Most importantly, we find in multiple tumor types that ATG5 somatic mutations and alternative mRNA splicing specifically disrupt the ATG16L1-binding pocket in ATG5 and impair the essential ATG5-ATG16L1 interactions that are initially required for ATG12-ATG5 conjugation.
Additional integrated in silico analysis suggests that rs78835907 tends to affect ATG16L1 expression, which in turn is correlated with tumor aggressiveness and patient prognosis.
Conversely, expression of ATG16L1 in epithelial cancer cells inhibited tumor growth, indicating that the effects of autophagy are compartment-specific.
Our results are also consistent with previous biomarker studies showing that the increased expression of known autophagy markers (such as ATG16L and the cathepsins) in the tumor stroma is specifically associated with metastatic tumor progression and/or poor clinical outcome.