What are the high-risk HPV types? Why?
- HPV 16, 18, 31
- Implicated in the pathogenesis of squamous cell carcinomas of the cervix, anogenital region, and head and neck (particularly tumors arising in the tonsillar mucosa)
- These cancers are sexually transmitted infections, caused by transmission of HPV
What % of women with breast cancer have no symptoms of it at time of dx and it is detected by screening with mammography?
Describe how hepatocellular injury via chronic viral infection may lead to increased carcinogenesis.
- Leads to compensatory proliferation of hepatocytes
- Regenerative process aided by growth factors, cytokines, chemokines, and o/bioactive substances produced by activated immune cells -> promote cell survival, tissue remodeling, and angiogenesis
- Activated immune cells also produce other mediators, like ROS, that are genotoxic and mutagenic.
- 1 key molecular step is activation of NF-κB pathway in hepatocytes in response to mediators derived from the activated immune cells -> activation of this pathway in hepatocytes blocks apoptosis, allowing dividing cells to incur genotoxic stress and accumulate mutations
How has melanoma genome sequencing been used to reinforce the belief that sun exposure has an important causative role in this disease?
- Has revealed a very large number of mutations that appear to stem from non-templated, error-prone repair of pyrimidine dimers, reinforcing the belief that sun exposure has an important causative role in melanoma
What are nitrites?
- Used as food preservatives, and cause nitrosylation of amines contained in the food
- The nitrosoamines so formed are suspected to be carcinogenic
Once injected into a gastric mucosal epithelial cell, what does the virulence factor, CagA do?
- CagA PAI also encodes a type 4 secretion sys used to "inject" CagA into target cell upon H. pylori attachment
- CagA localizes to inner surface of cell membrane and undergoes tyrosine phosphorylation via Src family kinases -> phosphorylated CagA interacts with SHP-2 tyrosine phosphatase, so functionally active, triggering a host cell morphological change to more motile pheno
- This phenotype mimics effect produced by hepatocyte growth factor which may participate in various aspects of cancer, including metastasis (+ RAS, + MEK -> image)
- CagA a highly Ag protein associated with a prominent inflammatory response by eliciting IL-8 production
- Both CagA + and - strains; around 60% in Western countries positive, but majority in East Asian positive
How do translocations activate proto-oncogenes?
- While any type of chrom rearrangement can activate proto-oncogenes, translocation is most common mech
- Can activate proto-oncogenes in two ways:
1. Promoter/enhancer substitution: overexpression of proto-oncogene by swapping its regulatory elements with those of another gene, esp. one that is highly expressed
2. Formation of fusion gene: coding sequences of 2 genes fused in part or whole -> expression of novel chimeric protein w/oncogenic properties
What is going on in this stomach sample?
Cancer cells invading (top right and lower left)
What are the 3 acquired conditions that predispose to cancer?
- Chronic inflammatory disorders
- Precursor lesions
- Immunodeficiency states
How is epigenetics related to carcinogenesis?
- Epigenetics: factors other than the DNA seq that regulate gene expression -> important role in aspects of malignant phenotype, incl expression of cancer genes, control of differentiation and self-renewal, and even drug sensitivity and drug resistance
- Factors include:
1. Histone modifications catalyzed by enzymes associated with chromatin regulatory complexes
2. DNA methylation via DNA methyltransferases
3. Other proteins that regulate higher order org of DNA (e.g., looping enhancer elements on gene promoters)
How can proto-oncogenes and TSGs be tumor antigens?
- Products of altered proto-oncogenes, TSGs, and "passenger" genes translated in cyto of tumor cells and entering MHC I where they may be recognized via CD8
- May also enter MHC II in APCs that phagocytose dead tumor cells, and be recognized by CD4+ T cells, too
- Some pts have circulating CD4+ and CD8+ T cells that can respond to peptides from mutated oncoproteins like RAS, p53, and BCR-ABL.
How is HPV genome integration implicated in malignant transformation?
- While site of viral integration in host chromosomes is random, pattern of integration is clonal -> cells in which viral genome has integrated show significantly more genomic instability
- B/c integration site random, no consistent assoc with a host proto-oncogene, but, integration interrupts viral DNA in E1/E2 open reading frame, so loss of E2 viral repressor & overexpression of oncoproteins E6 and E7
- Oncogenic potential of HPV can largely be explained byactivities of the two viral genes encoding E6 and E7
What causes the carcinogenicity of UVB light?
- Due to formation of pyrimidine dimers in DNA
- If the energy in a photon of UV light is absorbed by DNA, a chemical rxn occurs, leading to covalent cross-linking of pyrimidine bases, esp. adjacent thymidine residues in the same strand of DNA
- Distorts DNA helix and prevents proper pairing of dimer with bases in opposite DNA strand
- Pyrimidine dimers are repaired via nucleotide excision repair pathway, but this pathway can be overwhelmed w/excessive sun exposure
Pause. And reflect. Also, memorize this graphic.
What are these? How do they relate to neoplasia?
- Cafe au lait spots
- Neurofibromatosis Type 1 (NF1): auto dom disorder caused by mutations in TSG, neurofibromin, a negative regulator of the oncoprotein, Ras
- Disruption of neurofibromin function, leading to Ras hyperactivity; cardinal feature of NF1-associated tumors
- As would be anticipated for a tumor suppressor gene, sole normal neurofibromin allele mutated or silenced in tumors arising in NF1, which include neurofibromas
- Symptoms: learning disabilities, seizures, skeletal abnormalities, vascular abnormalities, pigmented iris nodules (Lisch nodules), and pigmented skin lesions (axillary freckling, café au lait spots) in various degrees
What is this? Describe the symptoms, mechanisms and associated neoplasias.
- Coalescing nests of intestinal carcinoid (carcinoid syndrome)
- Symptoms: attacks of cutaneous flushing (deep red erythema of face and neck; may become persistent erythema or cyanosis), diarrhea, cramps, nausea, cough, vomiting, etc.
- Mechanisms: serotonin, bradykinin (vasodilator)
- Neoplasias: bronchial adenoma (carcinoid), pancreatic, gastric carcinoma
What is the difference between lymphomas and leukemias?
- Lymphomas: solid hematologic malignancies
- Leukemias: liquid hematologic malignancies
How do HPV proteins promote many of the hallmarks of cancer?
- High-risk HPV types express oncogenic proteins that:
1. Inactivate tumor suppressors (p53, Rb, p21, p27)
2. Activate cyclins (E and A)
3. Inhibit apoptosis, and
4. Combat cellular senescence
- NOTE: the primacy of HPV infection in the causation of cervical cancer is confirmed by the effectiveness of HPV vaccines in preventing cervical cancer
Diagnose this Pap.
LSIL (low-grade squamous epithelial lesion)
What is this?
Intestinal metaplasia due to H. pylori -> precursor to dysplasia and carcinoma
What is this? What is a potential precursor?
- Endometrial adenocarcinoma, potentially predicated by simple endometrial hyperplasia
What are some examples of the carcrinogenicity of radiation?
- Electromagnetic (x-rays, γ rays) and particulate (α particles, β particles, protons, neutrons) radiations
- Miners of radioactive elements in Rocky Mountains have 10x increased incidence of lung cancers
- Follow-up of survivors of atomic bombs: initially marked increase in incidence of certain leukemias after avg latent period of about 7 years; later, incidence of many solid tumors with longer latent periods (e.g., carcinomas of the breast, colon, thyroid, and lung) increased
I know this says what it is. Just observe.
Cervical squamous cell carcinoma
Describe the actions of the HPV E7 virulence factor.
- E7 protein effects complement those of E6, centered on moving cells past G1/S cell cycle checkpoint
- Binds Rb protein, displacing E2F transcription factors normally sequestered by Rb, promoting progression through cell cycle (high-risk HPV E7 has higher affinity for Rb than low-risk HPV)
- E7 also inactivates CDK inhibitors p21 and p27
- High-risk HPVs (types 16, 18, and 31) E7 also binds and presumably activate cyclins E and A
Describe why CT scans are a concern for child health.
- Widespread use of computerized tomography (CT scans)
- Studies show that children who get 2 or 3 CT scans have 3x higher risk of leukemia, and those that have 5 to 10 scans have a 3x higher risk of brain tumors
- Overall risk in children is very low (roughly one excess leukemia and one excess brain tumor over 10 years per 10,000 CT scans), but emphasizes the need to minimize radiation exposure whenever possible
What is the difference b/t HPV genome integration in benign vs. cancerous papillomas? Why is this important?
- Benign warts: HPV genome maintained in non-integrated episomal form
- Cancers: HPV genome integrated into host genome
- Suggests that integration of viral DNA important for malignant transformation
How does DNA amplification lead to overexpression of oncogenes? Describe the two most important amplifications.
- May produce up to several hundred copies of the oncogene in the tumor cell
- Two mutually exclusive patterns are seen:
1. Multiple small extrachromosomal structures called double minutes
2. Homogeneous staining regions (HSRs): inserts of amplified genes in new chrom locations that may be distant from normal oncogene location
- 2 most important amplifications are:
1. NMYC: amplified in 25%-30% of neuroblastomas, and associated with poor prognosis
2. ERBB2: AMP in 20% of breast cancers -> Ab therapy directed against HER2 receptor encoded by ERBB2 an effective therapy (Trastuzumab)
Describe the epidemiology of childhood cancer.
- Accounts for 10% of deaths in children under 15 in US; about 60% of these deaths due to acute leukemias and brain tumors
- Very different types than those that occur in adults: leukemia, neuroblastoma, Wilms, retinoblastoma, and rhabdomyosarcoma most common in children (and carcinomas extraordinarily rare)
- Children get brain tumors more than adults, inlc. types that don't occur in adults; most are technically benign, but tend to be fatal b/c can't be sx removed, and often don't respond to non-sx therapies, so their autonomous growth in un-expandable skull compresses vital brain structures
How do chromosomal deletions cause loss of TSGs or the formation of oncogenes. Provide some examples.
- Very prevalent structural abnormality in tumor cells
- Deletion of specific regions of chroms associated with the loss of particular TSGs:
1. Deletions involving chromosome 13q14, site of the Rb gene, associated with retinoblastoma
2. Deletion of the VHL on chromosome 3p a very common event in renal cell carcinomas
- Not all deletions lead to loss of gene function; a few activate oncogenes through same mechanisms as chromosomal translocations:
1. Deletions on chrom 2q in subset of lung cancers produce an oncogenic EML4-ALK fusion gene encoding a constitutively active tyrosine kinase
2. It is likely that more “cryptic” deletions that activate oncogenes will be discovered
Why is there geographic variation in cancer prevalence?
- Thought to mainly stem from different environmental exposures
- Important environmental factors implicated in carcinogenesis include: infectious agents, smoking, alcohol, diet, obesity, reproductive history, and carcinogens