Diverse ‘just-right’ levels of chromosomal instability and their clinical implications in neoadjuvant treated gastric cancer

Abstract

Background The Cancer Genome Atlas (TCGA) consortium described EBV positivity(+), high microsatellite instability (MSI-H), genomic stability (GS) and chromosomal instability (CIN) as molecular subtypes in gastric carcinomas (GC). We investigated the predictive and prognostic value of these subtypes with emphasis on CIN in the context of neoadjuvant chemotherapy (CTx) in GC. Methods TCGA subgroups were determined for 612 resected adenocarcinomas of the stomach and gastro-oesophageal junction (291 without, 321 with CTx) and 143 biopsies before CTx. EBV and MSI-H were analysed by standard assays. CIN was detected by multiplex PCRs analysing 22 microsatellite markers. Besides the TCGA classification, CIN was divided into four CIN-subgroups: low, moderate, substantial, high. Mutation profiling was performed for 52 tumours by next-generation sequencing. Results EBV(+) (HR, 0.48; 95% CI, 0.23–1.02), MSI-H (HR, 0.56; 95% CI, 0.35–0.89) and GS (HR, 0.72; 95% CI, 0.45–1.13) were associated with increased survival compared to CIN in the resected tumours. Considering the extended CIN-classification, CIN-substantial was a negative prognostic factor in uni- and multivariable analysis in resected tumours with CTx (each p < 0.05). In biopsies before CTx, CIN-high predicted tumour regression (p = 0.026), but was not prognostically relevant. Conclusion A refined CIN classification reveals tumours with different biological characteristics and potential clinical implications.

Increasing frequency of gene copy number aberrations is associated with immunosuppression and predicts poor prognosis in gastric adenocarcinoma

“…These results are consistent with the literature suggesting a more favourable prognosis for EBV-positive or MSI gastric cancer 3 , 6–8 . In agreement with the present data, some previous studies 4 , 6 , 9 suggested that patients with CIN cancer have the poorest prognosis. However, there are also studies suggesting that CS cancers have the poorest prognosis 3 , 7 and others 2 , 10 showing no difference in survival between TCGA subtypes.…”

“…However, the relationship between CIN or GS subtype and patient prognosis is less clear. Some studies 4 , 6 , 9 have suggested that patients with CIN gastric cancer have the poorest prognosis. Others have concluded that the GS subtype is related to poor prognosis 3 , 7 , or that there is no relationship between survival and GS or CIN subtype 2 , 10 , 11 .…”

Integrative analysis indicates the potential values of ANKRD53 in stomach adenocarcinoma

“…Zhang et al [ 25 ] found that gastric cancer patients with CIN were prone to HER2-positive and mucinous adenocarcinoma. Kohlruss et al [ 26 ] investigated the use of CIN in neoadjuvant chemotherapy for gastric cancer. In conclusion, CIN offers a new direction for targeted therapy of malignant tumors.…”

DNA Damage Repair and Current Therapeutic Approaches in Gastric Cancer: A Comprehensive Review

“…Some groups have referred to CIN as aneuploidy or polyploidy, while others have defined CIN as multiple structural rearrangements or frequent changes in the chromosome number (Tsai et al, 2018). The formation of CIN is caused by the breakdown of the DNA replication fork induced by an oncogene, which leads to DSB and genomic instability (Kohlruss et al, 2021). Although CIN in cancer has been studied extensively, its exact cause remains unclear.…”