Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer.
BACKGROUND
Structural rearrangements form a major class of somatic variation in cancer genomes. Local chromosome shattering, termed chromothripsis, is a mechanism proposed to be the cause of clustered chromosomal rearrangements and was recently described to occur in a small percentage of tumors. The significance of these clusters for tumor development or metastatic spread is largely unclear.


RESULTS
We used genome-wide long mate-pair sequencing and SNP array profiling to reveal that chromothripsis is a widespread phenomenon in primary colorectal cancer and metastases. We find large and small chromothripsis events in nearly every colorectal tumor sample and show that several breakpoints of chromothripsis clusters and isolated rearrangements affect cancer genes, including NOTCH2, EXO1 and MLL3. We complemented the structural variation studies by sequencing the coding regions of a cancer exome in all colorectal tumor samples and found somatic mutations in 24 genes, including APC, KRAS, SMAD4 and PIK3CA. A pairwise comparison of somatic variations in primary and metastatic samples indicated that many chromothripsis clusters, isolated rearrangements and point mutations are exclusively present in either the primary tumor or the metastasis and may affect cancer genes in a lesion-specific manner.


CONCLUSIONS
We conclude that chromothripsis is a prevalent mechanism driving structural rearrangements in colorectal cancer and show that a complex interplay between point mutations, simple copy number changes and chromothripsis events drive colorectal tumor development and metastasis.
Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, Utrecht, 3584 CG, The Netherlands.
Wigard P
WP
Kloosterman
Marlous
M
Hoogstraat
Oscar
O
Paling
Masoumeh
M
Tavakoli-Yaraki
Ivo
I
Renkens
Joost S
JS
Vermaat
Markus J
MJ
van Roosmalen
Stef
S
van Lieshout
Isaac J
IJ
Nijman
Wijnand
W
Roessingh
Ruben
R
van 't Slot
José
J
van de Belt
Victor
V
Guryev
Marco
M
Koudijs
Emile
E
Voest
Edwin
E
Cuppen
D016022:Case-Control Studies; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019295:Computational Biology; D045643:DNA Repair Enzymes / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005090:Exodeoxyribonucleases / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D005787:Gene Frequency; D015321:Gene Rearrangement; D052138:Genes, Neoplasm; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008297:Male; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D051883:Receptor, Notch2 / Q000235:genetics
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C452979:KMT2C protein, human; C497764:NOTCH2 protein, human; D051883:Receptor, Notch2; C114331:EXO1 protein, human; D005090:Exodeoxyribonucleases; D045643:DNA Repair Enzymes