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

Conceptual framework for examining patterns of copy number alterations in human cancer

Changes in genomic copy number may also occur Going through whole genome doubling (WGD) and chromothripsis. These evolutionary events can be endemic during tumor development and can result in the evolution of very complex cancer genomes.

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


Many factors can lead to gains or losses of deoxyribonucleic acid (DNA) and the aneuploidy that leads to cancer. Some factors are – replication stress, spindle multipolarity and mitotic errors.

A new study published in Nature presented a conceptual framework for examining patterns of copy number alterations in human cancer. When implementing this framework or algorithm on 33 types of human cancers, 21 copy number signatures matching the copy number patterns of 97% of the samples among the 9,873 cancers tested were obtained.

These copy number signature frameworks could help study copy number patterns in all types of cancer and thus develop targeted tumor therapies. The identified signatures could delineate the prognostic implications of each cancer. Furthermore, the inclusion of copy number signatures as a bioinformatics tool could improve the accuracy of homologous recombination deficiency (HRD) testing.

About the study

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

Moreover, copy number signatures would also be able to predict cancer progression and prognosis based on the genomic changes it has already undergone. Whole genomic sequencing of tumors and genomic alterations would enable personalized cancer management strategies and the delivery of more personalized care.

The framework also described the copy number signatures that could be the most deleterious. Tumors that undergo chromothripsia – clustered rearrangements generating 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. Frame copy number analyzes indicated that glioblastoma patients with chromothripsis had a shorter survival time of six months.

The next step would be to fully predict the progression of cancers by determining the copy number signatures for each cancer, as well as the alterations and modifications during its growth.

The experiments also confirmed transitions in copy number signatures. Notably, one signature could be completely erased by the other after a whole genome doubling (WGD). Cancer with a diploid signature was susceptible to WGD. WGD can replace copy number 1 (CN1) with CN2. Meanwhile, the cancer may also show a signature transforming chromosomal instability (CIN). Or a combination of CIN and WGD or early chromosome loss followed by successive WGD events.

Studying the 21 signatures across various cancer types revealed the ploidy-associated signatures – CN1 and CN2, in most cancer types. Meanwhile, the CN4 signature was unique to uveal melanomaCN7 to breast cancer, CN10 to lung squamous cell carcinoma, CN18 to ovarian carcinoma, CN20 to liver cancer and CN21 was specific to paragangliomas.

On the other hand, CN4-CN8 signatures harbored a high total copy number and were detected in some tumor types with prevalent amplicon events. CN9-CN12 signatures showed variable patterns of hypodiploidy, while CN14 and CN16 signatures were more likely in chromophobe renal cell carcinoma and adrenocortical carcinoma. The CN17 signature was more likely to be present in tumor types described as HRD.

Additionally, cancer lineages cluster based on the prevalence of signatures. Interestingly, the signatures reflected the tumors’ unique evolutionary patterns. The most common signature with the highest level of amplification in eight cancer types was CN8 (an amplicon signature). CN8-specific enrichment was found based on cancer types in regions that harbored the amplified oncogenes.

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

Moreover, hypoxia is strongly associated with various patterns of genomic instability, including HRD in cancer genomes. Unlike single base substitutions (SBS) and insertions or deletions (ID) signatures, copy number signatures were not correlated with cancer risk factors such as gender, smoking status, or substance use. of alcohol. However, the association between age and copy number signature assignment in endometrial cancer was significant.


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

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