Oncology Nursing Brown Bag Lunch September 9, 2014

Deborah Tamura MS, RN, APNG

NCI, Dermatology DNA Repair Section

No Conflict of Interest

Diseases of DNA Repair: When the Life Guard of the

Gene Pool Goes on Strike

Learning Objectives At the completion of this presentation the participant will be able to: • Name a minimum of 3 diseases caused by

defective DNA repair. • List 3 symptoms of xeroderma pigmentosum and

trichothiodystrophy. • Describe patient education strategies to reduce

the risk of skin cancer in xeroderma pigmentosum patients.

DNA Repair – The Life Guard of the Gene Pool

DNA Damage Response

Inherited Diseases caused by Defective DNA Repair

Ultraviolet Radiation CAUSES

DNA Damage

Still trying to convince my daughter to protect her skin from the sun

UV PHOTOPRODUCTS

Gene Transcription disrupted at Site of Photoproduct

UV

UV DEFENSE MECHANISMS

Skin Cancer

Pigmentation & Skin Thickening

UV-Exposure

DNA Repair Cell Cycle Arrest

Apoptosis

DNA Damage DNA photoproducts

Mutation

Removal of Mutated Cells (Immune-Surveillance)

The Process of Nucleotide Excision

Repair

DNA Damage Identified

Damaged DNA Removed

Synthesize a New Segment of DNA and attach it to the Original strand of DNA

Genes Involved in Nucleotide Excision Repair

Identify Damage

Damaged DNA Removed

New DNA Segment Spliced into Place.

New Segment of DNA is Synthesized

TFIIH

XPE

CSA CSB

XPV (Variant)

G= Normal Gene

g= Mutated Gene

g= Mutated Gene

Function of normal gene compensates for mutant gene.

Autosomal Recessive Inheritance Males and Females Equally Affected Recurrence risk for each child is 1 in 4 or 25% Parents are not clinically affected and have no symptoms but are carriers for the condition

Carrier Father

Carrier Mother

Gg Gg Gg

Gg gg

Normal Carrier Carrier Affected

GG Gg

Xeroderma Pigmentosum Children of the Night

“Is this place UV safe?”

Means ‘Dry Pigmented Skin’ Caused by mutations in genes of NER (7) and Pol Eta – by pass polymerase (XP-Variant) One in million in the U.S. More common in Japan and the Middle East Occurs in all ethnic groups 10,000 fold increased risk of skin cancer

32 y/o >200 skin cancers died age 35 glioblastoma

2 y/o diagnosed at daycare center KA on lip

Xeroderma Pigmentosum

Signs and Symptoms Freckling before age 2 years Severe UV sensitivity (50% of patients have severe blistering sunburns) Early onset of skin cancers – often before age 10 Eye – photophobia; dry eyes, cancer on eye surfaces Neurodegeneration in approximately 25% of patients. More common in XP-A, XP- B, XP-D, XP-F and XP-G. Progressive hearing loss, loss of DTRs, ataxia, cognitive decline, recurrent aspiration

Nine month old in shade for 45 minutes

Sun Exposure and Xeroderma Pigmentosum

59 y/o male 37 y/o male

The Eye Complications in Xeroderma Pigmentosum

Severe Photosensitivity

Corneal Clouding, Pterigium

Malignancy on eye surface

Progressive Neuro-degeneration in Xeroderma Pigmentosum - Patient with

XP-A Mutations

Age 4 Age 17 Age 41 Died age 45

Neuro-Degeneration in Xeroderma Pigmentosum

Age 33 Died age 35

Died age 36 Age 17 Died age 20

XP-A XP-D

Patient Care Issues:

The UV Safe Lifestyle

“Mr. Sun is not my friend”.

The Well Dressed XP Person Sun block >SPF 30

applied several times per day

Hood covering ears back of neck with UV blocking face shield

Sunglasses – UV blocking with side shields

Long sleeved shirts Long pants or tights

under skirts Gloves Shoes and long socks Sun Protective Suit

Environmental Protection Avoiding the sun – stay indoors during daylight hours UV meter to measure ambient UV levels UV blocking window tints: house and car Avoid unshielded florescent lights and all halogen lighting Handicapped parking permit Avoid Cigarette smoke

The goal of UV protection is to have the lowest amount of UV exposure as possible

Patient Care Management Cancer Detection and Treatment Frequent self skin exams – at least weekly Regular dermatologic visits Photographs of lesions Prompt biopsy and surgical removal of suspicious

lesions Pharmacologic Interventions Aldara 5 FU Oral Retinoids

Referral to Patient Support Groups

Consequences of Late Diagnosis and Poor UV Protection

DIED AGE 33 YR

Early Diagnosis and Good Protection

Who has XP?

Supercalifragilisticexpialidocious Trichothiodystrophy

THANKS TO DR VERA PRICE

Trichothiodystrophy

About 100 patients reported in medical literature May be called PIBIDS, IBIDS, Tay Syndrome or Pollet Syndrome Mutations in XPD, XPB, TTDA and TTDN1 cause disease Disease symptoms caused by faulty gene transcription Severe Sun Sensitivity in Half of Patients

Collodion Membrane

Tiger Tail Banding of Hair

Ichthyosis - Dry Skin

Brittle Nails Short Hair - Sparse

Eyebrows

TrichothiodystrophySymptoms

High Rate of Pregnancy and neonatal complications

Trichothiodystrophy

Severe Delay

Autism Age 14 TTDN1

Age 25 Moderate

Delays

TTDA

Normal Development Age 5

Short Stature Severe Delay Age

Died age 9 yr

XP-D Mutations

Brain MRI Normal vs TTD Leukodystrophy

Normal Myelin

Dysmyelination

Complications of Trichothiodystrophy

Ophthalmologic Immune Dysfunction –

Frequent Infections Endocrine Abnormalities

– Hypogonadism (?) Poor Growth – bone

abnormalities 20 fold increased risk of

death before age 10

Patient Care Management of Trichothiodystrophy

Benefit from Multidisciplinary Approach Dermatology – follow skin and hair symptoms Neurology – assess for developmental delay Immunology – if frequent infections – IVIG Ophthalmology – follow cataracts and myopia

Advocate for rehabilitative and support services Refer to Patient Support Group

Cockayne Syndrome

COCKAYNE SYNDROME

3 y/o – Died 13 y/o Calcification in Basal Ganglia

Cockayne Syndrome Approximately 140 Patients Reported in

Literature Caused by Mutations in Genes: CSA or CSB CS/XP Overlap Mutations in XPB, XPD, XPG Defective Transcription Coupled Repair – Faulty

Repair of Actively Transcribing Genes Necessary for Normal Cell Function

Significantly Reduced Life Span

Cockayne Syndrome: Physical Features

Severe Growth Deficiency – Cachetic Dwarfism Wizened Face – Deep Set Eyes Sensorineural Hearing Loss Retinal Pigmentation – Corneal Opacity – Cataracts Slender Beak-Like Nose Photosensitive - Dry Skin, Senile Appearance

XERODERMA PIGMENTOSUM / COCKAYNE SYNDROME

XP/CS group B - XP11BE 28 yr Mother

Cockayne Syndrome: Associated Complications

Cardiovascular Problems – arrhythmias hypertension Hepato-splenomegaly Skeletal Abnormalities Neurologic – Progressive Neurodegeneration and Cerebral Atrophy

XERODERMA PIGMENTOSUM / COCKAYNE SYNDROME

6 yr XP20BE XP/CS group G 18 mo

Cockayne Syndrome Patient Care Issues

Supportive Interventions Rehabilitative Therapies PT, OT, Speech Therapy Special Education Classes

Feeding Tube for Failure to Thrive Hearing Aids Surgery for Cataracts Use of Sunscreens for Photosensitivity Refer to Patient Support Group

XP CS TTD Sun sensitivity + + + or -

Skin pigmentation \ cancer + - -

Ocular abnormalities + + +

Neurological abnormalities - or + + +

NER defect + + +

Environmental influence ++ - -

Developmental defect + ++ ++

Comparison of NER Diseases+

Diagnosis of DNA Repair Diseases

Clinical Features Detailed Medical History – How bad was the sunburn? Laboratory Testing

UV sensitivity Host cell reactivation assay Mutation analysis Polarizing light microscopy exam of hair

Family History – Autosomal Recessive Inheritance

• Age 2 months • Outside in covered stroller for 20 minutes

When the Diagnosis is a Bad Gene – Not a Bad Parent

UV Sensitivity Testing: Fibroblasts Exposed to Ultraviolet Radiation

Before Exposure Normal Cells After

UVC XP Cells After

UVC

17 Year old Uncle

8 Month old Nephew

MUTATION ANALYSIS OF XPG GENE

What Have We Learned in 40 years?

• Over 250 articles published relating to laboratory and clinical research of NER and DNA repair diseases

• There are more genes and more pathways to be identified in DNA repair

• Patients with TTD, XP and CS have mutations in the same genes but very different clinical features (Pleiotropy)

• UV protection works to prevent skin and ocular cancer in XP patients; does not prevent neurodegeneration

• XP patients may be at risk for multiple types of internal cancers

The Kraemer Lab

Principal Investigator: Dr. Ken Kraemer Associate Investigator: Dr. John DiGiovanna Senior Scientist: Dr. Sikandar Khan Visiting Post Doc: Dr. Christianne Kuschal Research Nurse: Debby Tamura MS, RN

All the post docs, medical students and post bacs who have worked in the lab for the past 35 years.

Your Cat Genetics Trivia for the Day The genetic factor which created the

Japanese Bobtail is completely different from the Manx, a naturally tailless cat.