19: Carcinogenesis and Skin

Question 1

What is the annual incidence of skin carcinomas compared to all other cancers?

Answer 1

The annual incidence of skin carcinomas is twofold higher than all other cancers combined.

Question 2

What are the primary causes of most skin cancers?

Answer 2

Most skin cancers are caused by UV radiation, along with other causes such as chemical carcinogens and oncogenic viruses.

Question 3

What is a notable exception in the pathogenesis of Basal Cell Carcinoma (BCC)?

Answer 3

A notable exception in the pathogenesis of BCC is that there are no precursor lesions identified and metastases are extremely rare.

Question 4

What are the fundamental alterations in cancers?

Answer 4

The fundamental alterations in cancers include:

1. Reduced requirement for growth stimuli
2. Increased responses to growth inhibitory and differentiation signals
3. Alterations in apoptosis
4. Delayed/blocked senescence
5. Angiogenesis
6. Invasion and metastasis
7. Metabolic programming
8. Evasion of elimination by the immune system

*All are present in advanced cancers.

Question 5

What is the difference between oncogenes and tumor suppressor genes?

Answer 5

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.

Question 6

What is the relationship between the PTCH1 gene and skin cancer risk?

Answer 6

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.

Question 7

What is the significance of the Hedgehog signaling pathway in BCC?

Answer 7

The Hedgehog signaling pathway is almost exclusively involved in the pathogenesis of Basal Cell Carcinoma (BCC), indicating its critical role in tumorigenesis.

Question 8

What genetic defect is responsible for xeroderma pigmentosum, and how does it increase cancer risk?

Answer 8

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.

Question 9

What syndrome is associated with a mutation in the PTCH1 gene, and what are its other clinical features?

Answer 9

The PTCH1 gene mutation is associated with Nevoid Basal Cell Carcinoma Syndrome, which includes cerebellar tumors, medulloblastoma, bifid ribs, frontal bossing, and palmar pits.

Question 10

What are the primary causes of skin cancers, and how do they differ between BCC and SCC?

Answer 10

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.

Question 11

What is the significance of intratumor heterogeneity in skin cancers, particularly in BCC and SCC?

Answer 11

Intratumor heterogeneity refers to the phenotypic differences within tumors, which can lead to:

1. Molecular heterogeneity: Different cell populations may acquire mutations that confer a proliferative or survival advantage, allowing them to invade and metastasize.
2. 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.

Question 12

How do oncogenes and tumor suppressor genes differ in their roles in skin cancer development?

Answer 12

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 |

Question 13

What are the implications of cancer stem cells in the treatment of skin cancers?

Answer 13

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.

Question 14

What is the role of the Hedgehog pathway in BCC tumorigenesis?

Answer 14

The Hedgehog pathway is almost exclusively involved in BCC tumorigenesis, where uncontrolled activation of this single oncogenic pathway is sufficient for tumor development.

Question 15

What are the two types of intratumor heterogeneity observed in tumors, and how do they differ?

Answer 15

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.

Question 16

Why are cancer stem cells significant in cancer therapy?

Answer 16

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.

Question 17

What is the cellular origin of superficial basal cell carcinoma (BCC), and how does it differ from nodular BCC?

Answer 17

Superficial BCC originates from epidermal basal cells, while nodular BCC originates from hair follicle epithelium.

Question 18

What is the driving force behind neoplastic progression in tumors with defective DNA repair?

Answer 18

The driving force behind neoplastic progression in tumors with defective DNA repair is the accumulation of mutations that confer proliferative or survival advantages.

Question 19

What factors contribute to intertumor heterogeneity?

Answer 19

Intertumor heterogeneity arises from phenotypic differences between tumors, transformation of different cell populations, and disparate growth rates of histologically similar tumor types.

Question 20

What is the significance of metabolic reprogramming in cancer biology?

Answer 20

Metabolic reprogramming in cancer allows tumor cells to adapt their metabolism to support rapid growth and survival under adverse conditions.

Question 21

Why is angiogenesis critical for tumor progression?

Answer 21

Angiogenesis is critical for tumor progression as it provides the tumor with a blood supply, delivering oxygen and nutrients necessary for growth and metastasis.

Question 22

What mechanisms might a tumor use to evade immune system elimination?

Answer 22

Tumors evade immune system elimination by altering antigen presentation, secreting immunosuppressive factors, and inducing regulatory T cells.

Question 23

How does delayed senescence contribute to cancer progression?

Answer 23

Delayed senescence allows tumor cells to bypass normal cellular aging processes, enabling continued proliferation and tumor growth.

Question 24

How do alterations in apoptosis contribute to cancer progression?

Answer 24

Alterations in apoptosis allow tumor cells to evade programmed cell death, leading to uncontrolled cell survival and proliferation.

Question 25

How does increased response to growth inhibitory signals differ from normal cellular behavior?

Answer 25

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.

Question 26

How does reduced requirement for growth stimuli benefit a tumor?

Answer 26

Reduced requirements for growth stimuli enable tumor cells to proliferate independently of external growth signals, promoting unchecked growth.

Question 27

What are the key steps involved in invasion and metastasis?

Answer 27

Invasion and metastasis involve tumor cells breaching the basement membrane, invading surrounding tissues, entering the bloodstream or lymphatics, and colonizing distant sites.

Question 28

What is the primary etiologic agent for all skin cancers?

Answer 28

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.

Question 29

What are the most frequently mutated tumor suppressor genes (TSGs) in skin cancer?

Answer 29

The most frequently mutated TSGs in skin cancer include TP53, CDKN2a, NOTCH, cadherin FAT, KMT2C, and KNSTRN.

Question 30

What is the significance of ERK signaling in squamous cell carcinoma (SCC)?

Answer 30

ERK signaling is important in SCC, and MEK inhibition has potential therapeutic and chemopreventive effects.

Question 31

How does UV radiation induce DNA damage?

Answer 31

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).

Question 32

What is the mutation burden in chronically UV-exposed skin?

Answer 32

Chronically UV-exposed skin harbors five mutations per megabase of DNA, indicating a high mutation burden.

Question 33

What role do alpha and beta HPVs play in skin cancer?

Answer 33

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).

Question 34

What is the mechanism behind squamous cell carcinomas (SCCs) developing in patients treated with Vemurafenib?

Answer 34

Vemurafenib, a BRAF inhibitor, can cause paradoxical ERK signaling, leading to hyperactivation of MEK/ERK signaling and suppression of apoptosis, which promotes SCC development.

Question 35

What is the increased risk of SCC associated with PUVA therapy?

Answer 35

PUVA therapy increases the risk of SCC by 100-fold.

Question 36

What is the signature UV mutation, and what type of DNA damage does it involve?

Answer 36

The signature UV mutation is CC->TT, involving cyclobutane pyrimidine dimers caused by UVB-induced DNA damage.

Question 37

Which viral proteins are involved in tumorigenesis in patients with a history of HPV infection?

Answer 37

HPV E6 binds to TP53, and E7 binds to RB1, driving tumorigenesis.

Question 38

How does the molecular profile of actinic keratosis (AK) compare to squamous cell carcinoma (SCC)?

Answer 38

The molecular profiles of actinic keratosis (AK) and squamous cell carcinoma (SCC) are indistinguishable.

Question 39

What is the role of viruses in Kaposi sarcoma?

Answer 39

Kaposi sarcoma is associated with viral carcinogenesis, where viruses hijack the host cell cycle machinery to replicate their genome, especially under immunosuppression.

Question 40

How does chronic exposure to UV radiation contribute to cancer development?

Answer 40

**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.

Question 41

What are the most common UV radiation-induced DNA photoproducts and their significance?

Answer 41

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.

Question 42

How does the mutation burden in chronically UV-exposed skin compare to normal skin?

Answer 42

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.

Question 43

What role do alpha and beta HPVs play in skin cancer, and how do they influence tumorigenesis?

Answer 43

**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.

Question 44

What is the significance of ERK signaling in the context of squamous cell carcinoma (SCC)?

Answer 44

**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.

Question 45

What type of DNA damage causes cyclobutane pyrimidine dimers, and how are they repaired?

Answer 45

Cyclobutane pyrimidine dimers are caused by UVB-induced DNA damage and are repaired by nucleotide excision repair mechanisms.

Question 46

What reactive species is involved in G->T transversions, and how is it generated?

Answer 46

G->T transversions are caused by adenine opposite 8-hydroxy-2-deoxyguanosine, generated by UV-induced reactive oxygen species (ROS) such as peroxynitrite.

Question 47

What are 'dark CPDs,' and how do they form?

Answer 47

'Dark CPDs' are cyclobutane pyrimidine dimers that form continuously after UV exposure has ceased, accounting for half of CPDs in melanocytes.

Question 48

How many mutations are typically found per megabase of DNA in chronically UV-exposed skin?

Answer 48

Chronically UV-exposed skin harbors five mutations per megabase of DNA.

Question 49

How does beta HPV contribute to tumorigenesis?

Answer 49

Beta HPV influences oncogenic effectors and processes to drive tumorigenesis, particularly in patients with epidermodysplasia verruciformis (EDV).

Question 50

How does beta HPV contribute to tumorigenesis in patients with a history of UV exposure?

Answer 50

Beta HPV influences oncogenic effectors and processes to drive tumorigenesis, particularly in patients with epidermodysplasia verruciformis (EDV).

Question 51

What are the high-risk types of alpha HPV and the cancers they are associated with?

Answer 51

High-risk types of alpha HPV include HPV 16 and 18, which are associated with cervical, anorectal, genital, and oropharyngeal cancers.

Question 52

What are the known chemical agents identified as human skin carcinogens?

Answer 52

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.

Question 53

What is the relationship between childhood exposure to ionizing radiation and skin cancer risk?

Answer 53

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.

Question 54

What are the cellular origins of Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC)?

Answer 54

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 |

Question 55

What is the significance of the simultaneous inactivation of Rb1 and Trp53 in the epidermis?

Answer 55

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.

Question 56

What is the role of DMBA in chemically induced skin cancer in rodents?

Answer 56

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.

Question 57

What is the effect of nicotinamide on skin cancer prevention?

Answer 57

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.

Question 58

What is the likely latency period for basal cell carcinoma (BCC) after childhood exposure to ionizing radiation?

Answer 58

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.

Question 59

What occupational exposure might have contributed to a pilot's melanoma diagnosis?

Answer 59

Pilots are exposed to cosmic ionizing radiation, which contributes to melanoma. The relative risk increase for melanoma in pilots is 3.5-fold.

Question 60

What other skin condition is associated with arsenic exposure?

Answer 60

Arsenic exposure is also associated with arsenical keratosis.

Question 61

What type of skin cancer is most commonly associated with Marjolin’s ulcer?

Answer 61

Marjolin’s ulcer is most commonly associated with squamous cell carcinoma (SCC), with a typical latency period of 37 years.

Question 62

What virus is most commonly associated with Merkel cell carcinoma (MCC)?

Answer 62

Merkel cell carcinoma (MCC) is most commonly associated with MCPyV, and its viral DNA is clonally integrated in MCCs.

Question 63

What other chemical carcinogens are known to cause squamous cell carcinoma (SCC)?

Answer 63

Other chemical carcinogens known to cause SCC include azathioprine, cyclosporine, mineral oil, and soots.

Question 64

What is the role of 8-methoxypsoralen in relation to solar radiation exposure?

Answer 64

8-Methoxypsoralen, when combined with solar radiation, increases the risk of melanoma.

Question 65

Who first identified the association between soot exposure and scrotal cancer?

Answer 65

Sir Percivall Pott first identified the association between soot exposure and scrotal cancer, attributing it to repeated exposure to chemical carcinogens in soot.

Question 66

What is the cellular origin of basal cell carcinoma (BCC) and what marker supports this origin?

Answer 66

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.

Question 67

What is the cellular origin of squamous cell carcinoma (SCC) and how does it differ from BCC?

Answer 67

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.

Question 68

What is the primary oncogenic mutation caused by DMBA?

Answer 68

DMBA causes activating Hras mutations, most often at Q61, with over 90% frequency.

Question 69

What specific reductions in skin cancer incidence are observed with nicotinamide supplementation?

Answer 69

Nicotinamide supplementation results in a 20% reduction in BCC and a 30% reduction in SCC at 3 months.

Question 70

What are the implications of childhood exposure to ionizing radiation in relation to BCC risk?

Answer 70

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.

Question 71

How do SCCs differ from BCCs in terms of cellular origin?

Answer 71

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.

Question 72

What role does the Hras mutation play in chemically induced skin cancer in rodents?

Answer 72

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.

Question 73

What is the significance of the Hedgehog pathway in BCC mouse models?

Answer 73

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.

Question 74

What are the hallmark characteristics of cancer as influenced by UV radiation?

Answer 74

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.

Question 75

What are the key steps in the process of UV radiation-induced carcinogenesis?

Answer 75

1. 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.

Question 76

How do different types of UV radiation contribute to mutagenesis?

Answer 76

UVA primarily causes oxidative damage, while UVB leads to more direct DNA damage, resulting in specific mutations.

Question 77

What are the genetic changes associated with the development of cutaneous squamous cell carcinoma (SCC)?

Answer 77

Key genetic changes include mutations in TP53, NOTCH1, and HRAS. In mice, mutations in mut Tpr1, mut Nras, and mut Hras are also noted.

Question 78

What are some known human carcinogens associated with skin cancer?

Answer 78

Known human carcinogens include arsenic, azathioprine, coal tar, coke oven emissions, cyclophosphamide, ionizing radiation, 8-methoxypsoralen, mineral oils, soots, and solar radiation.

Question 79

What is the significance of the burden of mutations in sun-exposed normal skin?

Answer 79

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.