Publications

Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis

Weaver, J.M.J., Ross-Innes, C.S., Shannon, N., Lynch, A.G., Forshew, T., Barbera, M., Murtaza, M., Ong, C.A.J., Lao-Sirieix, P., Dunning, M.J., Smith, L., Smith, M.L., Anderson, C.L., Carvalho, B., O’Donovan, M., Underwood, T.J., May, A.P., Grehan, N., Hardwick, R., Davies, J., Oloumi, A., Aparicio, S., Caldas, C., Eldridge, M.D., Edwards, P.A.W., Rosenfeld, N., Tavaré, S., Fitzgerald, R.C., OCCAMS consortium

Cancer genome sequencing studies have identified numerous driver genes but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from pre-malignant Barrett’s esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently-mutated genes and assessed clonal structure using whole-genome sequencing and amplicon-resequencing of 112 EACs. We next screened a cohort of 109 biopsies from two key transition points in the development of malignancy; benign metaplastic never-dysplastic Barrett’s esophagus (NDBE, n=66), and high-grade dysplasia (HGD, n=43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 were stage-specific, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett’s esophagus in a novel non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.

Citation

Weaver, J.M.J., Ross-Innes, C.S., Shannon, N., Lynch, A.G., Forshew, T., Barbera, M., Murtaza, M., Ong, C.A.J., Lao-Sirieix, P., Dunning, M.J., Smith, L., Smith, M.L., Anderson, C.L., Carvalho, B., O’Donovan, M., Underwood, T.J., May, A.P., Grehan, N., Hardwick, R., Davies, J., Oloumi, A., Aparicio, S., Caldas, C., Eldridge, M.D., Edwards, P.A.W., Rosenfeld, N., Tavaré, S., Fitzgerald, R.C., OCCAMS consortium "Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis" Nature Genetics (2015): 837–43