A stitch too late is my fate

Nature has some truly amazing things up her sleeve. Chromothripsis, a phenomenon discovered only about 4-5 years ago, stands for shattering of chromosomes to pieces; is an isolated event that was identified in both cancers and congenital abnormalities. Its discovery goes against the popular belief that evolution of cancers occurred due to sequential build up of independent genomic mutations in cancer-causing genes gradually accumulating the ‘hallmarks of cancer’. Such single catastrophic events are immediately slated to be reset by our natural DNA repair mechanisms that kick in and try to put the pieces back in order. But aberrant replication and imperfect random reassembly can lead to incorrect genomic rearrangements. Consequently, this event can lead to loss of tumor suppressors or amplifications of oncogenes at these chromosomal breakpoints.  One can only imagine the impact of this massive genomic instability in cancers. However, in recent news, a lady with an extremely rare autosomal dominant immune disease (only 60 cases are known worldwide) called WHIM’s syndrome (stands for Warts, Hypogammaglobulinemia, Infections and Myelokathexis) was cured of her condition when a possible chromothripsis event deleted the disease allele in one of her blood ‘stem’ cells. Stem cells give rise to a lot of blood cells of different lineages that will accordingly also carry of the ‘newly-corrected’ gene. Now that is what I call a miracle. 🙂 WHIM’s disease is caused by the defect in a single gene, CXCR4 (a chemokine receptor) on chromosome 2 (Chr.2) , that causes white blood cells to get stuck in the bone marrow instead of entering the blood stream. Examining her apparently ‘normal’ white blood cells showed that one copy of the Chr. 2 that harboured the CXCR4 gene, was 15% shorter than its other copy, resulting in the loss of not only the defective gene (allele) but 163 other normal genes. The loss of these genes did not have an apparent affect as a functional copy still exists on the sister chromosome (we have two copies of each chromosome corresponding to 23 pairs – one from each parent and hence the 2 functional copies (alleles) of each gene).

Using live cell imaging and single-cell genome sequencing, it was later found that the chromothripsis may occur in aberrant nuclear structures called micronuclei. Micronuclei are formed when a chromosome or a fragment of chromosome gets segregated from the daughter nuclei during cell division, undergoes crushing and breaking up and defective DNA replication and repair and is subsequently reincorporated into the main nucleus. Chromothripsis is characterized by alternating pattern of copy number variations, preservation of islands of heterozygosity among huge regions with loss of heterozygosity, clustering of the breakpoints, randomness of pairing of fragment ends (head-to-tail, tail-to-head, head-to-head and tail-to-tail) suggesting double stranded DNA breaks and a chaotic pattern of rearrangements.

The shattered chromosomes in chromothripsis that were not incorporated back into the derivative ‘stitched-up’ chromosome could possibly be linked to formation of extra-chromosomal double minutes (resulting from circularization of the double stranded DNA) that become readily amplified and may harbour many oncogenes. A study found evidence of oncogenic chromosomal double minutes in nearly 20% of TCGA glioblastoma clinical samples [1]. Nearly 80% of glioblastomas are said to harbour promoter mutations that activate TERT expression and the double minute chromosomes were shown to contain the TERT gene leading to its amplification [2]. Recently, chromothripsis events were shown to be occurring at a relatively high frequency in glioblastoma (39%) and shown to be clustered on Chr. 12 [3]. A pan-cancer analysis of somatic copy number alterations showed a striking case of chromothripsis in glioblastoma resulting in deletion of CDKN2A locus in 20 of 22 samples and co-amplification of CDK4 and MDM2 in 9 of 12 samples [4]. Surprisingly, chromothripsis events were concentrated on particular chromosomes rather than randomly distributed; particular Chr. 1, 4, 9, 12 and 15 are more susceptible to chromothripsis events [4]. We still need to understand the mechanisms that lead to chromothripsis and its implications on cancer pathogenesis such as, if it an early driving event or occurs in later stages of disease.

Lastly, although chromothripsis like genomic rearrangements have been discovered in the context of disease, it is possible this is a more general occurrence and an important reason behind the rapid evolution of the genomes in single large jumps required for organismal evolution rather than cumulative, small progressive steps.

1. Sanborn JZ, Salama SR, Grifford M et al. Double minute chromosomes in glioblastoma multiforme are revealed by precise reconstruction of oncogenic amplicons. Cancer Res, 73(19), 6036-6045 (2013).
2. Killela PJ, Reitman ZJ, Jiao Y et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A, 110(15), 6021-6026 (2013).
3. Malhotra A, Lindberg M, Faust GG et al. Breakpoint profiling of 64 cancer genomes reveals numerous complex rearrangements spawned by homology-independent mechanisms. Genome Res, 23(5), 762-776 (2013).
4. Zack TI, Schumacher SE, Carter SL et al. Pan-cancer patterns of somatic copy number alteration. Nat Genet, 45(10), 1134-1140 (2013).