Replication stress is one of the main causes of genomic instability in cancer cells. It has been shown in many cell models that replication stress is, in most cases, caused by alterations in the cell cycle, especially during early entry of cells into S phase. The work of Carpem team 2 (Bayard Q et al., Nat Commun, 2018) identified a new molecular subgroup of hepatocellular carcinoma (HCC) characterized by activation of cyclins A2 or E1 (involved in S-phase entry of the cell cycle), associated with a very high genomic instability. This subgroup of HCC presents a transcriptomic signature of replication stress and a characteristic signature of structural variants (SV) called RS1.
Recent work by this same team published in the journal Cancer Research, focused on the impact of replication stress on SVs in NCC-HCC. Using optical mapping and whole genome sequencing approaches, the authors showed that replication stress induces a continuous accumulation of VS during the progression of NSCLC, promoting the acquisition of new genetic alterations in the tumors. Taken together, this analysis sheds light on the mechanisms, dynamics and consequences of VS accumulation in replication-stressed tumors.