Chapter 079. Cancer Genetics (Part 3)

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Familial Cancer Syndromes A small fraction of cancers occur in patients with a genetic predisposition. In these families, the affected individuals have a predisposing loss-of-function mutation in one allele of a tumor-suppressor gene or caretaker gene. The tumors in these patients show a loss of the remaining normal allele as a result of somatic events (point mutations or deletions), in agreement with the Knudson hypothesis (Fig. 79-3). Thus, most cells of an individual with an inherited loss-of-function mutation in a tumor-suppressor gene are functionally normal, and only the rare cells that develop a mutation in the remaining normal allele...

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Chapter 079. Cancer Genetics (Part 3) Familial Cancer Syndromes A small fraction of cancers occur in patients with a genetic predisposition. In these families, the affected individuals have a predisposing loss-of-function mutation in one allele of a tumor-suppressor gene or caretaker gene. The tumors in these patients show a loss of the remaining normal allele as a result of somatic events (point mutations or deletions), in agreement with the Knudson hypothesis (Fig. 79-3). Thus, most cells of an individual with an inherited loss-of-function mutation in a tumor-suppressor gene are functionally normal, and only the rare cells that develop a mutation in the remaining normal allele will exhibit uncontrolled growth. The normal function of tumor suppressors is to restrain growth, to promote differentiation (gatekeeper genes), or to preserve genome integrity (caretaker genes).
Roughly 100 syndromes of familial cancer have been reported, although many are rare. The majority are inherited as autosomal dominant traits, although some of those associated with DNA repair abnormalities (xeroderma pigmentosum, Fanconi's anemia, ataxia telangiectasia) are autosomal recessive. Table 79-1 shows a number of cancer predisposition syndromes and the responsible genes. The current paradigm states that the genes mutated in familial syndromes can also be targets for somatic mutations in sporadic (noninherited) tumors. The study of cancer syndromes has thus provided invaluable insights into the mechanisms of progression for many tumor types. This section examines the case of inherited colon cancer in detail, but the same general lessons can be applied to all the cancer syndromes listed in Table 79-1. Table 79-1 Cancer Predisposition Syndromes and Associated Genes Syndrome Gene Chromo Inherit Tumors some ance Ataxia ATM 11q22- AR Breast telangiectasia q23 cancer Autoimmun FAS 10q24 AD Lymphom
e FASL 1q23 as lymphoproliferativ e syndrome Bloom BLM 15q26.1 AR Cancer of syndrome all types Cowden PTE 10q23 AD Breast, syndrome N thyroid Familial APC 5q21 AD Intestinal adenomatous adenoma, polyposis colorectal cancer Familial p16I 9p21 AD Melanoma melanoma NK4 , pancreatic cancer Familial WT1 11p13 AD Pediatric Wilms tumor kidney cancer
Hereditary BRC 17q21 AD Breast, breast/ovarian A1 ovarian, colon, 13q12.3 cancer prostate BRC A2 Hereditary CDH 16q22 AD Stomach diffuse gastric 1 cancers cancer Hereditary EXT1 8q24 AD Exostoses, multiple exostoses chondrosarcoma EXT2 11p11- 12 Hereditary HPC 1q24-25 AD Prostate prostate cancer 1 carcinoma Hereditary RB1 13q14.2 AD Retinoblas retinoblastoma toma, osteosarcoma
Hereditary MSH 2p16 AD Colon, nonpolyposis colon 2 endometrial, 3p21.3 cancer (HNPCC) ovarian, stomach, MLH 2p16 small bowel, 1 ureter carcinoma 7p22 MSH 6 PMS 2 Hereditary MET 7q31 AD Papillary papillary renal renal tumor carcinoma Juvenile SMA 18q21 AD Gastrointe polyposis D4 stinal, pancreatic cancers Li-Fraumeni TP53 17p13.1 AD Sarcoma, breast cancer
Multiple MEN 11q13 AD Parathyroi endocrine 1 d, endocrine, neoplasia type 1 pancreas, and pituitary Multiple RET 10q11.2 AD Medullary endocrine thyroid neoplasia type 2a carcinoma, pheochromocyto ma Neurofibro NF1 17q11.2 AD Neurofibr matosis type 1 oma, neurofibrosarcom a, brain tumor Neurofibro NF2 22q12.2 AD Vestibular matosis type 2 schwannoma, meningioma, spine
Nevoid PTC 9q22.3 AD Basal cell basal cell H carcinoma, carcinoma medulloblastoma, syndrome (Gorlin's jaw cysts syndrome) Tuberous TSC1 9q34 AD Angiofibr sclerosis oma, renal TSC2 16p13.3 angiomyolipoma Von VHL 3p25-26 AD Kidney, Hippel–Lindau cerebellum, pheochromocyto ma Note: AD, autosomal dominant; AR, autosomal recessive.