19: Carcinogenesis and Skin Flashcards
What is the annual incidence of skin carcinomas compared to all other cancers?
The annual incidence of skin carcinomas is twofold higher than all other cancers combined.
What are the primary causes of most skin cancers?
Most skin cancers are caused by UV radiation, along with other causes such as chemical carcinogens and oncogenic viruses.
What is a notable exception in the pathogenesis of Basal Cell Carcinoma (BCC)?
A notable exception in the pathogenesis of BCC is that there are no precursor lesions identified and metastases are extremely rare.
What are the fundamental alterations in cancers?
The fundamental alterations in cancers include:
- Reduced requirement for growth stimuli
- Increased responses to growth inhibitory and differentiation signals
- Alterations in apoptosis
- Delayed/blocked senescence
- Angiogenesis
- Invasion and metastasis
- Metabolic programming
- Evasion of elimination by the immune system
*All are present in advanced cancers.
What is the difference between oncogenes and tumor suppressor genes?
Oncogenes are genes that transform normal cells in culture and induce cancer in animals, derived from proto-oncogenes that act as positive regulators of cell proliferation.
Tumor suppressor genes negatively regulate cell proliferation, cause apoptosis, repair damaged DNA, and induce cellular differentiation. Both alleles must be inactivated to promote tumor development, unlike oncogenes where only one allele is required for activation.
What is the relationship between the PTCH1 gene and skin cancer risk?
The PTCH1 gene is associated with Xeroderma Pigmentosum, which significantly increases the risk of skin cancer by 10,000-fold before the age of 20 due to a defect in nucleotide excision repair.
What is the significance of the Hedgehog signaling pathway in BCC?
The Hedgehog signaling pathway is almost exclusively involved in the pathogenesis of Basal Cell Carcinoma (BCC), indicating its critical role in tumorigenesis.
What genetic defect is responsible for xeroderma pigmentosum, and how does it increase cancer risk?
Xeroderma pigmentosum is caused by a defect in nucleotide excision repair, leading to a 10,000-fold increased risk of skin cancer before the age of 20.
What syndrome is associated with a mutation in the PTCH1 gene, and what are its other clinical features?
The PTCH1 gene mutation is associated with Nevoid Basal Cell Carcinoma Syndrome, which includes cerebellar tumors, medulloblastoma, bifid ribs, frontal bossing, and palmar pits.
What are the primary causes of skin cancers, and how do they differ between BCC and SCC?
The primary causes of skin cancers include:
- UV radiation: Most skin cancers are caused by this.
- Chemical carcinogens: Contribute to skin cancer development.
- Oncogenic viruses: Another contributing factor.
Differences between BCC and SCC:
- BCC: Almost exclusively associated with the Hedgehog pathway.
- SCC: Relies on a varied set of gene mutations and oncogenic signaling.
What is the significance of intratumor heterogeneity in skin cancers, particularly in BCC and SCC?
Intratumor heterogeneity refers to the phenotypic differences within tumors, which can lead to:
- Molecular heterogeneity: Different cell populations may acquire mutations that confer a proliferative or survival advantage, allowing them to invade and metastasize.
- Biochemical heterogeneity: Tumor cells exhibit distinct oncogenic signaling properties and behaviors.
In BCC, this can result in different tumor subtypes such as superficial and nodular BCC, while in SCC, it can lead to varied growth rates of histologically similar tumors.
How do oncogenes and tumor suppressor genes differ in their roles in skin cancer development?
Oncogenes and tumor suppressor genes play opposing roles in cancer development:
Feature | Oncogenes | Tumor Suppressor Genes |
|———|———–|———————–|
| Function | Transform normal cells and induce cancer | Negatively regulate cell proliferation and induce apoptosis |
| Activation | Requires only one allele to be mutated | Requires both alleles to be inactivated for tumor development |
| Origin | Derived from proto-oncogenes | Typically involved in DNA repair and cellular differentiation |
What are the implications of cancer stem cells in the treatment of skin cancers?
Cancer stem cells are crucial in the treatment of skin cancers because:
- They represent a small population of self-renewing stem cells that can give rise to the majority of tumor cells.
- Targeting and effectively eliminating these cancer stem cells may lead to cures by removing the key cell population from which all remaining tumor cells arise.
- Understanding the properties of these cells can inform therapeutic strategies aimed at achieving long-term remission.
What is the role of the Hedgehog pathway in BCC tumorigenesis?
The Hedgehog pathway is almost exclusively involved in BCC tumorigenesis, where uncontrolled activation of this single oncogenic pathway is sufficient for tumor development.
What are the two types of intratumor heterogeneity observed in tumors, and how do they differ?
The two types of intratumor heterogeneity are molecular heterogeneity, which involves selection for cells with mutations conferring survival advantages, and biochemical heterogeneity, where tumor cells exhibit distinct oncogenic signaling properties.
Why are cancer stem cells significant in cancer therapy?
Cancer stem cells are significant because they are self-renewing and produce progeny that constitute the majority of tumor cells. Therapies targeting these cells may lead to cures by eliminating the key population from which all tumor cells arise.
What is the cellular origin of superficial basal cell carcinoma (BCC), and how does it differ from nodular BCC?
Superficial BCC originates from epidermal basal cells, while nodular BCC originates from hair follicle epithelium.
What is the driving force behind neoplastic progression in tumors with defective DNA repair?
The driving force behind neoplastic progression in tumors with defective DNA repair is the accumulation of mutations that confer proliferative or survival advantages.
What factors contribute to intertumor heterogeneity?
Intertumor heterogeneity arises from phenotypic differences between tumors, transformation of different cell populations, and disparate growth rates of histologically similar tumor types.
What is the significance of metabolic reprogramming in cancer biology?
Metabolic reprogramming in cancer allows tumor cells to adapt their metabolism to support rapid growth and survival under adverse conditions.
Why is angiogenesis critical for tumor progression?
Angiogenesis is critical for tumor progression as it provides the tumor with a blood supply, delivering oxygen and nutrients necessary for growth and metastasis.
What mechanisms might a tumor use to evade immune system elimination?
Tumors evade immune system elimination by altering antigen presentation, secreting immunosuppressive factors, and inducing regulatory T cells.
How does delayed senescence contribute to cancer progression?
Delayed senescence allows tumor cells to bypass normal cellular aging processes, enabling continued proliferation and tumor growth.
How do alterations in apoptosis contribute to cancer progression?
Alterations in apoptosis allow tumor cells to evade programmed cell death, leading to uncontrolled cell survival and proliferation.
How does increased response to growth inhibitory signals differ from normal cellular behavior?
Increased responses to growth inhibitory signals in tumors involve alterations that allow cells to proliferate despite inhibitory cues, unlike normal cells that halt growth under such conditions.
How does reduced requirement for growth stimuli benefit a tumor?
Reduced requirements for growth stimuli enable tumor cells to proliferate independently of external growth signals, promoting unchecked growth.
What are the key steps involved in invasion and metastasis?
Invasion and metastasis involve tumor cells breaching the basement membrane, invading surrounding tissues, entering the bloodstream or lymphatics, and colonizing distant sites.
What is the primary etiologic agent for all skin cancers?
UV radiation is the primary etiologic agent for all skin cancers and is considered a complete carcinogen, meaning chronic exposure alone is enough to induce cancer.
What are the most frequently mutated tumor suppressor genes (TSGs) in skin cancer?
The most frequently mutated TSGs in skin cancer include TP53, CDKN2a, NOTCH, cadherin FAT, KMT2C, and KNSTRN.
What is the significance of ERK signaling in squamous cell carcinoma (SCC)?
ERK signaling is important in SCC, and MEK inhibition has potential therapeutic and chemopreventive effects.
How does UV radiation induce DNA damage?
UV radiation induces DNA damage by creating photoproducts, primarily cyclobutane pyrimidine dimers, which occur when UVB and UVC are absorbed at the double bonds of pyrimidines (T and C).
What is the mutation burden in chronically UV-exposed skin?
Chronically UV-exposed skin harbors five mutations per megabase of DNA, indicating a high mutation burden.
What role do alpha and beta HPVs play in skin cancer?
Alpha HPVs are closely linked to cancer, with low-risk types causing condyloma and high-risk types associated with cervical, anorectal, genital, and oropharyngeal cancers. Beta HPVs are linked to warts and SCC in patients with epidermodysplasia verruciformis (EDV).
What is the mechanism behind squamous cell carcinomas (SCCs) developing in patients treated with Vemurafenib?
Vemurafenib, a BRAF inhibitor, can cause paradoxical ERK signaling, leading to hyperactivation of MEK/ERK signaling and suppression of apoptosis, which promotes SCC development.
What is the increased risk of SCC associated with PUVA therapy?
PUVA therapy increases the risk of SCC by 100-fold.
What is the signature UV mutation, and what type of DNA damage does it involve?
The signature UV mutation is CC->TT, involving cyclobutane pyrimidine dimers caused by UVB-induced DNA damage.
Which viral proteins are involved in tumorigenesis in patients with a history of HPV infection?
HPV E6 binds to TP53, and E7 binds to RB1, driving tumorigenesis.
How does the molecular profile of actinic keratosis (AK) compare to squamous cell carcinoma (SCC)?
The molecular profiles of actinic keratosis (AK) and squamous cell carcinoma (SCC) are indistinguishable.
What is the role of viruses in Kaposi sarcoma?
Kaposi sarcoma is associated with viral carcinogenesis, where viruses hijack the host cell cycle machinery to replicate their genome, especially under immunosuppression.
How does chronic exposure to UV radiation contribute to cancer development?
UV radiation (UVR) is the primary etiologic agent for all skin cancers and is considered a complete carcinogen. Chronic exposure to UVR alone is sufficient to induce cancer.
What are the most common UV radiation-induced DNA photoproducts and their significance?
The most common UV radiation-induced DNA photoproducts are cyclobutane pyrimidine dimers, particularly TT, as well as TC and CT. These photoproducts result from UVB and UVC absorption at the double bonds of pyrimidines, leading to DNA damage that can contribute to carcinogenesis.
How does the mutation burden in chronically UV-exposed skin compare to normal skin?
Chronically UV-exposed skin harbors five mutations per megabase of DNA, indicating a significantly higher mutation burden compared to normal skin, which is crucial for understanding the evolution of skin cancers.
What role do alpha and beta HPVs play in skin cancer, and how do they influence tumorigenesis?
Alpha HPVs are closely linked to skin cancer, with low-risk types causing condyloma and high-risk types associated with cervical and other cancers. They drive tumorigenesis by binding to tumor suppressor genes such as E6 - TP53 and E7 - RB1. Beta HPVs are associated with warts and SCC in patients with epidermodysplasia verruciformis (EDV) but are not required for tumor maintenance.
What is the significance of ERK signaling in the context of squamous cell carcinoma (SCC)?
ERK signaling is important in SCC, as it is involved in the development and progression of the disease. Inhibition of MEK has potential therapeutic and chemopreventive effects, highlighting the need for targeted therapies in SCC management.
What type of DNA damage causes cyclobutane pyrimidine dimers, and how are they repaired?
Cyclobutane pyrimidine dimers are caused by UVB-induced DNA damage and are repaired by nucleotide excision repair mechanisms.
What reactive species is involved in G->T transversions, and how is it generated?
G->T transversions are caused by adenine opposite 8-hydroxy-2-deoxyguanosine, generated by UV-induced reactive oxygen species (ROS) such as peroxynitrite.
What are ‘dark CPDs,’ and how do they form?
‘Dark CPDs’ are cyclobutane pyrimidine dimers that form continuously after UV exposure has ceased, accounting for half of CPDs in melanocytes.
How many mutations are typically found per megabase of DNA in chronically UV-exposed skin?
Chronically UV-exposed skin harbors five mutations per megabase of DNA.
How does beta HPV contribute to tumorigenesis?
Beta HPV influences oncogenic effectors and processes to drive tumorigenesis, particularly in patients with epidermodysplasia verruciformis (EDV).
How does beta HPV contribute to tumorigenesis in patients with a history of UV exposure?
Beta HPV influences oncogenic effectors and processes to drive tumorigenesis, particularly in patients with epidermodysplasia verruciformis (EDV).
What are the high-risk types of alpha HPV and the cancers they are associated with?
High-risk types of alpha HPV include HPV 16 and 18, which are associated with cervical, anorectal, genital, and oropharyngeal cancers.
What are the known chemical agents identified as human skin carcinogens?
The known chemical agents identified as human skin carcinogens include arsenic, azathioprine, coal tar, coke-oven emissions, cyclosporine A, 8-methoxypsoralen, mineral oils, and soots.
What is the relationship between childhood exposure to ionizing radiation and skin cancer risk?
Childhood exposure to ionizing radiation is associated with a significantly increased risk of Basal Cell Carcinoma (BCC) with a latency of over 20 years, particularly in fair-complected individuals.
What are the cellular origins of Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC)?
The cellular origins are:
Cancer Type | Cellular Origin |
|————-|—————-|
| BCC | Epidermal basal layer or hair follicle outer root sheath |
| SCC | Epidermis, with cells undergoing terminal differentiation to form squames resembling cells in the cornified layer of epidermis |
What is the significance of the simultaneous inactivation of Rb1 and Trp53 in the epidermis?
The simultaneous inactivation of Rb1 and Trp53 in the epidermis is sufficient to induce Squamous Cell Carcinoma (SCC) in mice, indicating a critical role of these tumor suppressor genes in skin cancer development.
What is the role of DMBA in chemically induced skin cancer in rodents?
DMBA (7,12-dimethylbenz[a]anthracene) is applied initially and is metabolized into a potent mutagen that causes activating Hras mutations, most often at Q61 with over 90% frequency, leading to skin cancer development in rodents.
What is the effect of nicotinamide on skin cancer prevention?
Nicotinamide has been shown to reduce the incidence of skin cancers, with a 20% and 30% reduction of Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC), respectively, at 3 months, and an 11% reduction in actinic keratoses.
What is the likely latency period for basal cell carcinoma (BCC) after childhood exposure to ionizing radiation?
The latency period for BCC after childhood exposure to ionizing radiation is over 20 years. Factors contributing to this risk include fair complexion and the interaction between UV and ionizing radiation exposures.
What occupational exposure might have contributed to a pilot’s melanoma diagnosis?
Pilots are exposed to cosmic ionizing radiation, which contributes to melanoma. The relative risk increase for melanoma in pilots is 3.5-fold.
What other skin condition is associated with arsenic exposure?
Arsenic exposure is also associated with arsenical keratosis.
What type of skin cancer is most commonly associated with Marjolin’s ulcer?
Marjolin’s ulcer is most commonly associated with squamous cell carcinoma (SCC), with a typical latency period of 37 years.
What virus is most commonly associated with Merkel cell carcinoma (MCC)?
Merkel cell carcinoma (MCC) is most commonly associated with MCPyV, and its viral DNA is clonally integrated in MCCs.
What other chemical carcinogens are known to cause squamous cell carcinoma (SCC)?
Other chemical carcinogens known to cause SCC include azathioprine, cyclosporine, mineral oil, and soots.
What is the role of 8-methoxypsoralen in relation to solar radiation exposure?
8-Methoxypsoralen, when combined with solar radiation, increases the risk of melanoma.
Who first identified the association between soot exposure and scrotal cancer?
Sir Percivall Pott first identified the association between soot exposure and scrotal cancer, attributing it to repeated exposure to chemical carcinogens in soot.
What is the cellular origin of basal cell carcinoma (BCC) and what marker supports this origin?
The cellular origin of BCC is the epidermal basal layer or hair follicle outer root sheath, supported by the expression of the ORS marker keratin 17.
What is the cellular origin of squamous cell carcinoma (SCC) and how does it differ from BCC?
The cellular origin of SCC is the epidermis, as SCC cells undergo terminal differentiation to form squames, unlike BCC, which originates from the hair follicle outer root sheath.
What is the primary oncogenic mutation caused by DMBA?
DMBA causes activating Hras mutations, most often at Q61, with over 90% frequency.
What specific reductions in skin cancer incidence are observed with nicotinamide supplementation?
Nicotinamide supplementation results in a 20% reduction in BCC and a 30% reduction in SCC at 3 months.
What are the implications of childhood exposure to ionizing radiation in relation to BCC risk?
Childhood exposure to ionizing radiation is associated with a significantly increased risk of BCC with a latency of over 20 years, particularly in fair-complected individuals.
How do SCCs differ from BCCs in terms of cellular origin?
SCCs harbor cells that undergo terminal differentiation to form squames resembling cells in the cornified layer of epidermis, indicating that SCCs are derived from epidermis rather than hair follicles, while BCC tumor cells originate from the epidermal basal layer or hair follicle outer root sheath.
What role does the Hras mutation play in chemically induced skin cancer in rodents?
The Hras mutation is activated by DMBA, which is metabolized into a potent mutagen, causing mutations most often at Q61 with over 90% frequency, leading to the development of skin cancer in rodent models.
What is the significance of the Hedgehog pathway in BCC mouse models?
The Hedgehog pathway is significant in BCC mouse models as it is involved in the development and progression of Basal Cell Carcinoma (BCC), indicating a potential target for therapeutic intervention.
What are the hallmark characteristics of cancer as influenced by UV radiation?
The hallmark characteristics of cancer include sustaining proliferative signaling, evading growth suppressors, avoiding immune destruction, enabling replicative immortality, deregulating cellular energetics, resisting cell death, genome instability and mutation, inducing angiogenesis, activating invasion and metastasis, and tumor-promoting inflammation.
What are the key steps in the process of UV radiation-induced carcinogenesis?
- DNA lesions occur due to UV exposure, primarily cyclobutane dimers. 2. DNA damage responses include cell cycle arrest, DNA repair mechanisms, and apoptosis. 3. DNA mutations can lead to dysfunctional tumor suppressors, enhancing UV carcinogenesis. 4. Clonal expansion and additional mutations contribute to tumor formation and malignant progression.
How do different types of UV radiation contribute to mutagenesis?
UVA primarily causes oxidative damage, while UVB leads to more direct DNA damage, resulting in specific mutations.
What are the genetic changes associated with the development of cutaneous squamous cell carcinoma (SCC)?
Key genetic changes include mutations in TP53, NOTCH1, and HRAS. In mice, mutations in mut Tpr1, mut Nras, and mut Hras are also noted.
What are some known human carcinogens associated with skin cancer?
Known human carcinogens include arsenic, azathioprine, coal tar, coke oven emissions, cyclophosphamide, ionizing radiation, 8-methoxypsoralen, mineral oils, soots, and solar radiation.
What is the significance of the burden of mutations in sun-exposed normal skin?
The burden of mutations in sun-exposed normal skin indicates the cumulative effect of UV exposure on skin cells, leading to a higher risk of developing skin cancers such as SCC and BCC.
