Study: Signatures of copy number alterations in human cancer. Image Credit: Kjpargeter/Shutterstock

Conceptual framework to investigate the patterns of copy number changes in human cancer

Changes in the number of genomic copies can also occur through complete genome doubling (WGD) and chromothripsis. These evolutionary events can run rampant during tumor development and culminate in the evolution of highly complex cancer genomes.

Study: Signatures of copy number changes in human cancer† Image Credit: Kjpargeter/Shutterstock


Numerous factors can lead to gain or loss of deoxyribonucleic acid (DNA) and aneuploidy that cause cancer. Some factors are – replication stress, spindle multipolarity and mitotic errors.

A new study published in Nature presented a conceptual framework to investigate the patterns of copy number changes in human cancer. When implementing this framework or algorithm on 33 human cancers, 21 produced signatures with copy numbers that matched the copy number patterns of 97% of the samples from the 9,873 cancers tested.

These copy number signature frameworks can help investigate copy number patterns in all cancers and develop targeted anti-tumor therapies. The signatures identified can delineate the prognostic implications of each cancer. In addition, the inclusion of copy number signatures as a bioinformatic tool could improve the accuracy of homologous recombination deficiency (HRD) assays.

About the study

The proposed framework could select common patterns of chromosomal arrangements from composite genomes. These patterns are then categorized and copy number signatures typed. These signatures can predict cancer progression and help develop targeted treatments based on cancer characteristics and aggressiveness.

In addition, the copy number signatures could also predict cancer progression and prognosis based on the genomic changes it has already undergone. Full genomic sequencing of tumors and the genomic changes would allow for customized cancer management strategies and more personalized care.

The framework also described the signatures with copy numbers that could be most damaging. Tumors undergoing chromothripsis – clustered rearrangements that generate oscillating copy number patterns, had the worst prognosis and compromised patient survival. For example, glioblastoma, an aggressive neurological cancer, is associated with the worst patient survival. The copy number framework analyzes indicated that glioblastoma patients with chromothripsis had a six-month shorter survival span.

The next step would be to fully predict the progression of cancers by determining the number of signatures for each cancer, along with the changes and modifications during growth.

The experiments also confirmed the transitions in the copy number signatures. Remarkably, one signature can be completely obliterated by the other after whole genome doubling (WGD). Cancer with a diploid signature would likely undergo WGD. WGD can change copy number 1 (CN1) to CN2. Meanwhile, cancer may also exhibit a chromosomal instability (CIN) transforming signature. Or a combination of CIN and WGD or early chromosomal losses followed by successive WGD events.

Examining the 21 signatures across different cancers revealed the ploidy-associated signatures – CN1 and CN2, in most cancers. Meanwhile, the CN4 signature was unique to reveal melanomaCN7 against breast cancer, CN10 against squamous lung carcinoma, CN18 ovarian carcinoma, CN20 liver cancer and CN21 was specific for paragangliomas.

On the other hand, CN4-CN8 signatures harbored high total copy numbers and were detected in certain tumor types with frequent amplicon events. Signatures CN9-CN12 had variable patterns of hypodiploidy, while signatures CN14 and CN16 were more likely in chromophobic renal cell carcinoma and adrenal cortical carcinoma. Signature CN17 was more likely to be present in tumor types described as HRD.

In addition, the cancer lines cluster based on the prevalence of signatures. Interestingly, the signatures reflected tumors’ unique evolutionary patterns. The most common signature with the highest level of amplification in eight cancer types was CN8 (an amplicon signature). Specific enrichment of CN8 was found based on the cancer types in the regions harboring the amplified oncogenes.

Allele-specific deletion of a segment of DNA containing an essential gene results in loss of heterozygosity (LOH). Such regions can cause deleterious mutations and can be considered a therapeutic target. The findings also revealed that the regions with conserved heterozygosity harbored higher concentrations of essential genes and were more likely to incur genomic losses. These areas can be explored in therapies.

In addition, hypoxia is strongly associated with several patterns of genomic instability, including HRD in cancer genomes. Unlike single base substitution signatures (SBSs) and insertions or deletions (IDs), both copy number signatures did not correlate with cancer risk factors such as gender, smoking status, or alcohol use. However, the association between age and signature number assignment in endometrial cancer was significant.


Nevertheless, the discovery is in its infancy; future experiments and research will be able to discover models best suited to answer specific clinical or biological questions. These findings represent the first step towards a pan-cancer approach to genomic signatures derived from allele-specific profiles.

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