Page 256 - 20dynamics of cancer
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INHERITANCE                                                 241

                              individuals, r ≈ 0.5 (Huson et al. 1989). Thus, qpr ≈ 10 −4 , which implies
                              a high germline mutation rate.
                                Few families transmit a mutation through several generations, and
                              most cases arise from new mutations (Gutmann and Collins 2002). A
                              wide variety of DNA lesions occur in the gene, including translocations,
                              large chromosomal deletions, smaller deletions within the gene, small
                              rearrangements within the gene, and point mutations. No particular
                              mutational hotspots have been detected. This large gene spans almost
                              9 kb of coding DNA over at least 57 exons and, including the intron
                              regions, approximately 300 kb of total DNA. Perhaps the large size con-
                              tributes to the high rate at which loss of function mutations arise. It will
                              be interesting to learn if other special attributes of this gene cause the
                              apparently elevated mutation rate.


                              Hereditary breast cancer.—Mutations in BRCA1, which has an impor-
                              tant function in the repair of double-strand DNA breaks, confer a high
                              probability of developing breast or ovarian cancer (Couch and Weber
                              2002). Current estimates for the penetrance of breast cancer in carriers
                              of BRCA1 mutations range from 56% to 86% (Couch and Weber 2002).
                              Lack of functional BRCA1 leads to chromosomal abnormalities (Welcsh
                              and King 2001), a common feature of cancer cells. The median age of
                              onset is approximately 50 years (Ford et al. 1998), which is later than for
                              most of the other cancers that follow dominant Mendelian inheritance.
                              The frequency of BRCA1 mutant alleles and associated cases varies in
                              different populations over the range 10 −3 –10 −2  (Tonin et al. 1995; Couch
                              and Weber 1996; Struewing et al. 1997; Couch and Weber 2002). No data
                              measure the decrease in reproduction in carriers of BRCA1 mutations:
                              a reasonable guess would be in the range 10 −2 –10 −1 . These values give
                              an estimate for qpr of 10 −5 –10 −3 , which is somewhat higher than the
                              standard assumption of 10 −6 –10 −5  for the mutation rate.
                                Welcsh and King (2001) suggested that BRCA1 may have an elevated
                              somatic mutation rate because of the high density of repetitive DNA
                              elements in the gene. Those repeats may also cause a higher germline
                              mutation rate, which would explain the higher than expected frequency
                              of variants in populations.
                                Alternatively, Harpending and Cochran (2006) argued that natural se-
                              lection of BRCA1 variants may be more strongly affected by that gene’s
                              role in early brain growth and development rather than in DNA repair.
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