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Communicated by Francis S. Collins, National Institutes of Health, Bethesda, MD (received for review April 10, 2000)
Article Figures & SI
Figures
- Figure 1
A schematic representation of results from the tree analysis of nonrandom genomic alterations of BRCAX breast carcinomas. The root represents a normal diploid mammary cell, whereas only events above the 95th percentile of the distribution are shown (see text for details). (A) Shown is how the observed probabilities of events and observed joint probabilities of pairs could be used to assign a weight to each possible “edge” between pairs and events. The edge represents a putative cause-and-effect relationship between events, whereas clusters of events may define a genetic subclass of tumors. (B) The result obtained from the best fitting distance matrix, weighted Fitch tree (see text for details). Both independent probabilistic approaches thus led to the following finding: The loss of chromosome 13 seems to be an early event in the pathogenesis of BRCAX breast cancers, and it is not strongly associated with other early or late events.
- Figure 2
Pedigree Lund 5 shown with the CGH profiles of chromosome 13, demonstrating loss of 13q21-q22 in all five tumors from the four affected individuals. The haplotypes with markers from 13q are shown next to the CGH profiles (the marker map is located on the left). Markers located near BRCA2 were not shared between the affected individuals (D13S260 and D13S267). At 13q21-q22, however, all five affected women shared a 7 cM haplotype (red box). Below the CGH profile of a bilateral breast cancer is the original CGH image (FITC hybridization with tumor DNA). The interstitial 13q21-q22 loss can be observed as an absence of FITC signal (green color) in the middle of the chromosome (a). Hybridization with a Texas red-labeled yeast artificial chromosome probe for marker D13S1257 demonstrates that the region of the shared haplotype coincided with the region of deletion by CGH (b).
Tables
- Table 1
Ten most common somatic alterations in BRCAX cancers (percentage of cases), as compared to other hereditary and unselected breast cancers by CGH
Location BRCAX BRCA1 (7) BRCA2 (7) Unselected (10) Loss 13q21–q31 56 55 73* 26 Gain 1q22–q32 46 55 53 66 Loss 6q16–q24 41 27 60 18 Gain 17q23 39 46 87 18 Gain 8q23–q24 36 73 53 49 Gain 16p13–p12 34 27 40 38 Loss 11q14–q24 30 23 53 18 Gain 19q 30 18 40 20 Loss 9p23–p21 26 27 40 20 Loss Xq 26 40 47 20 -
↵* Target area 13cen–q21.
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- Table 2
Combined lod scores from the 77 families at several values of theta for markers on 13q
Marker cM lod score at θ 0.00 0.05 0.10 0.20 D13S260 −8.24 −4.81 −2.92 −1.01 D13S1701 1.6 −4.36 −2.48 −1.43 −0.39 D13S267 0 −2.35 −1.16 −0.56 −0.04 D13S1301 20.3 −1.75 −0.69 −0.16 0.23 D13S1313 0.8 0.94 1.13 1.18 0.98 D13S1317 1.9 −1.87 −0.18 0.58 0.96 D13S1262 0 −4.01 −2.03 −1.09 −0.21 D13S275 0.8 −0.24 0.7 0.98 0.87 D13S1296 0.8 −0.27 0.79 1.13 1.05 D13S1308 0 1.61 2.56 2.76 2.19 D13S1291 0.5 −2.64 −0.85 −0.03 0.52 D13S152 2.6 −5.58 −2.12 −0.67 0.41 D13S1257 0 −0.4 0.64 1.14 1.26 D13S745 0 0.63 0.86 0.89 0.68 D13S791 0 −1.55 0.36 0.99 1.09 D13S1326 0 −3.34 −1.2 −0.28 0.32 D13S1249 0.7 −0.45 0.16 0.47 0.59 D13S166 0 −4.93 −2.03 −0.7 0.39 D13S269 1.0 −1.66 −0.2 0.5 0.85 D13S162 1.4 −1.13 0.68 1.39 1.55 D13S1306 1.2 −3.01 −0.98 −0.07 0.51 D13S160 1.8 −2.26 −0.5 0.18 0.47 D13S1255 1.6 −2.87 −1.08 −0.16 0.48 -
The markers D13S260, D13S1701 and D13S267 flank the BRCA2 gene. The peak lod score of 2.76 was seen at marker D13S1308 at θ = 0.10.
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Lod scores greater than 1.0 are shown in bold.
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Interval within markers Maximum multipoint lod within the interval Maximum multipoint Hlod within the interval (α) D13S260–D13S1701 −10.72 0 (0) D13S1701–D13S1301 −1.27 0.05 (0.17) D13S1301–D13S1262 −4.16 0 (0) D13S1262–D13S1296 −1.26 1.50 (0.37) D13S1296–D13S1308 2.60 3.46 (0.65) D13S1308–D13S1291 −0.52 1.49 (0.42) D13S1291–D13S152 −6.08 0.06 (0.09) D13S152–D13S1257 −4.08 0.76 (0.29) D13S1257–D13S745 −2.25 0.90 (0.39) D13S745–D13S791 −0.88 0.95 (0.43) D13S791–D13S1326 −5.45 0.16 (0.16) D13S1326–D13S166 −5.65 0.26 (0.16) D13S166–D13S269 −5.64 0.39 (0.17) D13S269–D13S162 −2.60 0.66 (0.25) D13S162–D13S160 −2.92 0.68 (0.31) -
Lod scores greater than 1.0 are shown in bold. α denotes the percentage of families linked.
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Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus
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