DNA replication and repair disorders Notes

NOTES NOTES DNA REPLICATION & REPAIR DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Group of rare, inherited disorders; mutations in DNA maintenance, repair genes → spectrum of cancers (typically early-onset cancer diagnosis) SIGNS & SYMPTOMS ▪ See individual conditions DIAGNOSIS LAB RESULTS ▪ Genetic sequencing OTHER DIAGNOSTICS ▪ Family history TREATMENT OTHER INTERVENTIONS ▪ Adequate malignancy surveillance ▪ Minimize sun, radiation exposure BLOOM SYNDROME osms.it/bloom-syndrome PATHOLOGY & CAUSES ▪ Rare autosomal recessive disease; extreme susceptibility to DNA damage, immune deficiency, cancer Pathogenesis ▪ Instability of DNA duplexes during recombination, repair, replication → DNA mutation → oncogenesis CAUSES ▪ Mutation in BLM gene on chromosome 15q26.1 ▫ Encodes RecG helicase (AKA Bloom syndrome protein): helps maintain stability of DNA when duplexes 158 OSMOSIS.ORG unwound during recombination, repair, replication RISK FACTORS ▪ Individuals of Ashkenazi Jewish descent COMPLICATIONS ▪ Infertility (more common in individuals who are biologically male) ▪ Dehydration due to reflux, vomiting, diarrhea in infancy ▪ Immunodeficiency → secondary infection, early predisposition to cancer ▪ Limited intellectual ability ▪ Fetal intrauterine growth restriction

Chapter 24 DNA Replication & Repair Disorders SIGNS & SYMPTOMS ▪ Microcephaly with proportionate small stature ▪ Sparse subcutaneous adipose tissue ▪ Integument: childhood rash (erythematous on nose, cheeks; worsens after sun exposure; persists 1–2 years); cafe-au-lait spots; hypopigmented skin lesions ▪ Facial anomalies DIAGNOSIS LAB RESULTS ▪ Karyotype analysis ▪ Genetic testing (mutated BLM gene) ▪ ↓ immunoglobulins (IgM, IgA deficit > IgG), effector memory T-cells, memory B-cells OTHER DIAGNOSTICS Physical examination ▪ Typical facies; body habitus; integument examination (erythematous rash, hyper/ hypopigmented lesions) TREATMENT OTHER INTERVENTIONS ▪ No therapeutic options Management ▪ Minimize radiation exposure (MRI/ ultrasound for diagnostic imaging); protect face from sun; IgG replacement for severe hypogammaglobulinemia; monitor fluid levels in infants Figure 24.1 A male child with Bloom syndrome. He has telangiectatic facial erythema, typical of the condition. LI–FRAUMENI SYNDROME osms.it/li-fraumeni_syndrome PATHOLOGY & CAUSES ▪ Syndrome caused mutation of guardian of genome (TP53) → wide array of malignancies Pathogenesis ▪ Abnormal TP53 function → abnormal checkpoint inhibition, tumor suppression → damaged DNA cell proliferation → malignant transformation ▪ Abnormal TP53 function → dysregulated apoptosis signaling → proliferation of DNAdamaged cells → malignant transformation Diseases ▪ Sarcoma, leukemia, breast cancer, brain tumors (e.g. medulloblastomas, choroid plexus carcinomas), adrenocortical carcinoma OSMOSIS.ORG 159

CAUSES ▪ Autosomal dominant mutation on gene TP53, located on 17p3.1 chromosome (mostly missense mutations in exons 5, 8) COMPLICATIONS ▪ Radiation-associated cancers SIGNS & SYMPTOMS Sarcomas ▪ Growing, painless mass (arises with compression of surrounding structures) Osteosarcoma ▪ Localized pain for several months; soft tissue mass tender to palpation, commonly of long bones (e.g. femur, humerus) Breast cancer ▪ Breast mass (most common) Brain tumors ▪ Focal neurologic deficit Adrenocortical carcinomas ▪ Abdominal mass; hormone excess syndrome (e.g. Cushing, hyperaldosteronism, virilization, feminization) DIAGNOSIS LAB RESULTS ▪ Genetic conformational testing ▪ ↑ hormonal levels in functional adrenocortical carcinoma, alkaline phosphatase in osteosarcoma setting OTHER DIAGNOSTICS History ▪ Presence of malignancy ▪ Family history (diagnosis requires all three) ▫ Sarcoma diagnosed before age 45 ▫ First-degree relative with any cancer before age 45 ▫ First/second-degree relative with any cancer before age 45/sarcoma at any age 160 OSMOSIS.ORG TREATMENT SURGERY Resection ▪ Choroid plexus carcinoma (malignancyspecific therapy) Mastectomy + radiation therapy ▪ Breast cancer (malignancy-specific therapy) OTHER INTERVENTIONS ▪ Management: surveillance of individuals, family members of diagnosed individuals ▫ Annual skin examination ▫ Noninvasive breast cancer screening at 18–20 years ▫ Regular diagnostic testing begins at 20–25 ▫ Colorectal cancer screening every 2–5 years, starting at 25 ▫ Whole body MRI recommended by American Association for Cancer Research ▪ Screening for ▫ Individuals with breast cancer < 31 years ▫ Individuals with adrenocortical carcinoma, regardless of age/family history ▫ Individuals with choroid plexus carcinoma ▫ Individuals with childhood sarcoma (except Ewing sarcoma)

Chapter 24 DNA Replication & Repair Disorders XERODERMA PIGMENTOSUM osms.it/xeroderma-pigmentosum PATHOLOGY & CAUSES ▪ Rare autosomal recessive disease of nucleotide excision repair (NER) gene; extreme photosensitivity, early development of skin cancer ▪ Pathogenesis: UV light in setting of mutated NER gene → cross-linking of pyrimidine residues → inability for removal of covalently-linked pyrimidine residues → epithelial DNA mutation → ↑ oncogenesis risk TREATMENT OTHER INTERVENTIONS ▪ No curative therapy ▪ Avoid sun ▪ Sunscreen, proper clothing (minimize photoreactivity, mitigate cancer risk) ▪ Basal, squamous cell cancer surveillance: annual skin examination CAUSES ▪ Autosomal recessive mutation of NER gene on chromosome 9q22 COMPLICATIONS ▪ Basal, squamous cell carcinomas; melanoma ▪ Ocular: keratitis, opacification of cornea, iritis with synechiae formation, melanoma of choroid ▪ Neurologic abnormalities: primary neuronal degeneration ▪ Radiation complications: chromosome breakage → oncogenesis SIGNS & SYMPTOMS ▪ Extreme photosensitivity to sunlight, abnormal pigmentation, xerosis (abnormal dryness of skin), telangiectasia, skin atrophy Figure 24.2 A female child with xeroderma pigmentosum. There are numerous hyperkeratoses on the face as well as innumerable solar lentigines. Corneal scarring is also present. DIAGNOSIS OTHER DIAGNOSTICS ▪ Clinical diagnosis: family history, photoreactivity history, physical examination (e.g. integument, ocular examination; xerosis, skin fragility, ocular complications) OSMOSIS.ORG 161