19 - Carcinogenesis and Skin Flashcards
Combined incidence of SCC and BCC is likely to be at least _____fold higher than that of all other cancers combined
Two
Whereas single base mutations in early SCC lesions frequently are characteristic of _____-induced damage, later changes are associated with _____
UV light
Genomic instability
_____ mutations are characteristic of chemical mutagens used to initiate tumor formation
Ras
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
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
Tumors contain a small number of self-renewing stem cells that produce transient-amplifying and differentiating progeny
Cancer stem cells or
Tumor-initiating cells
Constitute the overwhelming majority if cells in a tumor
Transient-amplifying and differentiating progeny
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
Any gene that can transform normal cells in culture and induce cancer in animals
Oncogene
Most oncogenes are derived from
Proto-oncogenes
Negatively regulate cell proliferation, cause apoptosis, repair damaged DNA, or induce cellular differentation
Tumor suppressor genes
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
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
NBCCS is caused by germline mutations disrupting the
PTCH1 gene
Deregulated activity of the ______ pathway is detected in essentially all BCCs
Hedgehog
Inherited cancer syndromes that exclusively predispose to cutaneous SCC
None
Extreme photosensitivity and stark acceleration in the onset of skin cancer
Lack of nucleotide excision repair
Xeroderma pigmentosum
Subepidermal blistering, nonhealing wounds, high predisposition to SCC
Caused by loss-of-function mutations in COL7A1
Recessive dystrophic epidermolysis bullosa
Susceptibility to keratoacanthomas
Heterozygous germline inactivation of TGF-betaR1
Smith-Ferguson syndrome
_____ mutations occur at more than 70% frequency across all SCCs
TP53
_____ 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
_____ amplication is a common lineage-specific driver of SCC
SOX2
Upregulation of _____ and _____ prheay signaling across the progression sequence of SCC development
ERK
mTOR (mammalian target of rapamycin)
BRAF inhibition used for
Melanoma
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
TT
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
TC
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
5
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
- 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
10
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
