TABLE 3-3 Examples of Autosomal Recessive Disorders of DNA Damage Response

Disorder

Genes or Locus

Defect Proposed

Major Clinical Features

Cancer

Approximate Prevalence (per live births)

Xeroderma pigmentosum

XP-A to XP-G and XPV

Excision or postreplication repair

Photosensitivity and cancer of UVR-exposed skin

Squamous cell skin carcinoma, basal cell carcinoma, and melanoma

1 in 250,000

Cockaynes syndrome

CS-A, CS-B

Transcribed strand repair

Photosensitivity, dwarfism

No excess

a

Trichothiodystrophy

XP-D

Excision repair

Photosensitivity, abnormal sulfur-deficient hair

Variable excess (skin)

a

Ataxia-telangiectasia

ATM

Kinase activity

Radiosensitivity, neuro-and immunodeficiency

Lymphoma

1 in 100,000

Nijmegen breakage syndrome

NBS

NHEJ factor (Mrell/RAD50/nbs)

Radiosensitivity, microencephaly, immunodeficiency

Lymphoma

a

Fanconi’s anemia

FA-A to FA-C

DNA cross-link repair

Bone marrow deficiency, skeletal abnormalities

Leukemia

1 in 300,000

aLess than 1 in 100,000.

TABLE 3-4 Examples of Autosomal Dominant Disorders of Tumor Suppressor Genes, Proto-oncogenes, and DNA Damage Response or Repair Genes

Disorder

Genes or Locus

Defect Proposed

Cancer

Approximate Prevalence (per live births)

Tumor-Suppressor Disorders

Familial adenomatous polyposis

APC

Transcriptional regulation

Colorectal cancer (multiple polyps)

1 in 8000

Von Hippel-Lindau disease

VHL

Transcriptional regulation

Renal cancer

1 in 30,000

Denys Drash syndrome

WT1

Transcriptional regulation

Nephroblastoma (+ others)

?

Neurofibromatosis type 1

NF-1

GTPase regulation

Neurofibroma Schwannoma

1 in 3000

Neurofibromatosis type 2

NF-2

Cytoskeletal linkage

Meningioma Neurofibroma

1 in 30,000

Nevoid basal cell carcinoma syndrome

PTC

Cellular signaling

Basal cell skin cancer

Medulloblastoma

1 in 50,000

Tuberous sclerosis

TSC1

TSC2

Cellular signaling

Cellular signaling

Benign lesions of skin, nervous tissue, heart, and kidneys

1 in 20,000

Retinoblastoma

RB1

Transcriptional regulation

Retinal tumors, bone or soft-tissue sarcoma, brain cancer, and melanoma

1 in 25,000

Proto-oncogene Disorders

Multiple endocrine neoplasia (2A and 2B) and familial medullary thyroid cancer

RET

Cellular signaling

Thyroid or parathyroid neoplasms

?

DNA Damage Response or Repair Disorders

Hereditary nonpolyposis colon cancer

MLH1, MSH2, PMS1, PMS2

DNA mismatch repair, apoptosis

Colon cancer, endometrial cancer

1 in 2000

Li-Fraumeni syndrome

TP53 (others?)

DNA damage recognition

Various

1 in 50,000

Heritable breast or ovarian cancer

BRCA-1

BRCA-2

Transcriptional regulation, DNA repair

Breast or ovarian cancer

Breast cancer (also male)

1 in 1000



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