Somatic whole genome dynamics of precancer in Barrett’s esophagus reveals features associated with disease progression

Abstract

While the genomes of normal tissues undergo dynamic changes over time, little is understood about the temporal-spatial dynamics of genomes in premalignant tissues that progress to cancer compared to those that remain cancer-free. Here we use whole genome sequencing to contrast genomic alterations in 427 longitudinal samples from 40 patients with stable Barrett’s esophagus compared to 40 Barrett’s patients who progressed to esophageal adenocarcinoma (ESAD). We show the same somatic mutational processes are active in Barrett’s tissue regardless of outcome, with high levels of mutation, ESAD gene and focal chromosomal alterations, and similar mutational signatures. The critical distinction between stable Barrett’s versus those who progress to cancer is acquisition and expansion of TP53−/− cell populations having complex structural variants and high-level amplifications, which are detectable up to six years prior to a cancer diagnosis. These findings reveal the timing of common somatic genome dynamics in stable Barrett’s esophagus and define key genomic features specific to progression to esophageal adenocarcinoma, both of which are critical for cancer prevention and early detection strategies.

Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus

“…Our results strongly suggest that ecDNAs usually arise in regions of HGD in patients with Barrett’s oesophagus, and nearly always in the context of TP53 alteration. These results complement previous reports that found that TP53 alteration and altered copy number might drive the transition from metaplasia to dysplasia 10 , 13 , 14 , 45 , 46 , showing the cooperative nature of various genetic and epigenetic alterations, and suggesting that ecDNA formation represents a particularly potent driver of transformation and could be an opportunity for specific therapeutic intervention. Moreover, our analysis of a single patient across time supports and extends a report 46 suggesting that TP53 alteration results in polyploid tumours with multiple amplified or gained regions providing a reservoir for amplifying oncogenes.…”

“…4) to other genomic features, such as TP53. Disruption of TP53 enables genomic instability 13,14,28,29 , and we found a strong association in both FHCC and Cambridge samples between the TP53 alteration status (Methods, 'TP53 alteration analysis') and the presence of ecDNA (Extended Data Fig. 6a,b).…”

“…However, the relative paucity of pre-cancer-to-cancer longitudinal studies, together with the challenges of interpreting clonality in the face of non-Mendelian genetics, have made it difficult to determine whether ecDNAs arise early in tumorigenesis and contribute to the transformation of dysplasia into cancer. Previous reports have hypothesized or reported the existence of ecDNA in pre-cancer samples derived from individuals with Barrett’s oesophagus 11 , 14 , 24 , 25 suggesting that ecDNA has a role in the malignant transformation to EAC 11 . Two surveillance studies of patients with Barrett’s oesophagus, including a longitudinal case–control study with multi-regional WGS sampling, and a completely independent, cross-sectional surveillance cohort, with full histological correlatives, provided us with an opportunity to study the role of ecDNA in the transition from Barrett’s oesophagus to EAC.…”

“…We analysed WGS data from oesophageal biopsies collected in an independent, prospectively collected case–control study conducted at the Fred Hutchinson Cancer Center (FHCC) of patients with Barrett’s oesophagus 14 (Fig. 1b ), including 40 patients with a cancer outcome and 40 patients who did not develop cancer (non-cancer outcome) during the study period or during follow-up (mean: 10.5 years; Supplementary Table 2 ).…”

AI-assisted discovery of an ethnicity-influenced driver of cell transformation in esophageal and gastroesophageal junction adenocarcinomas

“…In the case of AAs, the homozygous SNP rs2814778 , which disrupts a binding site for the GATA1 erythroid transcription factor, resulting in a ACKR1 -null phenotype ( Figure 7A ), is known to cause low ANC ( 18 , 19 ). We used a case-control study ( 20 ) that included 80 patients with BE (n = 40 who progressed to EACs and 40 who did not [nonprogressors]); this cohort was selected from a larger case-cohort study within the Seattle Barrett’s Esophagus Program at the Fred Hutchinson Cancer Research Center. Germline data from this cohort were analyzed for the occurrence of 10 SNPs that increase or decrease the ANC, as determined in various studies in the United States ( Supplemental Methods ).…”