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. 2008 Aug 6;105(32):11264–11269. doi: 10.1073/pnas.0802970105

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© 2008 by The National Academy of Sciences of the USA

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Fig. 4. — Proposed model for the progression of copy number variable DNA regions in the Li–Fraumeni cancer predisposition syndrome. Shown is a model of copy number variable DNA regions in patients with sporadic (top row) or inherited cancer (bottom row). (A) The total number of CNVs in the genomes of healthy individuals is similar. Non-cancer predisposed individuals have intact DNA repair mechanisms that maintain the number of CNVs close to this baseline (Fig. 1A). Despite efficient repair machinery, CNVs still occur 100–10,000 times more frequently than point mutations in the human genome (5). This is largely facilitated by the genomic sequence architecture. The precise mechanisms that give rise to most human CNVs are not known; however, nonallelic homologous recombination (NAHR) and nonhomologous end joining (NHEJ) are thought to be involved (6). Both NHEJ and NAHR are processes by which double-strand (ds) DNA breaks are repaired. The ubiquity and nonrandom distribution of CNVs in humans highlights genomic regions that are intrinsically unstable. (B) CNVs are more abundant in Li–Fraumeni cancer predisposed TP53 mutation carriers because of germline TP53 haploinsufficiency. TP53, as the “guardian of the genome” (26), suppresses cell cycle advance and DNA replication after dsDNA damage. Furthermore, TP53 is involved in the very processes known to give rise to CNVs, including suppressing the level of homologous recombination. Although defective TP53 is known to cause increased copy number variation and instability in tumors (23–25), our data suggests a new model wherein these alterations arise much earlier in cancer-prone individuals. We have observed this increase of CNVs in primary LFS lymphocyte DNA, but this effect may be more dramatic in other cells undergoing rapid remodeling, replicative stress, or in the normal tissue of patients with other cancer predisposition disorders. (C) CNVs become fertile ground for changes in cancer. Genomic instability may be preferentially directed toward CNV regions that are hotspots for recombination as suggested by our observation (Fig. 3) that CNVs can act as the genetic foundation on which larger somatic chromosomal deletions and duplications develop in tumors (shown here as arrows from CNVs in blood to those in tumor DNA). Tumor changes may be secondary to an underlying nontumor CNV or arise de novo at the same locus. It is likely that the sequence architecture of genomic regions that gives rise to CNVs also facilitates large somatic alterations. In this model, CNVs are seen as crucial regions in both sporadic and inherited tumors. Furthermore, the early age of onset of inherited tumors might be explained by the patient's increased CNV frequency. CNVs should therefore be viewed as important contributors to the inborn and acquired genetic changes that give rise to cancer. CNVs are shown as (one copy loss), (two copy loss), or (one copy gain). Inherited CNVs are represented in black, acquired CNVs are in red, and tumor-specific CNVs are in blue.

Inline graphic — Proposed model for the progression of copy number variable DNA regions in the Li–Fraumeni cancer predisposition syndrome. Shown is a model of copy number variable DNA regions in patients with sporadic (top row) or inherited cancer (bottom row). (A) The total number of CNVs in the genomes of healthy individuals is similar. Non-cancer predisposed individuals have intact DNA repair mechanisms that maintain the number of CNVs close to this baseline (Fig. 1A). Despite efficient repair machinery, CNVs still occur 100–10,000 times more frequently than point mutations in the human genome (5). This is largely facilitated by the genomic sequence architecture. The precise mechanisms that give rise to most human CNVs are not known; however, nonallelic homologous recombination (NAHR) and nonhomologous end joining (NHEJ) are thought to be involved (6). Both NHEJ and NAHR are processes by which double-strand (ds) DNA breaks are repaired. The ubiquity and nonrandom distribution of CNVs in humans highlights genomic regions that are intrinsically unstable. (B) CNVs are more abundant in Li–Fraumeni cancer predisposed TP53 mutation carriers because of germline TP53 haploinsufficiency. TP53, as the “guardian of the genome” (26), suppresses cell cycle advance and DNA replication after dsDNA damage. Furthermore, TP53 is involved in the very processes known to give rise to CNVs, including suppressing the level of homologous recombination. Although defective TP53 is known to cause increased copy number variation and instability in tumors (23–25), our data suggests a new model wherein these alterations arise much earlier in cancer-prone individuals. We have observed this increase of CNVs in primary LFS lymphocyte DNA, but this effect may be more dramatic in other cells undergoing rapid remodeling, replicative stress, or in the normal tissue of patients with other cancer predisposition disorders. (C) CNVs become fertile ground for changes in cancer. Genomic instability may be preferentially directed toward CNV regions that are hotspots for recombination as suggested by our observation (Fig. 3) that CNVs can act as the genetic foundation on which larger somatic chromosomal deletions and duplications develop in tumors (shown here as arrows from CNVs in blood to those in tumor DNA). Tumor changes may be secondary to an underlying nontumor CNV or arise de novo at the same locus. It is likely that the sequence architecture of genomic regions that gives rise to CNVs also facilitates large somatic alterations. In this model, CNVs are seen as crucial regions in both sporadic and inherited tumors. Furthermore, the early age of onset of inherited tumors might be explained by the patient's increased CNV frequency. CNVs should therefore be viewed as important contributors to the inborn and acquired genetic changes that give rise to cancer. CNVs are shown as (one copy loss), (two copy loss), or (one copy gain). Inherited CNVs are represented in black, acquired CNVs are in red, and tumor-specific CNVs are in blue.

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