19 - Carcinogenesis and Skin Flashcards by dvojnd rivera

Combined incidence of SCC and BCC is likely to be at least _____fold higher than that of all other cancers combined

Two

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Whereas single base mutations in early SCC lesions frequently are characteristic of _____-induced damage, later changes are associated with _____

UV light

Genomic instability

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_____ mutations are characteristic of chemical mutagens used to initiate tumor formation

Ras

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Most events occur early in the progression sequence in (UV-induced tumors/chemical carcinogenesis), but in (UV-induced tumors/chemical carcinogenesis), most events occur late and often do not bear the signatures of the original mutagen

UV-induced tumors

Chemical carcinogenesis

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A driving force underlying neoplastic progression is ______, which enables the accumulation of mutations involving oncogenes and tumor suppressor genes that contribute to the observed abberations in tumor cell function

Defective DNA repair

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Tumors contain a small number of self-renewing stem cells that produce transient-amplifying and differentiating progeny

Cancer stem cells or

Tumor-initiating cells

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Constitute the overwhelming majority if cells in a tumor

Transient-amplifying and differentiating progeny

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Y/N: Transformation of different cell populations produces different tumor subtypes, so a tumor’s cell of origin is a key determinant of its ultimate phenotype

Yes

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Any gene that can transform normal cells in culture and induce cancer in animals

Oncogene

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Most oncogenes are derived from

Proto-oncogenes

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Negatively regulate cell proliferation, cause apoptosis, repair damaged DNA, or induce cellular differentation

Tumor suppressor genes

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In contrast to (oncogenes/tumor suppressor genes), which typically require that only one allele undergo activation via mutation, both alleles of (oncogenes/tumor suppressor genes) must be inactivated to promote tumor development

Oncogenes

Tumor suppressor genes

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Markedly increased risk of developing BCCs which arise at a younger age and appear in greater numbers
Predisposed to the development of a pediatric brain tumor arising in the cerebellum, medulloblastoma, as well as a variety of other defects throughout the body, including bifid ribs, calcified falx cerebri, odontogenic keratocysts, frontal bossing, palmar pits

Nevoid BCC syndrome

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NBCCS is caused by germline mutations disrupting the

PTCH1 gene

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Deregulated activity of the ______ pathway is detected in essentially all BCCs

Hedgehog

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Inherited cancer syndromes that exclusively predispose to cutaneous SCC

None

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Extreme photosensitivity and stark acceleration in the onset of skin cancer
Lack of nucleotide excision repair

Xeroderma pigmentosum

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Subepidermal blistering, nonhealing wounds, high predisposition to SCC
Caused by loss-of-function mutations in COL7A1

Recessive dystrophic epidermolysis bullosa

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Susceptibility to keratoacanthomas

Heterozygous germline inactivation of TGF-betaR1

Smith-Ferguson syndrome

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_____ mutations occur at more than 70% frequency across all SCCs

TP53

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_____ famiy genes are mutated in more than 70% of cutaneous SCC, 20% of oral head and neck SCC, 13% of lung SCC, and 10% of esophageal SCC

NOTCH

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_____ amplication is a common lineage-specific driver of SCC

SOX2

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Upregulation of _____ and _____ prheay signaling across the progression sequence of SCC development

ERK

mTOR (mammalian target of rapamycin)

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BRAF inhibition used for

Melanoma

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SMO inhibition used for

BCC

First FDA-approved BRAF inhibitor

Vemurafenib

More potent BRAF inhibitors less frequently observed adverse effects such as development of SCC and keratoacanthoma-like lesions

Dabrafenib | Encorafenib

The concomitant use of _____ with BRAF inhibitors almost completely suppress the emergence of SCCs

MEK

The long-term treatment of BCCs with the SMO inhibitor _____ has occasionally been associated with the evolution of treated tumors to a SCC morphology

Vismodegib

Primary etiologic agent for all skin cancers | Major carcinogen in the human environment

Ultraviolet radiation

Most clear-cut etiologic factor in human malignancy

Ultraviolet radiation

With PUVA therapy, the risk of SCC was more than _____-fold higher and the risk of BCC was more than _____-fold higher

100 | 11

UVB and UVC tend to be absorbed at the

5-6 double bond of pyrimidines (thymine and cytosine)

If two adjacent pyrimidines are activated, the resulting open bond cross-react, creating a

Cyclobutane pyrimidine dimer

Most frequent CPD

A single bond between the 6 position of one pyrimidine and the exocyclic group of the other instead creates a

Pyrimidine (6-4) pyrimidone photoproduct

Most frequent (6-4)PP

Although there is _____-fold more UVA than UVB in sunlight, UVA requires up to _____-fold greater doses fo some of its biological effects

20 | 1000

Ratio of DNA photoproducts

6 CPDs per 1 (6-4)PP

Accounts for only 5% of UVR but produces majority of UV-induced DNA lesions

UVB

UV signature mutation

C > T

UVA fingerprint changes

T > G

UV-induced generation of the ROS _____ was found to interact with melanin, resulting in chemoexcitation of electrons in melanin to extremely high-energy states, analogous to reactions that culminante in bioluminescence

Peroxynitrite

Instead of generating light, excited electrons in melanin can directly interact with DNA, resulting in continuous CPD formation for hours after UVA or UVB exposure has ceased, so-called

“Dark CPDs”

Chronically UV-exposed clinically and histologically normal-appearing epidermis harbors about _____ mutations per megabase of DNA

Have the highest mutational loads of any human cancer

Skin cancer

Estimates of the rate of progression of AK to SCC range from _____% at 1 year to _____% in 4 years

0. 6 | 2. 6

Y/N: Molecular profiles of most AKs are largely indistinguishable from those of well-differentiated invasive SCC

Yes

Virus-associated cancers comprise up to _____% of all human malignancies

Y/N: Viral transformation is a dead end for viruses

Yes

More than 200 types of HPVs have been identified and grouped into five genera, with the _____ HPV types most closely linked to cancer

Alpha | Beta

Produce condylomata, cervical cancer, most anorectal cancers, and a sizeable fraction of genital and oropharyngeal cancers

Alpha HPVs

Linked to the development of cutaneous warts and SCC in individuals with epidermodysplasia verruciformis

Beta HPVs

Unlike the (alpha/beta) HPVs, there has been no evidence for viral transcripts in skin cancers, indicating that (alpha/beta) HPVs are not required for tumor maintenance

Alpha | Beta

Y/N: Human polyomavirus infections are ubiquitous

Yes

Associated with the development of posttransplant nephropathy

BKPyV

Causes progressive multifocal leukoencephalopathy

JCPyV

Associated with pruritic and dyskeratotic dermatoses

HPyV6 | HPyV7

Associated with trichodysplasia spinulosa

TSPyV

Detected in about 80% of Merkel cell carcinomas

MCPyV

First link between an occupational exposure and the development of cancer First example of chemical carcinogenesis

Scrotal cancer in chimney sweeps

The excess risk of skin cancer associated with ionizing radiation exposure is almost exclusively confined to

BCC

Skin cancers that arise in sites of chronic ulcers or scars, most often caused by burns

Marjolin ulcers

Marjolin ulcers most often occur on

Lower extremities | Scalp

Almost 90% of Marjolin tumors are

SCC

Y/N: Marjolin ulcer SCCs are less aggressive

No - highly aggressive

Only benign papillomas developed in mice with Hras expression targeted to

Interfollicular epidermis

Expression of Hras in _____ that included stem cells led to spontaneous SCC development

Hair follicle epithelia

Two most frequently mutated genes in SCC

Notch1 | Trp53

Mutations in sporadic BCCs

PTCH1 or SMO

Hair follicle stem cells are largely resistant to SCC development during

Telogen

Low-level Hedgehog signaling produced _____ and high-level signaling yielded _____

Basaloid hamartomas | Nodular tumors

Most frequently used rodent model for UV-induced skin cancers Outbred strain that lacks a functional Hairless gene - undergo one round of anagen soon after birth, after which point follicles degenerate into cystic structures

Immunocompetent Hairless mouse