Cancer arises as the consequence of mutations and epigenetic alterations that activate oncogenes and inactivate tumor suppressor genes. Through a genome-wide screen for methylated genes in colon neoplasms, we identified aberrantly methylated RET in colorectal cancer. RET, a transmembrane receptor tyrosine kinase and a receptor for the GDNF-family ligands, was one of the first oncogenes to be identified and has been shown to be an oncogene in thyroid cancer and pheochromocytoma. However, unexpectedly, we found RET is methylated in 27% of colon adenomas and in 63% of colorectal cancers, and now provide evidence that RET has tumor suppressor activity in colon cancer. The aberrant methylation of RET correlates with decreased RET expression, whereas the restoration of RET in colorectal cancer cell lines results in apoptosis. Furthermore, in support of a tumor suppressor function of RET, mutant RET has also been found in primary colorectal cancer. We now show that these mutations inactivate RET, which is consistent with RET being a tumor suppressor gene in the colon. These findings suggest that the aberrant methylation of RET and the mutational inactivation of RET promote colorectal cancer formation and that RET can serve as a tumor suppressor gene in the colon. Moreover, the increased frequency of methylated RET in colon cancers compared to adenomas suggests RET inactivation is involved in the progression of colon adenomas to cancer.

C urrently, 3 vaccines have been granted Emergency Use Authorization for coronavirus disease 2019 prevention in the United States. These include the messenger RNA (mRNA) platform vaccines (mRNA-1273; Moderna/National Institutes of Health) and BNT162b2 (Pfizer-BioNTech) and an adenovirus vector vaccine (Ad26.CoV2.S; Johnson & Johnson), which were 94%, 95%, and 67% effective against COVID-19 infection in their phase III registry trials against the endemic variants at the time, respectively. 1-3 All 3 vaccines target the viral spike (S) protein that facilitates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into host cells via its receptor binding domain, which interacts with angiotensin-converting enzyme 2. 4 Although the mRNA platform vaccines are 2-dose vaccines administered 3-4 weeks apart, the Ad26.CoV2.S is administered as a single dose. Another adenovirus vector vaccine (ChAdOx1; Astrazeneca), not yet authorized in the United States, is intended as a 2-dose regimen with an interval of 8-12 weeks.Patients with inflammatory bowel disease (IBD) on corticosteroids, immunomodulators, and advanced therapies may have normal to slightly decreased humoral responses to the SARS-CoV-2 mRNA vaccine platforms. 1 In addition, patients receiving infliximab and/or thiopurines have significantly lower rates of seroconversion than those on vedolizumab monotherapy after a single dose of either BNT162b2 or ChAdOx1. 2 A study of solid organ transplant recipients showed decreased humoral responses to Ad26.CoV2.S vaccine relative to both mRNA platform vaccines, although it is unknown whether these findings are generalizable to other immune compromised populations. 5 Q5 We aimed to assess for differences in serologic responses among patients with IBD who received Ad26.CoV2.S relative to those receiving mRNA-1273 or BNT162b2. Among 353 vaccine recipients with IBD participating in a prospective SARS-CoV-2 vaccine registry without prior COVID-19 infection and who had completed a full vaccine regimen, 148 (42%), 193 (55%), and 12 (3%) received mRNA-1273, BNT162b2, and Ad26.CoV2.S, respectively. Demographic and disease characteristics were similar across vaccine groups (mean age, 51 years, 62% were female) (Supplementary Table 1). Approximately 290 (83.1%) participants were on immune-modifying therapies (IMTs), as defined by receipt of advanced therapies (biologics or JAK inhibitors, 80.2%), immunomodulators (16.6%), and/or systemic corticosteroids (6.6%) at the time of initial vaccination. At least 2 weeks after completion of the vaccine regimen, positive antibody levels were detected in 121 (100%), 142 (99%), and 9 (90%) patients receiving mRNA-1273, BNT162b2, and Ad26.CoV2.S, respectively (Figure 1A). Quantitative log 10 (anti-Spike IgG

New-onset IBD was significantly associated with a past history of bariatric surgery. This potential association needs to be confirmed in future prospective studies.