The study suggests that specific CIMP markers, such as p16 ( INK4a ) and MINT31, should be further verified as potential epigenetic targets for the design of efficient chemotherapy regimens. We also identified a subset of colorectal cancer, possibly comprising APC methylation-KRAS mutation-p16 ( INK4a ) methylation.

Chemosensitive SNP markers were identified using a novel three-step process. The candidate marker LIFR rs3729740 and possibly ISX rs361863 will hopefully predict responsive patients to cetuximab regimens, although further validation is needed in large cohorts.

No abstract

Improved methods for predicting chemoresponsiveness involving the identification of polymorphic markers is highly desirable, considering narrow therapeutic index and frequent resistance to anticancer regimens. The genome-wide screening of chemosensitive single nucleotide polymorphisms (SNPs) was undertaken in association with in vitro chemosensitivity assays in 104 colorectal cancer patients for the initial screening step. Allele frequency, linkage disequilibrium, potential function, and Hardy-Weinberg equilibrium of the candidate SNPs were then determined for the identifying step. Finally, clinical association analysis in the other 260 evaluable patients or cell viability assays of transfected RKO cells was used to verify candidate SNPs for the validation step. In total, 12 SNPs to six regimens were initially chosen during the screening and identifying steps. In patients receiving fluoropyrimidine-based adjuvant chemotherapy, the substitution alleles of GPC5 rs553717 (AA) correlated significantly with tumor recurrence and shorter disease-free survival (P = 0.019 and 0.023, respectively). Interestingly, RKO cells expressing mutant GPC5 showed enhanced cell death in response to 5-FU in cytotoxicity assays. Patients that were homozygous for the reference alleles SSTR4 rs2567608 (AA) and EPHA7 rs2278107 (TT) showed lower disease control rates in response to irinotecan and oxaliplatin regimens, respectively, than those with substitution alleles (P = 0.022 and 0.014, respectively). Thus, we identified chemosensitive SNP markers using a novel three step process of genome-wide analysis consisting of in vitro screening, identification, and validation. The candidate chemosensitive SNP markers identified in our study, including those identified in vitro, can now be further verified in a large cohort study. (Cancer Sci 2010; 101: 1007-1013 C olorectal cancer is one of the four most commonly diagnosed cancers and is responsible for over 10% of cancerrelated deaths in most developed countries.(1,2) Up to 50% of patients who receive curative operations experience recurrence and 20% of all patients present with metastatic disease at diagnosis.(3) Fluoropyrimidine-based chemotherapy has become an adjunct to surgery to reduce recurrence in patients with stage III and high-risk stage II colorectal cancer.(4) Systemic chemotherapy of metastatic colorectal cancers has been shown to prolong survival and improve quality of life. Several clinical trials have shown that both oxaliplatin and irinotecan can be successfully combined with 5-fluorouracil and leucovorin (FL) as a first-line treatment for patients with metastatic colorectal carcinoma, and that this regimen leads to high response rates and effectively improves overall survival.(4) Approximately 37 clinical trials are currently underway to evaluate the therapeutic efficacy of histone deacetylase inhibitors in hematological and solid malignancies with few end-point outcomes to date.

Our findings firstly demonstrated the chemo-responsiveness of colorectal cancers to HDAC inhibitors with therapeutic efficacy comparable to the established regimens. Additionally, tumor growth and heredity were significantly associated with specific regimens, supporting their possible role as chemosensitive predictors.

No abstract

Two novel genes, GALR2 and ALX4, have been identified as chemosensitive methylation candidates to bevacizumab and cetuximab regimens, respectively. As our study did not include a clinical association study, the two candidates should be validated in large clinical cohorts, hopefully predicting responsive patients to targeted regimens.

<p>PDF file - 2.6MB, Genome-wide association with in vitro chemosensitivity to targeted regimens: FRB (A), FXB (B), FRC (C), and FXC (D). Association of SNPs with the inhibition ratio was tested by linear regression analysis. P-values of < 0.001 are indicated by red dots. FRB, FOLFIRI + bevacizumab; FXB, FOLFOX + bevacizumab; FRC, FOLFIRI + cetuximab; FXC, FOLFOX + cetuximab.</p>