Fig. 1: CDKN2A LoF occurrence in BE and EAC.
a, Gene composition of chromosome 9p21 locus. b, Canonical EAC drivers damaged in at least 5% of EACs (n = 1,032 patients). All cell cycle regulators are reported in bold. c, Alterations in cell cycle regulators in BE and EAC. CDKN2A gene products (p14-ARF and p16-INK4a) regulate the cell cycle through the E2F genes93. p14-ARF blocks MDM2 and TP53 degradation, which induces CDKN1A transcription. CDKN1A in turn inhibits the CCNE1/CDK2 complex ultimately blocking cell cycle through E2F1 inhibition. p16-INK4a directly inhibits the CCND/CDK6/CDK4 complex preventing RB1 phosphorylation. Unphosphorylated RB1 can bind E2F1, leading to cell cycle arrest. CDKN2A LoF favors cell cycle progression resulting in uncontrolled cell proliferation. Values within the circle represent the proportion of EACs, P-BEs and NP-BEs with at least one damaged cell cycle regulator (except TP53). d, Canonical EAC drivers damaged in at least 5% of P-BEs (n = 257 patients). e, Paired BE-EACs (n = 66 patients) with CDKN2A LoF. Clonally related alterations refer to either identical CDKN2A alterations in both lesions or CDKN2A alterations in BE that could further evolve in EAC. f, Canonical drivers damaged in at least 5% of NP-BEs (n = 99 patients). Alteration frequency of EAC canonical drivers in b, d and f is indicated in brackets. The alteration frequency of all EAC drivers in the three cohorts is available in Supplementary Table 2. FHCRC, Fred Hutchinson Cancer Research Center; LoF, loss of function; MSKCC, Memorial Sloan Kettering Cancer Center; NP-BE, non-progressor Barrett’s esophagus; EAC, esophageal adenocarcinoma; P-BE, progressor Barrett’s esophagus; SNV, single-nucleotide variant; TCGA, The Cancer Genome Atlas; UoC, University of Cambridge.
