Unfavorable expression of pharmacologic markers in mucinous colorectal cancer (CRC)

Abstract

Abstract Introduction: Patients with mucinous CRC generally have worse prognoses than those with the non-mucinous variety. The reason for this disparity is unclear but may result from a differential response to adjuvant chemotherapy. We examined known molecular markers for response to common chemotherapy in these two histologic subtypes. Methods: Medical records of surgically-treated patients with stage III CRC were reviewed for demographic data and outcome. Twenty-one patients with mucinous and thirty with non-mucinous tumors were matched for age, gender, tumor size, grade and location, and number of lymph node metastases. Total RNA from the tumors and adjacent normal mucosa was isolated and reverse transcribed. Quantitative expression levels of drug pathway genes were determined using TaqMan RT-PCR (5-FU: TYMS, DPYD, ECGF1; oxaliplatin: GSTP1, ERCC1 & 2; irinotecan: ABCB1, ABCG2, CYP3A4, UGT1A1, CES2, TOP1). Results: Mucinous tumors significantly overexpressed both TYMS and GSTP1 relative to non-mucinous tumors and patient-matched normal mucosa. No significant differences in expression of the remaining markers were found. Mean follow-up was 20 months; 17 patients had recurrent disease. Among patients receiving 5-FU, those with mucinous CRC experienced shorter disease-free survival than those with non-mucinous tumors (median DFS 13.8 vs. 46.5 months, p = 0.053). ∗ . Mucinous Non-mucinous Mucosa Tumor Mucosa Tumor TYMS 4.1 ± 0.4 17.7 ± 5.8 ∗† 4.9 ± 0.7 9.6 ± 2.3 ∗ GSTP1 60 ± 9.6 193 ± 40.4 ∗† 51 ± 7.1 139 ± 32.7 ∗ ∗ Denotes p † Denotes p Conclusions: Mucinous tumors overexpressed markers of resistance to 5-FU and oxaliplatin. Additionally, DFS was decreased in patients with mucinous CRC who were given 5-FU. Expression differences in genes influencing chemotherapeutic response may contribute to shorter times to recurrence in patients with mucinous tumors, suggesting that mucin staining should be evaluated in developmental trials for novel CRC treatments.