Aberrant chromosomal architecture is one of the most common features of cancer genome that often leads to chromosomal instability. In an article published on 3 January 2018 in the Nature Reviews Clinical Oncology, the investigators from the Francis Crick Institute and University College London Cancer Institute led by Charles Swanton describe the principles governing chromosomal instability in cancer, how it might influence sensitivity to immune-checkpoint inhibition and elaborate the vulnerabilities associated with chromosomal instability that offer potential therapeutic opportunities.
Aberrant chromosomal architecture ranges from small insertions or deletions to large chromosomal alterations
Aneuploidy, defined as the presence of an abnormal number of chromosomes, is one of the most striking and widespread features of human cancers. The vast majority of tumours also display various types of somatic copy-number alterations, including segmental aneuploidies, focal events, and/or whole-chromosome aneuploidies.
Considering the most frequent cancers, approximately 60% of non-small-cell lung cancers, 60–80% of breast tumours, 70% of colorectal tumours and 30% of prostate tumours deviate from a diploid karyotype.
Tumours that do not harbour gross aneuploidy often display hypermutation owing to mismatch-repair deficiencies or mutations in DNA polymerase-ɛ and/or DNA polymerase-δ catalytic subunit 1, which might reflect the maximum amount of genetic instability that cancer cells can handle without inducing lethality.
Chromosomal instability refers to the ongoing acquisition of genomic alterations that can involve either a gain or loss of whole chromosomes or structural aberrations, which range from point mutations to small-scale genomic alterations and gross chromosomal rearrangements. However, aneuploidy and chromosomal instability might differ in their prognostic value.
Chromosomal instability underpins intratumoural heterogeneity, resulting in the temporal and spatial diversification of tumour subclones. Chromosomal instability accelerates phenotypic adaptation under selective pressures encountered during tumour evolution and therapy, leading to anticancer drug resistance, treatment failure, disease recurrence and poor clinical outcome.
Identifying novel strategies to modulate chromosomal instability is, therefore, of paramount importance for the successful treatment of cancer. Modern sequencing and analytical methods greatly facilitate the identification and cataloguing of somatic copy-number alterations and offer new possibilities to better exploit chromosomal instability dynamics.
A deeper understanding of the vulnerabilities associated with chromosomal instability and the development of clinically applicable biomarkers are needed both for patient stratification and to leverage new therapeutic opportunities. Tackling chromosomal instability is essential for the success of personalised medicine.
Sansregret L, Vanhaesebroeck B, Swanton C. Determinants and clinical implications of chromosomal instability in cancer. Nature Reviews Clinical Oncology; Published online 3 January 2018. doi:10.1038/nrclinonc.2017.198