ShatterProof: operational detection and quantification of chromothripsis

Abstract

BackgroundChromothripsis, a newly discovered type of complex genomic rearrangement, has been implicated in the evolution of several types of cancers. To date, it has been described in bone cancer, SHH-medulloblastoma and acute myeloid leukemia, amongst others, however there are still no formal or automated methods for detecting or annotating it in high throughput sequencing data. As such, findings of chromothripsis are difficult to compare and many cases likely escape detection altogether.ResultsWe introduce ShatterProof, a software tool for detecting and quantifying chromothriptic events. ShatterProof takes structural variation calls (translocations, copy-number variations, short insertions and loss of heterozygosity) produced by any algorithm and using an operational definition of chromothripsis performs robust statistical tests to accurately predict the presence and location of chromothriptic events. Validation of our tool was conducted using clinical data sets including matched normal, prostate cancer samples in addition to the colorectal cancer and SCLC data sets used in the original description of chromothripsis.ConclusionsShatterProof is computationally efficient, having low memory requirements and near linear computation time. This allows it to become a standard component of sequencing analysis pipelines, enabling researchers to routinely and accurately assess samples for chromothripsis. Source code and documentation can be found at http://search.cpan.org/~sgovind/Shatterproof.

Chromothripsis: potential origin in gametogenesis and preimplantation cell divisions. A review

“…This does not signify that unbalanced chromothripsis events do not occur in germline or during postzygotic divisions, but it strongly emphasizes the effect of selective pressure as a bias factor in the assessment of congenital chromothripsis because only balanced chromothripsis outcomes compatible with life have been found in individuals to date. Altogether, these key-features define a molecular signature of chromothripsis (30)(31)(32) and have important implications for understanding how and where chromothripsis arises.…”

Chromothripsis in Oncology: Literature Review and Case Report

“…Кроме того, неплохие результаты в плане выявления и характеристики феномена были получены при использовании техники однонуклеотидного поли-морфизма (single nucleotide polymorphism -SNP) [1,[5][6][7][8]. Важный вклад в стандартизацию и улучшение получаемых в этих исследованиях результатов вносит разработанный недавно тест «shatterproof» [9]. На молекулярном уровне он позволяет не только контролировать достоверность и выраженность ожидаемого в клетках хромосомного распада, но и оценивать его принадлежность к феномену хромо-трипсиса.…”

“…Следует отметить, что между отдельными вариантами опухолей разница более существенная [4,12,42]. Высокая частота хро-мотрипсиса свойственна опухолям костей [1], раку мо-лочной железы [42,43], простаты [42,44], кишечника [4,9] и пищевода [13]. Реже этот феномен встречается при раке печени [42] и мочеполовой системы [4,42,45].…”

The path to routine use of genomic biomarkers in the cancer clinic

“…Chromothripsis, for example, is generally described as a chromosome "shattering" event where a single chromosome acquires a large number of mutations of different types (Stephens et al 2011). There is no singular definition of chromothripsis and even only a few operational ways of identifying it (Lapuk et al 2012;Govind et al 2014). Similarly, there is not yet a standard library of mutational signatures or standard algorithms to call them uniformly across data sets.…”