Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer

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.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.Colorectal cancer develops from a benign adenomatous polyp into an invasive cancer, which can metastasize to distant sites such as the liver [1]. Tumor progression is associated with a variety of genetic changes and chromosome instability often leads to loss of tumor suppressor genes, such as APC, TP53 and SMAD4.High-throughput DNA sequencing has indicated that there are between 1, 000 and 10, 000 somatic mutations in the genomes of adult solid cancers [2-5]. Furthermore, next-generation sequencing has revolutionized our possibilities to profile genetic changes in cancer genomes, yielding important insights into the genes and mechanisms that contribute to cancer development and progression [5,6]. Systematic sequence analysis of coding regions in primary and metastatic tumor genomes has shown that only a few m