges from T1-4. Higher number indicates larger size.
• Nodal involvement: N0 means there is no absence of nodal involvement, while N1 indicates it is presence.
• Presence of metastatic disease: M0 means metastasis is absent, where M1 means it is present.
• Staging info can be further defined by histology grade (G), stage with Roman numerals I-IV.
• Specialized classifications can also be used, like Duke's criteria for colorectal cancer. Ann Arbor for Hodgkin's

Tumor Markers

• Tumor markers are present in or produced by cancer cells and are found in blood, urine, stool, or tumors.
• Genomic markers are also used, including tumor gene mutations, patterns of tumor gene expression, and non-genetic changes in tumor DNA.
• Tumor markers are useful for estimating prognosis, detecting residual disease, assessing treatment response, and monitoring cancer, including resistance to treatment.
• Burkitt's Lymphoma: Includes t(8;14) that can initiate myc translocation and upregulation of bcl-2 which can prevent release of cytochrome c (will not activate caspase => will not have apoptosis)

Genomic Markers

• Proto-oncogenes: include ERBB2, RAS, ABL, and MYC
• Suppressor genes: include Tp53 and RB
• Anti-apoptosis genes: include BCL2
• DNA repair genes: mismatch, excision/repair pyrimidine dimers
• Apoptosis gene: includes BAX

Tumor Markers

• ABL is used for non-receptor TK activity and t(9:22); also CML
• HER (ERBB2) is useful for Receptor tyrosine-protein kinase erbB-2 and amplification; also Breast
• MYC is used for Nuclear transcription and T(8:14); also Burkitt's
• N-MYC is used for Nuclear transcription and Amplification; also Neuroblastoma
• RAS is used for GTP signal transduction and Point mutation; also Leukemia: lung, colon, pancreas
• APC prevents nuclear transcription and is a tumor suppressor; important for for Familial Polyposis and Colorectal/Gastric carcinoma
• BRCA1/BRCA2 produces proteins and regulates DNA repair; also Breast, ovary, prostate
• RB inhibits G1 to S phase and is a tumor suppressor; also Retinoblastoma and Osteosarcoma
• TP53 also inhibits G1 to S phase and is a tumor suppressor along with transcription factor; also Lung, colon, and breast