Beyond the clinical applications, the data presented in the article by Zhu et al1 also suggest potential insight into the mechanisms underlying GRP78 protumorigenic activity. The intronic rs430397 polymorphism studied is one of approximately 200 known olymorphisms within the GRP78 gene. Intronic and silent exonic polymorphisms have received less attention, but are beginning to be recognized for their potential contribution to the development and/or progression of a variety of diseases, including cancer. The location of the rs430397 polymorphism just upstream from the intron/exon boundary suggests that this sequence variation may affect the function of the classic splice site region, potentially impacting isoform generation. Beyond the classic splice site region, intronic and exonic splicing enhancer or intronic and exonic splicing silencing sites are found throughout the introns and exons of genes. Sequence alterations in any of these intronic (or exonic) sites can lead to major alterations in the levels of expression and relative isoform abundances.8 When the alteration of an intronic gene sequence has a direct effect on the expression or activity of that gene, it is referred to as a cis-acting mutation. Alternate splicing as a result of cis-acting mutations can affect expression by altering the efficiency of translation or mRNA stability. Indeed, alternate splicing has been demonstrated to favor cytosolic over ER localization of GRP78.2 However, this isoform involves alternate splicing of the 5′ portion of the pre-mRNA. With the location of rs430397 in the fifth of seven GRP78 introns, one might speculate that it would be more likely to have an effect on the 3′ portion of the mRNA, perhaps leading to alterations in translation, stability, or other properties. Increased RNA and protein expression in association with the rs430397 A/A genotype is demonstrated in the current publication (see e-Appendix 1 in the article by Zhu et al1). It should be noted, though, that most splicing alterations known to contribute to malignant progression have been the result of trans-acting mutations in which regulators of pre-mRNA splicing (ie, factors that interact with intronic splicing enhancers) are affected.8 Thus, investigations of the impact of the rs430397 polymorphism on protein localization, isoform generation, cell function, and other properties could be of great interest and significant importance to understanding the role it may play in lung cancer.