The RAS gene family is among the most studied and best characterized of the known cancer-related genes. Of the three human ras isoforms, KRAS is the most frequently altered gene, with mutations occurring in 17%–25% of all cancers. In particular, approximately 30%–40% of colon cancers harbor a KRAS mutation. KRAS mutations in colon cancers have been associated with poorer survival and increased tumor aggressiveness. Additionally, KRAS mutations in colorectal cancer lead to resistance to select treatment strategies. In this review we examine the history of KRAS, its prognostic value in patients with colorectal cancer, and evidence supporting its predictive value in determining appropriate therapies for patients with colorectal cancer.

Background Mutations in KRAS and TP53 are common in colorectal carcinogenesis and are associated with resistance to therapy. Rectal cancers carrying both mutations are less likely to respond to neoadjuvant chemoradiation therapy (CRT) compared to wildtype tumors. Codon-specific KRAS mutations are associated with variable resistance to targeted therapies, but their association with rectal cancer response to CRT remains unclear. Our objective was to establish a correlation between specific KRAS mutations and rectal cancer response to CRT, and investigate if the correlation was related to a different association between KRAS and TP53 mutations. Methods One hundred forty-eight stage II–III rectal cancer patients underwent pre-operative CRT followed by surgery. DNA was extracted from pretreatment tumor biopsies and paired normal surgical tissues and KRAS and TP53 genotyping was performed. Specific KRAS mutations were then correlated with tumor response, and with concurrent TP53 mutation. Results Sixty patients had KRAS mutation; 12 in codon 13, and 48 in other locations. Eighty patients had TP53 mutation; 27 had concurrent KRAS/TP53 mutations. Tumors with any KRAS mutation were less likely to have a pCR compared to wildtype KRAS (p=0.006). Specifically, no tumors with KRAS codon 13 mutations had a pCR (p=0.03). Tumors with KRAS codon 13 mutations also had a higher incidence of concurrent TP53 mutation compared to tumors with other KRAS mutations (p=0.02). Conclusions Mutations in different KRAS codons may have different effects on rectal cancer resistance to CRT. This variable resistance may be related to a different frequency of TP53 mutations in KRAS mutant tumors.

Cancer stem cells (CSCs) have key roles in treatment resistance, tumour metastasis and relapse. Using colorectal cancer (CC) cell lines, patient-derived xenograft (PDX) tissues and patient tissues, here we report that CC CSCs, which resist chemoradiation, have higher SUMO activating enzyme (E1) and global SUMOylation levels than non-CSCs. Knockdown of SUMO E1 or SUMO conjugating enzyme (E2) inhibits CC CSC maintenance and self-renewal, while overexpression of SUMO E1 or E2 increases CC cell stemness. We found that SUMOylation regulates CSCs through Oct-1, a transcription factor for aldehyde dehydrogenases (ALDHs). ALDH activity is not only a marker for CSCs but also important in CSC biology. SUMO does not modify Oct-1 directly, but regulates the expression of TRIM21 that enhances Oct-1 ubiquitination and, consequently, reducing Oct-1 stability. In summary, our findings suggest that SUMOylation could be a target to inhibit CSCs and ultimately to reduce treatment resistance, tumour metastasis and relapse.

Background The standard treatment for locally advanced rectal cancer is pre-operative chemoradiation and total mesorectal excision. After surgery, tumors are classified according to the depth of tumor invasion, nodal involvement, and tumor regression grade. However, these staging systems do not provide information about the distribution of residual cancer cells within the bowel wall. Objective To determine the distribution of residual cancer cells in each layer of the bowel wall in rectal cancer specimens. Design Prospective Phase II study. Setting Multi-institutional. Patients 153 patients with stage II or stage III rectal cancer. Interventions Patients were treated with chemoradiation and surgery. Surgical specimen tumor tissue was analyzed and the distribution of residual cancer cells in each layer of the bowel wall was determined. Main Outcome Measures Statistical analysis was used to examine the correlation of residual cancer cells in each layer of the bowel wall with the clinical/pathological stage and tumor regression grade. Results Forty-two of 153 (27%) patients had complete response in the bowel wall (ypT0). Of the remaining 111 patients who had residual cancer cells, 5 (3%) were ypTis, 12 (8%) were ypT1, 41 (27%) were ypT2, 50 (33%) were ypT3, and 3 (2%) were ypT4. Of the 94 patients with ypT2-4 tumors, 12 (13%) had cancer cells in the mucosa and 53 (56%) had cancer cells in the submucosa; 92 (98%) had cancer cells in the muscularis propria. Pretreatment cT stage correlated with distribution of residual cancer cells. Tumor regression grade was not associated with distribution of residual cancer cells after chemoradiation. Limitations Patients received different chemotherapy regimens. Conclusions Residual cancer cells in rectal cancer specimens after chemoradiation are preferentially located close to the invasive front. This should be considered when designing strategies to diagnose complete pathologic response and when investigating the mechanisms of tumor resistance to chemoradiation.