These data provide the most comprehensive, high-resolution analysis to date of SCNA patterns across the three most common forms of gut adenocarcinoma. Our cohort size enhanced the ability to detect significant SCNAs, and we identified several focused areas of recurrent genomic alteration pointing toward genes that may contribute to cancer. Notably, the genomes of EA and GC cancers contain alterations selected for their contributions to the process of both intestinal metaplasia and malignant transformation to adenocarcinoma.
We observed more focal amplifications in upper GI adenocarcinomas compared to CRC. Unlike CRC, EA and GC emerge in a setting of bile and acid injury, which may generate DNA strand breaks and contribute to the high rates of SCNA (44
). Alternatively, distinct DNA repair pathways or selection for differing stimuli may account for these differences. It is unclear why the enhanced rates of focal amplifications in EA/GC were not matched by a similarly increased rate of focal deletions nor why the rates of deletion in GC fell below those in EA or CRC. Although the loci of the most significant amplifications peaks fell at known or plausible oncogenes, many focal deletions peaks lie in potential fragile sites. Thus, the mechanisms and selection pressures underlying deletions may differ from those responsible for amplification.
transcription factor genes lie in the second and sixth most significant amplification peaks across the full dataset, respectively. The developmental role of these transcription factors and selective amplification in GI cancers suggests that they may add to the growing number of lineage-survival transcription factor oncogenes (45
). A parallel phenomenon is amplification of SOX2
in squamous esophageal and lung carcinomas (46
), an event absent in EA.
A key clinical observation emerging from these data is that focally amplified RTKs were observed most prominently in EA and GC, suggesting that genomic amplifications will be more important biomarkers in upper gastrointestinal cancers than in CRC. Recent clinical trials reveal benefit when the HER2-directed antibody trastuzumab is combined with chemotherapy in treating ERBB2
-amplified or – overexpressing GC/EA (11
). The presence of ERBB2
amplifications in 6% of CRCs suggests that ERBB2-directed therapy may benefit select CRC patients (47
). Additionally, based on evidence that KRAS
mutation negatively predicts cetuximab response, highly prevalent KRAS
amplification in upper GI tumors may similarly impact clinical decisions. When KRAS
is evaluated as a biomarker in upper GI cancers, it will be important to examine both SCNAs and point mutations. Our data also point to other genomic amplifications of clinical relevance. CDK6
) and VEGFA
focal amplifications may serve as a marker of response to targeted inhibitors. More broadly, these data point to the inclusion of gene amplifications to guide therapy in upper gastrointestinal adenocarcinomas.
While these data suggest that many patients with EA or GC may benefit from treatment targeting an amplified RTK, it is unlikely that therapies directed against these targets alone will lead to durable responses. The progression-free survival provided by single-agent therapy with trastuzumab in GC/EA has been modest (11
). The presence of complex SCNA profiles in these tumors suggest there could be co-occurring alterations that confer primary resistance (49
) or enhanced genomic instability that speeds acquired resistance. In our cohort, the rates of co-occurrence between RTK-associated and other events did not significantly deviate from what would be expected for statistically independent events. However, co-occurrences were detected, and the rates with which individual pairs of events co-occur are likely to inform combinational treatment strategies. While evaluation of RTK-targeted agents is needed, the genomic complexity and variability of these cancers suggests that combination inhibitor strategies will ultimately be essential.
Beyond these immediately clinically relevant targets, these data provide enhanced insight into specific genes responsible for different subtypes of gastrointestinal adenocarcinoma. Despite a shared intestinal origin, upper gastrointestinal cancers exhibit many distinct events from those seen in CRC, such as alteration of cell cycle regulators (CCND1, CCNE1, CDK6, CDKN2A). Moreover, as evidenced by the selective deletion of RUNX1 in EA, clear genomic differences exist between EA and GC. While our analysis has helped identify loci of recurrent alteration and potential targets of these events, many recurrent regions of SCNA do not contain known oncogenes or tumor suppressors. One challenge moving forward will be to determine which of these regions harbor additional genes or non-coding elements that contribute toward intestinal metaplasia or transformation to cancer. High-resolution genome analyses of large sample numbers, as presented here, can guide future studies and inform the development of strategies to reverse the effects of the somatic genetic events that drive these cancers.