CREBBP Mutation as a Culprit for Negative SSTR2 PET in Neuroendocrine Tumors.

Purpose: This study aimed to elucidate the molecular and genetic factors contributing to negative Ga-DOTATATE PET imaging in neuroendocrine tumors (NETs). By integrating whole exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq), we sought to unravel the interplay between negative results of Ga-DOTATATE PET and genetic mutations in NETs.

Methods: A total of 18 patients with lung, ileal, or pancreatic NETs who underwent Ga-DOTATATE and F-FDG PET/CT scans as part of their initial diagnostic workup were retrospectively reviewed. WES analysis was conducted to investigate the genetic profile of circulating tumor cells of patients with negative Ga-DOTATATE scans. Leveraging scRNA-seq and single-cell somatic variant calling analysis, we compared the mutation burden and genetic hallmarks of NET cells with high /positive SSTR2 expression to those with negative/low SSTR2 expression.

Results: Our analysis identified an association between negative Ga-DOTATATE scans and reduced survival rates, regardless of tumor grade. WES highlighted a predominance of missense mutations, including CREBBP mutation, particularly in patients with negative PET results (incidence of %67 vs. %0). We observed a deleterious mutation in the SSTR2, likely accounting for the observed negative PET scans (incidence of %33). Single-cell single nucleotide variant (SNV) analysis showed that the total unique mutation burden in cells with negative/low SSTR2 expression was significantly higher compared to cells with positive/high expression; and notably, the CREBBP mutation was observed in more than 50% of patients and approximately 35% of NET cells. These results indicate that the frequency of CREBBP mutations is nearly as high as other well-known NET mutations such as MEN1, PTEN, and RB1. Additionally, CREBBP mutations are significantly more frequent in tumors with negative/low SSTR2 expression.

Conclusion: This study suggests that CREBBP mutations in NETs may potentially alter SSTR2 expression, indicating that patients with the mutated CREBBP genotype may not be suitable candidates for SSTR2-targeted PET imaging and radionuclide therapy.