Howlett-Commentary

Howlett-Commentary - 65 64 63 62 61 60 59 58 57 56 55 54 53...

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Unformatted text preview: 65 64 63 62 61 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 JULY 2002 VOL 297 SCIENCE www.sciencemag.org 534 S C I E N C E S C O M PA S S I mportant discoveries are sometimes so neat and satisfying that, in retrospect, they seem obvious. So it is with the find- ing described by Howlett et al . ( 1 ) on page 606 of this issue. These authors disclose that the inheritance of two defective copies of the BRCA2 breast cancer susceptibility gene ( 2 ) can lead to Fanconi anemia (FA) ( 3 ), a complex disorder characterized by congenital abnormalities, progressive bone marrow failure, and cancer susceptibility. Heterozygous carriers of BRCA2 muta- tions inherit a high risk of developing breast cancer (up to 85%) and other cancers such as ovarian and pancreatic. No developmental or other obvious defects have been noted in these individuals. The BRCA2 protein is thought to be important in the repair of DNA damage by homologous recombination, at least in part by regulating the activity of RAD51 ( 2 ). Cells lacking BRCA2 inaccurately repair damaged DNA, leading to gene mutation and progres- sion of tumors, and are particularly sensitive to DNA cross-linking agents. Most patients with FA present within the first decade of life with bone marrow failure and cancer, typically acute myeloid leukemia and squamous cell carcinoma, usually of the head and neck ( 3 ). This is accompanied by congenital abnormalities such as growth re- tardation and skeletal defects (microcephaly and absent radii or thumbs), kidney defects, and abnormal skin pigmentation. The het- erogeneity of the disease leads to difficulties in making a firm clinical diagnosis, and therefore the cellular hypersensitivity to...
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