A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy

Abstract

The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-genome sequencing data obtained from chemo-naive and chemo-treated samples. The quality of whole-genomic sequencing data is comparable across all samples regardless of chemotherapy status. Inclusion of samples collected post-chemotherapy increased the proportion of late-stage tumors. When comparing matched pre-and post-chemotherapy samples from 10 cases, the mutational signatures, copy number, and SNV mutational profiles reflect the expected heterogeneity in this disease. Analysis of SNVs in relation to allele-specific copy-number changes pinpoints the common ancestor to a point prior to chemotherapy. For cases in which pre-and post-chemotherapy samples do show substantial differences, the timing of the divergence is near-synchronous with endoreduplication. Comparison across a large prospective cohort (62 treatment-naive, 58 chemotherapy-treated samples) reveals no significant differences in the overall mutation rate, mutation signatures, specific recurrent point mutations, or copy-number events in respect to chemotherapy status. In conclusion, whole-genome sequencing of samples obtained following neoadjuvant chemotherapy is representative of the genomic landscape of esophageal adenocarcinoma. Excluding these samples reduces the material available for cataloging and introduces a bias toward the earlier stages of cancer.

Integrated proteogenomic analysis of metastatic thoracic tumors identifies APOBEC mutagenesis and copy number alterations as drivers of proteogenomic tumor evolution and heterogeneity

“…Given that all patients in our cohort received prior treatment, we cannot exclude the possibility that therapy contributed to the observed findings. However, recent studies assessing tumors pre-and post-chemotherapy in multiple tumor types did not find an increase in overall mutational load or a significant increase in APOBEC-signature mutations 37,38 . Moreover, the patients in our cohort with the highest level of APOBEC-mutagenesis, RA003 and RA006, received the least therapy prior to autopsy.…”

Integrated genomics and comprehensive validation reveal novel drivers of genomic evolution in esophageal adenocarcinoma

“…Like most other cancers, a marked genomic instability has also been observed in EAC and its premalignant states 3,4,9,10 . Consistently, the EAC genome is highly aberrant 9 and the cancer is heterogeneous and chemoresistant 11 . Therefore, identification of genes which drive genomic evolution can help develop effective strategies for prevention and treatment of EAC.…”

“…EAC genome is highly aberrant with ∼ ten single-nucleotide variations per million base pair 9 . Genomic instability and its consequences can probably be attributed to chemoresistant nature of EAC 11 . There is also evidence which suggests that genomic instability contributes to disease progression 12 and associates with poor survival in EAC 13 .…”

In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors

“…We also analyzed the mutational spectra of 140 esophageal adenocarcinomas (ESADs), of which 68 had been treated with cisplatin prior to surgery (Noorani et al 2017 Figure 3C). The TC and TG DNSs, were less frequent in the tumors than in the experimental data, but nevertheless showed very similar sequence context preferences.…”

“…This study used whole genome sequencing data from 264 HCCs from Japan (Fujimoto et al 2016) and 78 from Hong Kong (Kan et al 2013) and 140 ESADs (Noorani et al 2017). Additionally, we used whole genome sequencing data of 24 lung adenocarcinomas (Imielinski et al 2012) and 112 melanomas.…”