Figure 1.
The ‘Monosomic’ pattern of karyotype evolution followed by most breast tumors, with endoreduplication.
A) and B) In the monosomic pattern of evolution [16], [17], each unbalanced translocation reduces the chromosome number by one, and leaves regions of loss of heterozygosity (LOH). C) Often, at some point, endoreduplication occurs, i.e. the whole chromosome complement doubles, to give a duplicated translocation and pairs of chromosome segments showing regions of loss of heterozygosity (dashed boxes). The process may then continue with more unbalanced translocations.
Figure 2.
The structure of the HCC1187 genome.
A) Spectral karyotype as in [44]. Chromosomes are named A-Z and a-k based on their relative sizes as in [12]. Cytogenetic description of the karyotype is in Table S1 in File S2. B) Circos plot [45] of the HCC1187 genome: Chromosome ideograms around the outside, oriented clockwise pter to qter. Moving inward, the pale grey and dark grey boxes are chromosome segments observed by array painting [12] with their chromosome of origin indicated. Their parent of origin (light grey and dark grey) was deduced from the number of allelotypes given by PICNIC segmentation (Fig. S1 in File S1). Note that assignment of parents 1 and 2 does not transfer between chromosomes. Dark blue line, total copy number, equivalent to array CGH, from PICNIC. Red line, copy number of the minor allele; where this is zero, the genome is homozygous. Chromosome segments that share a translocation breakpoint were assumed to have the same parental origin. Inner links represent interchromosome translocations identified previously [12]–[14].
Figure 3.
Chromosome segments in HCC1187 and their most probable state before endoreduplication.
Chromosome ideograms are drawn around the outside as in Fig. 2. Outer rings are array painting segments as in Fig. 2. Inner rings are chromosome segments that must have been present before endoreduplication. Coloured circles are different types of mutations, on the outer chromosome segment on which they were observed: truncating (red), non-synonymous (blue), small deletion (yellow), small duplication (black), expressed gene fusion (light blue). Mutations that were on two copies of a chromosome segment probably occurred before endoreduplication and are also shown on the inner, pre-endoreduplication genome. Dashed grey boxes on chromosome 1 and 11 indicate regions where parental origin was undetermined, because PICNIC segmentation suggested additional rearrangements had taken place.
Figure 4.
Point mutations on chromosome 6, and whether they occurred before or after endoreduplication.
A) Deducing the parental origin of chromosome 6 segments: the simplest explanation for the allele combinations (blue and red lines on the aCGH plot) in terms of parental origin. Both copies of chromosome 6 I (chromosome 6 fragments are designated 6 I, 6A, 6D as in ref. [12]) originate from parent 1 and the chromosome 6 segments of 6A and 6D originate from parent 2. Several small copy number steps are omitted for clarity. B) Sequence traces show whether mutations are on each isolated chromosome. HSD17B8: Chromosome 6I (2 copies) homozygous G>T mutation (black arrow); chromosome 6A and 6D, no mutation. NCB5OR: Chromosome 6, heterozygous mutant (black arrow). C) The likely evolution of the segments of chromosome 6: unbalanced translocation of one copy of chromosome 6 was followed by duplication of both chromosomes during endoreduplication. HSD17B8 was mutated on each copy of chromosome 6I, but not on 6A or 6D, while NCB5OR/CYB5R4 was mutated on only one copy of chromosome 6I. The pre-endoreduplication state was likely to be one normal copy of chromosome 6 with the other having a mutation in HSD17B8 and having suffered unbalanced translocation. The NCB5OR/CYB5R4 mutation occurred after endoreduplication.
Table 1.
Summary of Mutations in HCC1187 and their timing.