Changes in the number of genomic copies can also occur through whole genome duplication (WGD) and chromotripsy. These evolutionary events can be rampant during tumor development and can occur in the evolution of highly complex cancer genomes.
Study: Signatures of alterations in the number of copies in human cancer. Image credit: Kjpargeter / Shutterstock
Fund
Numerous factors can lead to gains or losses of deoxyribonucleic acid (DNA) and aneuploidy leading to cancer. Some factors are: replication stress, screw multipolarity, and mitotic errors.
A new study published in Nature presented a conceptual framework for examining patterns of alterations in the number of copies in human cancer. By implementing this framework or algorithm in 33 types of human cancers, 21 copy number signatures were obtained that matched the copy number patterns of 97% of the samples among the 9,873 cancers tested.
These copy number signature frames could help investigate patterns of copy numbers in all types of cancer and therefore develop therapies aimed at tumors. The identified signatures could delineate the prognostic implications of each cancer. In addition, the inclusion of copy number signatures as a bioinformatics tool could improve the accuracy of homologous recombination (HRD) deficiency testing.
About the study
The proposed framework could select common patterns of chromosomal arrangements from composite genomes. These patterns are then sorted and the signatures of the copy number are written. These signatures can predict the progression of cancer and help develop targeted treatments based on the characteristics and aggressiveness of the cancer.
In addition, copy number signatures could also predict the progression and prognosis of cancer based on the genomic changes it has already undergone. Complete genomic sequencing of tumors and genomic alterations would allow for personalized cancer management strategies and more personalized attention.
The frame also showed the signatures of the copy numbers that could be the most damaging. Tumors suffering from chromotrypsis: grouped rearrangements that generate patterns in the number of oscillating copies had the worst prognosis and compromised patient survival. For example, glioblastoma, an aggressive neurological cancer, is associated with poorer patient survival. Analyzes of the copy number frame indicated that patients with glioblastoma with chromomotripsis had a shorter survival period of six months.
The next step would be to completely predict the progression of the cancers by determining the signatures of the number of copies of each cancer, along with the alterations and modifications during their growth.
The experiments also confirmed the transitions in the signatures of the copy numbers. Notably, one signature could be completely deleted by the other after a whole genome duplication (WGD). Cancer with a diploid signature is likely to suffer from WGD. WGD can change copy number 1 (CN1) to CN2. Meanwhile, cancer may also show a signature that transforms chromosomal instability (CIN). Or a combination of CIN and WGD or early chromosomal loss followed by successive WGD events.
The survey of the 21 signatures across various types of cancer revealed the signatures associated with ploidy: CN1 and CN2, in most types of cancer. Meanwhile, the CN4 signature was unique for uveal melanoma, CN7 for breast cancer, CN10 for squamous cell carcinoma, CN18 ovarian carcinoma, CN20 liver cancer, and CN21 was specific for paragangliomas.
On the other hand, CN4-CN8 signatures contained a high number of total copies and were detected in certain types of tumors with prevalent amplicon events. CN9-CN12 signatures had varying patterns of hypodiploidy, while CN14 and CN16 signatures were more likely in chromophobic renal cell carcinoma and adrenocortical carcinoma. The CN17 signature was more likely to be present in the tumor types described as HRD.
In addition, cancer lineages are grouped according to the prevalence of signatures. Interestingly, the signatures reflected the unique evolutionary patterns of the tumors. The most common signature with the highest amplification level in eight cancers was CN8 (an amplicon signature). CN8-specific enrichment was found based on cancer types in the regions that housed the amplified oncogenes.
Specific allele deletion of a DNA segment containing an essential gene results in loss of heterozygosity (LOH). These areas can produce harmful mutations and can be considered a therapeutic target. The findings also revealed that regions of retained heterozygosity harbored higher concentrations of essential genes and were more likely to suffer genomic losses. These areas can be explored in therapy.
In addition, hypoxia is strongly associated with several patterns of genomic instability, including HRD in cancer genomes. Unlike single-base substitution (SBS) signatures and insertion or deletion (ID) signatures, copy number signatures did not correlate with cancer risk factors such as gender, smoking status, or alcohol intake. However, the association between age and signature attribution of copy number in endometrial cancer was significant.
Conclusion
However, the discovery is in its nascent stage; future experiments and research will be able to discover the most appropriate models for answering specific clinical or biological questions. These findings represent the first step toward a pan-cancer approach to genomic signatures derived from allele-specific profiles.