Genomic variation as a marker of response to neoadjuvant therapy in locally advanced rectal cancer.

There is variation in the responsiveness of locally advanced rectal cancer to neoadjuvant chemoradiation, from complete response to total resistance. This study compared genetic variation in rectal cancer patients who had a complete response to chemoradiation versus poor response, using tumor tissue samples sequenced with genomics analysis software. Rectal cancer patients treated with chemoradiation and proctectomy June 2006-March 2017 were grouped based on response to chemoradiation: those with no residual tumor after surgery (CR, complete responders, AJCC-CPR tumor grade 0, n = 8), and those with poor response (PR, AJCC-CPR tumor grade two or three on surgical resection, n = 8). We identified 195 variants in 83 genes in tissue specimens implicated in colorectal cancer biopathways. PR patients showed mutations in four genes not mutated in complete responders: KDM6A, ABL1, DAXX-ZBTB22, and KRAS. Ten genes were mutated only in the CR group, including ARID1A, PMS2, JAK1, CREBBP, MTOR, RB1, PRKAR1A, FBXW7, ATM C11orf65, and KMT2D, with specific discriminating variants noted in DMNT3A, KDM6A, MTOR, APC, and TP53. Although conclusions may be limited by small sample size in this pilot study, we identified multiple genetic variations in tumor DNA from rectal cancer patients who are poor responders to neoadjuvant chemoradiation, compared to complete responders.

Repression of androgen receptor transcription through the E2F1/DNMT1 axis.

Although androgen receptor (AR) function has been extensively studied, regulation of the AR gene itself has been much less characterized. In this study, we observed a dramatic reduction in the expression of androgen receptor mRNA and protein in hyperproliferative prostate epithelium of keratin 5 promoter driven E2F1 transgenic mice. To confirm an inhibitory function for E2F1 on AR transcription, we showed that E2F1 inhibited the transcription of endogenous AR mRNA, subsequent AR protein, and AR promoter activity in both human and mouse epithelial cells. E2F1 also inhibited androgen-stimulated activation of two AR target gene promoters. To elucidate the molecular mechanism of E2F-mediated inhibition of AR, we evaluated the effects of two functional E2F1 mutants on AR promoter activity and found that the transactivation domain appears to mediate E2F1 repression of the AR promoter. Because DNMT1 is a functional intermediate of E2F1 we examined DNMT1 function in AR repression. Repression of endogenous AR in normal human prostate epithelial cells was relieved by DNMT1 shRNA knock down. DNMT1 was shown to be physically associated within the AR minimal promoter located 22 bps from the transcription start site; however, methylation remained unchanged at the promoter regardless of DNMT1 expression. Taken together, our results suggest that DNMT1 operates either as a functional intermediary or in cooperation with E2F1 inhibiting AR gene expression in a methylation independent manner.