A 4-gene signature predicts survival of patients with resected adenocarcinoma of the esophagus, junction, and gastric cardia.
OBJECTIVE
The incidence of esophageal and junctional adenocarcinoma has increased 6-fold in the past 30 years and 5-year survival remains approximately 20%. Current staging is limited in its ability to predict survival which has ramifications for treatment choices. The aim of this study was to generate and validate a molecular prognostic signature for esophageal adenocarcinoma.


METHODS
Gene expression profiling was performed and the resulting 42,000 gene signatures correlated with clinical and pathologic features for 75 snap-frozen esophageal and junctional resection specimens. External validation of selected targets was performed on 371 independent cases using immunohistochemistry to maximize clinical applicability.


RESULTS
A total of 119 genes were associated significantly with survival and 270 genes with the number of involved lymph nodes. Filtering of these lists resulted in a shortlist of 10 genes taken forward to validation. Four genes proved to be prognostic at the protein level (deoxycytidine kinase [DCK], 3'-phosphoadenosine 5'-phosphosulfate synthase 2 [PAPSS2], sirtuin 2 [SIRT2], and tripartite motif-containing 44 [TRIM44]) and were combined to create a molecular prognostic signature. This 4-gene signature was highly predictive of survival in the independent external validation cohort (0/4 genes dysregulated 5-year survival, 58%; 95% confidence interval [CI], 36%-80%; 1-2/4 genes dysregulated 5-year survival, 26%; 95% CI, 20%-32%; and 3-4/4 genes dysregulated 5-year survival, 14%; 95% CI, 4%-24% (P = .001). Furthermore, this 4-gene signature was independently prognostic in a multivariable model together with the existing clinical TNM staging system (P = .013).


CONCLUSIONS
This study has generated a clinically applicable prognostic gene signature that independently predicts survival in an external validation cohort and may inform management decisions.
Peters
Christopher J
CJ
MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, United Kingdom.
Rees
Jonathan R E
JR
Hardwick
Richard H
RH
Hardwick
James S
JS
Vowler
Sarah L
SL
Ong
Chin-Ann J
CA
Zhang
Chunsheng
C
Save
Vicki
V
O'Donovan
Maria
M
Rassl
Doris
D
Alderson
Derek
D
Caldas
Carlos
C
Fitzgerald
Rebecca C
RC
D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002299:Cardia / Q000601:surgery; D004938:Esophageal Neoplasms / Q000235:genetics / Q000401:mortality / Q000601:surgery; D004943:Esophagogastric Junction / Q000601:surgery; D004947:Esophagus / Q000601:surgery; D005260:Female; D020869:Gene Expression Profiling / Q000592:standards*; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D013274:Stomach Neoplasms / Q000235:genetics / Q000401:mortality / Q000601:surgery
D005819:Genetic Markers