Ultraviolet Rays

Slide 1 · Ultraviolet Rays

Radiation carcinogenesis, DNA repair and cutaneous neoplasia

Mechanisms → mutation signatures → skin cancer pathology

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives: Interpret UV-associated carcinogenesis

Differentiate UV wavelength ranges and explain why exposure varies with pigmentation.

Trace UVB photolesions through nucleotide excision repair and mutagenesis.

Use xeroderma pigmentosum and mutation signatures as causal evidence.

Connect exposure and molecular events to actinic keratosis, SCC, BCC and melanoma.

Slide 3 · Ultraviolet light as a physical carcinogen

Solar UV is radiant energy capable of generating mutagenic DNA lesions.

Its most important pathology consequences concern cutaneous cancers.

Carcinogenic action links environmental exposure to cellular genomic instability.

The outcome reflects the interaction of exposure, pigment protection and repair.

An exposure is not a tumor: Transformation requires selected cellular alterations.

Slide 4 · The causal chain: Exposure to cutaneous malignancy

Sunlight / UV exposure

DNA photolesion

Repair failure or mutagenic resolution

Mutation-bearing clone

Cutaneous tumor

UV damage initiates an opportunity for mutations.

Selection and subsequent alterations are required for neoplasia.

Slide 5 · Radiant energy: UV versus ionizing radiation

Dimension

Ultraviolet light

Ionizing radiation

Principal lesion discussed

Pyrimidine dimers

DNA strand breaks and DNA cross-linkage

Main cancer context

Sun-exposed skin

Several tissues, sometimes after long latency

Inherited repair illustration

Xeroderma pigmentosum / NER

Other DNA damage-response defects

Teaching distinction

Photochemical adjacent-base lesion

More varied direct and indirect DNA injury

Slide 6 · Solar ultraviolet bands and the ozone filter

Wavelength ranges stated

UVC

200–280 nm

UVB

280–320 nm

UVA

320–400 nm

UVC: Described as filtered by stratospheric ozone

UVB: Emphasized as the main direct DNA-damaging solar band

Wavelength labels are categories, not a quantitative solar spectrum.

Slide 7 · Solar UV: Three defined wavelength groups

UVC

200–280 nm. Potently mutagenic in principle; Naturally screened by the ozone layer.

UVB

280–320 nm. Directly linked by Robbins to cutaneous carcinogenesis through pyrimidine dimers.

UVA

320–400 nm. Defined in the source spectrum; The focused passage does not detail UVA mechanisms.

Do not interpret the limited treatment of UVA as evidence that it is harmless.

Slide 8 · The atmosphere modifies biologically relevant exposure

The ozone layer intercepts solar UVC before it reaches the skin.

UVB reaches the skin and can produce carcinogenic photochemical DNA injury.

The wavelength distribution reaching tissue matters more than mutagenicity in isolation.

Hence environmental filtering modifies the exposure that cells actually experience.

Slide 9 · Three determinants of UV cancer risk

Radiation

UV wavelength influences the kind and biological relevance of DNA damage.

Exposure

Intensity and duration alter the burden of incident photons reaching skin.

Host phenotype

Melanin quantity and the capacity to respond to UV lesions modify biological injury.

Risk is multifactorial; The source does not give a numerical risk equation.

Slide 10 · Why pigmentation changes UV vulnerability

Melanin absorbs incident UV energy and attenuates injury to cellular DNA.

Epidermal melanocytes synthesize melanin and transfer it to keratinocytes.

Skin pigmentation therefore changes effective DNA exposure at a given sunlight intensity.

Pigmentation is protective, not absolute immunity from skin cancers.

Slide 11 · Epidermal cells explain the major UV-associated tumors

Skin surface

Keratinocyte layers

Melanocyte → melanin transfer

Dermis

Schematic: Keratinocytes give rise to SCC/BCC; Melanocytes give rise to melanoma.

Slide 12 · Fair skin and poor tanning are clinically relevant

Robbins singles out fair skin that burns readily and does not tan.

Limited melanin shielding helps explain higher susceptibility to UV injury.

Strong sunlight exposure compounds the vulnerability of lightly pigmented skin.

A high-risk phenotype describes susceptibility; It is not diagnostic of malignancy.

Do not infer that darkly pigmented patients cannot develop melanoma or SCC.

Slide 13 · Geography and exposure intensity interact

Queensland, Australia, as a high-sunlight exposure setting.

Fair skin plus strong sunlight is a particularly high-risk combination.

Location is an exposure modifier rather than a biological mutation.

Mechanistic interpretation must distinguish environmental dose from host sensitivity.

Slide 14 · How sunlight reaches the genomic target

Incident solar UV

Partial interception by melanin

Photon absorbed by DNA

Pyrimidine photochemistry

Melanin reduces exposure but does not eliminate the potential for DNA injury.

Direct DNA absorption can generate a characteristic photoproduct.

Slide 15 · The endpoint is mutation, not simply sunburn

Acute visible injury and long-term oncogenic changes are distinct outcomes.

A DNA lesion may be repaired accurately without permanent sequence change.

If an unrepaired lesion is bypassed or resolved inaccurately, mutations may result.

A mutagenic event matters for cancer when it affects a surviving, proliferating lineage.

Slide 16 · Keratinocytes and melanocytes define different tumors

Keratinocytes form the epidermal epithelial barrier and its proliferating layers.

Melanocytes reside within the epidermis and produce photoprotective melanin.

Squamous and basal cell carcinomas arise from epithelial lineages.

Melanoma is a malignant neoplasm of melanocytic lineage.

Slide 17 · Adjacent pyrimidines form a UV-induced photolesion

Before photochemical injury

After UVB photon absorption

A

T

T

A

T

A

C

G

Normal base pairing

A

T

T

A

T

A

C

G

Covalent linkage

Conceptual illustration: Two adjacent pyrimidines on one strand become covalently linked.

Slide 18 · Why adjacent thymidines are especially important

Pyrimidines in the same DNA strand can become covalently linked after UV exposure.

The textbook particularly emphasizes neighboring thymidine residues.

The lesion is a chemical change in DNA—not a protein cross-link or chromosome break.

A dimer spans neighboring bases and disrupts the geometry of double-stranded DNA.

Slide 19 · A photon-to-lesion mechanism

UV photon absorbed by DNA

Pyrimidine covalent linkage

DNA helix distortion

Faulty complementary pairing

UVB carcinogenesis begins at the molecular scale.

The abnormal structure is a substrate for cellular DNA-repair systems.

Slide 20 · Helix distortion has replicative consequences

A covalently linked pyrimidine pair distorts the normal double helix.

The damaged bases cannot pair properly with the opposite strand.

Persistent lesions interfere with faithful copying of genetic information.

Accurate repair before propagation protects sequence integrity.

Slide 21 · Nucleotide excision repair as genome protection

Recognition of damaged DNA

Removal of lesion-containing segment

Restoration of DNA continuity

Simplified conceptual sequence, not a full biochemical protein inventory.

A repair network involving at least 30 proteins.

Slide 22 · NER is a multicomponent repair mechanism

The UV passage identifies nucleotide excision repair (NER) as the dimer repair pathway.

Repair requires the coordinated functions of 30 or more proteins.

Pathway integrity matters because DNA synthesis must resume from accurate sequence.

An inherited defect in one required component can markedly increase cancer susceptibility.

Slide 23 · Repair capacity determines whether DNA injury persists

UVB-induced pyrimidine dimer

NER completes accurate repair

Unrepaired lesion persists / error-prone bypass or repair

Genome integrity preserved

Mutations may become fixed

Repair saturation with excessive exposure; The exact threshold is not supplied.

Slide 24 · Excessive UV exposure may overwhelm repair

That high solar exposure can exceed NER repair capacity.

Some lesions may then persist or be resolved through more error-prone processes.

Cell survival in this setting can come at the price of new DNA mutations.

The passage does not supply a numerical NER saturation threshold.

Repair saturation is framed as a hypothesis by the source, not an established dose cut-off.

Slide 25 · Cell survival and mutagenesis are not equivalent

Photolesion

Attempted repair / lesion tolerance

Surviving DNA sequence

Potential driver mutation

Survival does not imply fidelity: Inaccurate resolution can fix a mutation.

A driver mutation alone need not produce a fully malignant phenotype.

Slide 26 · Repair outcomes after UV photodamage

Accurate resolution

Original sequence restored; No fixed mutation from that lesion.

Mutagenic resolution

An incorrect base substitution may be inherited by daughter cells.

Persistent lesion

Replication and cell viability may be compromised unless the lesion is managed.

These are mechanistic teaching outcomes, not measured proportions.

Slide 27 · Why repair genes function as cancer-susceptibility genes

Genome maintenance suppresses the accumulation of oncogenic lesions.

When repair fails, the same exposure can produce more permanent mutations.

Inherited defective repair amplifies susceptibility to environmentally induced cancers.

This is an example of genomic instability enabling malignant transformation.

Slide 28 · Xeroderma pigmentosum: The genetic experiment

Xeroderma pigmentosum (XP) results from inherited loss of NER function.

The disorder produces profound susceptibility to UV-exposed skin cancers.

Both cutaneous squamous cell and basal cell carcinomas are emphasized in Chapter 7.

XP illustrates that DNA repair—not exposure alone—governs cancer vulnerability.

Slide 29 · Xeroderma pigmentosum: Gene to phenotype

Inherited NER defect

Defective dimer repair

Rapid accumulation of UV-linked mutations

Early / multiple skin malignancies

Inherited repair deficiency magnifies the carcinogenic consequences of sunlight.

The link is mechanistic and epidemiologic, not a morphology-only association.

Slide 30 · XP and the meaning of repair-pathway specificity

XP highlights defects in nucleotide excision repair.

The key unrepaired lesions are UV-induced pyrimidine dimers.

This contrasts with mismatch repair syndromes, which accumulate replication errors.

Different repair failures create different genomic vulnerabilities and cancer patterns.

Mismatch-repair contrast comes from adjacent Ch 7 “DNA Mismatch Repair Factors.”

Slide 31 · XP links constitutional risk to somatic mutations

The repair defect is present as an inherited cellular susceptibility.

UV-induced mutations then arise somatically in exposed skin cells.

Tumor formation reflects the later acquisition and selection of oncogenic changes.

A germline repair defect should not be confused with a tumor-specific driver mutation.

Slide 32 · Genome sequencing can reveal the cause of mutation

Mutagens can leave reproducible patterns of base substitution in tumor genomes.

A UV signature associated with faulty resolution of pyrimidine dimers.

The signature provides molecular evidence implicating the damaging exposure.

A signature is mechanistic evidence, not proof of when any one exposure occurred.

Slide 33 · Using mutation signatures as causal evidence

Exposure produces DNA lesion

Characteristic repair / error pattern

Mutations accumulate in tumor

Genome-wide signature recognized

Concordance between molecular damage and observed substitutions strengthens causal inference.

Mutation signatures complement clinical and epidemiologic observations.

Slide 34 · Melanoma genomics resolved a key controversy

Sun-exposed melanomas contain numerous mutations bearing a UV-associated signature.

This pattern supports a causal role for UV-induced DNA injury in many melanomas.

This evidence with earlier controversy about melanoma etiology.

The inference is strongest for melanomas arising in sun-exposed skin.

Slide 35 · A mutational signature is not the same as a driver

The UV signature describes the process that generated mutations.

A driver mutation confers a selective advantage on the neoplastic lineage.

A skin tumor can contain many passenger substitutions alongside causal driver lesions.

Do not equate high mutational burden with one specific molecular pathway.

Slide 36 · Actinic keratosis: A visible precursor in sun-damaged skin

Actinic keratoses typically arise on chronically sun-exposed cutaneous surfaces.

They are especially frequent in lightly pigmented individuals.

Lesions may exhibit progressive epithelial dysplasia toward cutaneous SCC.

They may also remain stable or regress rather than necessarily progress.

Slide 37 · Actinic keratosis: Clinicopathologic correlation

Clinical appearance

Rough or sandpaper-like keratotic lesions; Usually small, often face or dorsal hands.

Microscopic atypia

Atypia typically affects lower epidermal layers; Hyperkeratosis and parakeratosis are common.

Adjacent sun damage

Dermal solar elastosis reflects chronically sun-damaged connective tissue.

A clinical impression is insufficient for histologic grading of atypia.

Slide 38 · Actinic keratosis: Atypia starts in lower epidermis

Reference epidermis

Illustrated abnormality

Basement membrane

Dermis

Schematic: Lower-layer atypia with an intact basement membrane.

Slide 39 · Solar elastosis records cumulative dermal damage

UV-exposed skin can show thickened abnormal elastic material in superficial dermis.

Blue-gray elastotic fibers beneath actinic keratoses.

This finding supports chronic photodamage of the surrounding tissue.

Solar elastosis is a contextual feature, not an independent diagnosis of carcinoma.

Slide 40 · SCC in situ: Atypia throughout the epidermis

Reference epidermis

Illustrated abnormality

Basement membrane

Dermis

Schematic: Full-thickness atypia without basement membrane breach.

Slide 41 · Invasive SCC: Atypical cells traverse the basement membrane

Reference epidermis

Illustrated abnormality

Basement membrane

Dermis

Schematic: Dermal tumor groups indicate stromal invasion; Not an H&E image.

Slide 42 · TP53 mutations connect photodamage to early SCC

Chapter 25 describes TP53 mutations in actinic keratoses.

UV-associated substitutions occur at sites of pyrimidine dimer damage.

Early p53 dysfunction reduces a key genomic integrity safeguard.

Further driver alterations are required during progression to invasive carcinoma.

Slide 43 · From UV damage to cutaneous SCC

Repeated UV DNA injury

Mutations in keratinocytes

Actinic dysplasia / altered growth

In situ atypia

Invasive SCC

An illustrative progression model, not an obligatory route for every tumor.

The basement membrane separates in situ disease from invasion.

Slide 44 · Cutaneous SCC has multiple etiologic contexts

Lifetime sun exposure is a dominant epidemiologic determinant.

Immunosuppression following transplantation or chemotherapy increases risk.

Old burns, chronic ulcers and chemical carcinogens are additional associations.

The presence of SCC is not by itself proof of UV as the sole cause.

Slide 45 · Cutaneous SCC: A multistep driver process

Loss of p53 activity is an important early molecular event.

Additional changes increasing RAS signaling may promote proliferation.

Reduced Notch signaling is another contributor.

Each alteration acts within a mutation-bearing epithelial clone.

Slide 46 · SCC morphology must establish invasion

In situ disease: Atypical keratinocytes involve epidermal thickness.

Invasion: Atypical squamous nests or tongues extend into dermis.

Keratinization varies with the degree of tumor differentiation.

Poorly differentiated tumors may require keratin immunostains to verify lineage.

Slide 47 · Why UV-associated SCC is clinically consequential

Most cutaneous SCC can be recognized and treated locally.

Unlike BCC, SCC has a meaningful capacity for nodal spread.

Advanced disease can be locally destructive or metastatic.

Morphologic diagnosis informs both clinical management and prognosis.

Slide 48 · Basal cell carcinoma: UV-associated but molecularly distinct

BCC often develops at sun-exposed sites in lightly pigmented older adults.

Its principal oncogenic pathway involves excessive Hedgehog signaling.

Most BCCs are locally aggressive, slow growing and rarely metastatic.

The UV connection operates through acquired mutations rather than a unique UV-specific morphology.

Slide 49 · Basal cell carcinoma: Oncogenic Hedgehog signaling

Regulated signaling

PTCH loss of function

PTCH suppresses SMO

No ligand → pathway off

GLI activity restrained

PTCH inhibition lost

SMO signaling permitted

GLI-driven tumor cell growth

UV-signature substitutions in a subset of sporadic PTCH mutations.

Slide 50 · UV signatures are detected in PTCH mutations

PTCH is a tumor suppressor restraining Smoothened-dependent signaling.

Loss-of-function PTCH changes occur frequently in sporadic BCC.

UV-associated C→T transitions in a subset of PTCH mutations.

The UV signature supplies direct molecular support for the exposure–BCC link.

Slide 51 · BCC morphology: Recognition points

Clinically, lesions may be pearly papules with telangiectatic vessels.

Microscopy shows basaloid nests, often with peripheral palisading.

Stromal retraction clefts may border tumor islands.

The morphology differs from keratinizing invasive cutaneous SCC.

Slide 52 · Cutaneous SCC versus BCC: Practical differences

Dimension

Cutaneous SCC

Basal cell carcinoma

Major lineage

Squamous keratinocyte differentiation

Basaloid epithelial neoplasm

Useful histology

Atypical squamous cells, keratinization

Basaloid nests, palisading, stromal clefts

Characteristic driver context

TP53, RAS/Notch alterations

PTCH/SMO/GLI Hedgehog pathway

Metastatic behavior

Potential for regional/distant spread

Metastasis extremely rare

Slide 53 · Melanoma: UV injury in a different cell lineage

Melanoma arises from melanocytes rather than keratinocytes.

Sun-exposed cutaneous melanomas show high UV-signature mutational burdens.

Low melanin production increases UV vulnerability in some genetic backgrounds.

Familial predisposition and other factors also influence melanoma development.

Slide 54 · The sunlight–melanoma link is not uniform

Melanomas can occur on sites with little or no UV exposure.

Melanoma also occurs in individuals with more highly pigmented skin.

Intermittent severe sunburns may be important, but exposure patterns are complex.

Avoid assuming that every melanoma arose through a solar UV pathway.

Slide 55 · Melanoma drivers are separable from UV damage

Cell-cycle lesions (e.g., CDKN2A dysfunction) support proliferation.

BRAF/RAS pathway activation supplies progrowth signals in many tumors.

Telomerase activation supports replicative persistence.

A UV signature describes damage history; These alterations describe selection.

Slide 56 · Melanoma progression: Radial versus vertical growth

Radial growth phase

Vertical growth phase

Schematic, not specimen: Downward dermal invasion defines the vertical component.

Slide 57 · Recognizing melanoma in a pathology context

Clinical suspicion may arise from irregular shape, color variation or changing lesions.

Microscopic assessment determines architecture, atypia and invasion.

Radial growth describes lateral spread; Vertical growth includes dermal invasion.

The UV causal pathway must not be confused with pathologic stage.

Slide 58 · Three major skin cancers linked to solar UV

Feature

SCC

BCC

Melanoma

Cell lineage

Squamous epithelial

Basaloid epithelial

Melanocytic

UV-related molecular evidence

TP53 photodamage changes

PTCH UV-type substitutions

Genome-wide UV signatures

Key teaching morphology

Keratinization / invasion

Palisading / retraction

Atypical melanocytes / invasion

Clinical concern

Nodal or distant metastasis

Primarily local destruction

Potential for aggressive spread

Slide 59 · Cumulative injury versus varied melanoma exposure

Lifetime sun exposure closely correlates with SCC and BCC incidence.

In melanoma, the relationship with sunlight is more heterogeneous.

The UV signature demonstrates a mechanism even when individual exposure histories vary.

Exposure pattern, cell lineage and tumor genotype should be considered separately.

Slide 60 · UV-induced injury can coexist with immune effects

Chapter 25 notes chronic sunlight may blunt cutaneous immune responsiveness.

Reduced immune elimination of damaged cells a possible contributor to SCC.

Immunosuppression is independently associated with an elevated cutaneous SCC risk.

These immunologic associations supplement the direct DNA-damage mechanism.

Source indicates immune effects as partly uncertain rather than a complete pathway.

Slide 61 · The UV mutational signature has wider skin pathology relevance

Many sun-exposed SCCs and melanomas contain extensive DNA substitutions.

A subset of sporadic BCC driver mutations carry UV-type base substitutions.

Robbins also describes UV-signature–driven Merkel carcinomas without viral causation.

Distinct neoplastic lineages can share the same initiating environmental mutagen.

Slide 62 · Interpret the type of evidence correctly

Observation

Supported inference

What it does not prove

High UV-associated mutations

Prior UV-like DNA damaging process

Exact lifetime dose or age at exposure

XP with multiple skin cancers

NER protects against UV mutagenesis

All sporadic cancers have germline NER defects

Actinic keratosis with TP53 mutation

Early molecular damage in precursor

Inevitable evolution to invasive SCC

Melanoma on unexposed site

UV is not universally necessary

UV is unimportant in exposed melanomas

Slide 63 · Applied case: Extreme repair susceptibility

Clinical vignette

A young person has many keratinocytic malignancies in sunlight-exposed skin and a documented inherited nucleotide excision repair defect.

Which molecular lesion is not being repaired effectively?

Reasoning: UV-induced pyrimidine dimers. The inherited defect defines xeroderma pigmentosum and greatly increases UV-related skin cancer risk.

Slide 64 · Applied case: Grading epidermal dysplasia

Clinical vignette

A keratotic lesion arises on a chronically sun-exposed forearm. Histology shows atypical keratinocytes concentrated in the basal epidermis with an intact basement membrane.

What precursor pattern fits, and what would signal progression?

Reasoning: Actinic keratosis is compatible with lower-layer atypia. Full-thickness atypia indicates SCC in situ; Dermal invasion establishes invasive SCC.

Slide 65 · Applied case: Linking tumor genotype to exposure

Clinical vignette

A cutaneous malignancy arising on a sun-exposed site has an exceptionally high burden of substitutions bearing the characteristic UV-repair signature.

Does this prove a particular single sunburn caused the cancer?

Reasoning: No. It strongly implicates the UV-like mutagenic mechanism but cannot reconstruct the dose or time of an individual exposure.

Slide 66 · Applied case: Distinguish the principal epithelial cancers

Clinical vignette

A slow-growing pearly facial papule shows dermal islands of basaloid cells with peripheral palisading and stromal clefting.

Which cutaneous cancer is favored, and what pathway is characteristic?

Reasoning: Basal cell carcinoma. Constitutive Hedgehog signaling—commonly through PTCH loss—is central to its oncogenic biology.

Slide 67 · Integrated carcinogenesis model

Environment: Incident UV

Protection: Melanin

Damage: Pyrimidine dimers

Repair: NER or mutation

Selection: Skin cancer

Different steps explain why similar exposure does not lead to identical outcomes.

The final cancer phenotype depends on the affected lineage and drivers.

Slide 68 · Core pathology conclusions

UVB produces covalent pyrimidine dimers that disrupt DNA pairing.

NER normally repairs these lesions; Deficient repair amplifies mutational risk.

Genomic UV signatures substantiate the UV contribution to cutaneous melanoma.

SCC, BCC and melanoma differ in lineage, driver pathways and morphology.

Slide 69 · Clinical interpretation and limitations

Photodamage, repair susceptibility and sun exposure act together—not in isolation.

Histology establishes the lesion type; Mutation signature supports mechanism.

Sun-damage–associated tumors are not necessarily caused exclusively by UV.

No quantitative risk prediction, diagnostic cutoff or treatment guideline is inferred here.

Slide 70 · Sources and selected Robbins cross-references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026). Chapter 7: Radiation Carcinogenesis; Ultraviolet Rays, p. 289.

Chapter 7: Nucleotide Excision Repair Factors, pp. 281–282.

Chapter 25: The Skin—melanocytes, melanoma, actinic keratosis, cutaneous SCC and BCC, pp. 1028–1043.

Only original editable teaching schematics are included; no extracted textbook photos or histology figures are reproduced.