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Kirsten ras Mutations in Patients With Colorectal Cancer: the Multicenter "RASCAL" Study
Abstract and Figures
Kirsten ras (Ki-ras) gene mutations occur early in the progression of colorectal adenoma to carcinoma. The aim of this collaborative study was to clarify the association between Ki-ras mutations, patient outcome, and tumor characteristics by use of data from colorectal cancer patients worldwide.
Investigators who had published data on Ki-ras and colorectal cancer were invited to complete a questionnaire for each patient entered into a database. Two-sided statistical tests were used to analyze data.
Patients (n = 2721) were recruited from 22 groups in 13 countries. Mutations of Ki-ras codon 12 (wild type = GGT = glycine) or codon 13 (wild type = GGC = glycine) were detected in 37.7% of the tumors; 80.8% (584 of 723) of all the specified mutations occurred in codon 12, and 78.1% (565 of 723) of all the specified mutations were at the second base of either codon. Mutations were not associated with sex, age, tumor site, or Dukes' stage. Mutation rates seen in patients with sporadic tumors were comparable to those observed in patients with a predisposing cause for their cancer. Poorly differentiated tumors were less frequently mutated (P = .002). Multivariate analysis suggested that the presence of a mutation increased risk of recurrence (P<.001) and death (P = .004). In particular, any mutation of guanine (G) to thymine (T) but not to adenine (A) or to cytosine (C) increased the risk of recurrence (P = .006) and death (P<.001). When individual, specific mutations were evaluated, only valine codon 12 was found to convey an independent, increased risk of recurrence (P = .007) and death (P = .004).
Ki-ras mutations are associated with increased risk of relapse and death, but some mutations are more aggressive than others.
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... Overall survival (OS) was statistically significantly different between MSI and MSS CRC for right colon cancer, whereas it was not for left colon cancer [20]. KRAS mutations involving either codon 12 or 13 can be identified in 40% of tumors; they were independently associated with a worse prognosis [21][22][23][24][25][26][27], especially G12V [22], which is particularly related to an adverse outcome; also KRAS G12C and G13D were linked with rather poor survival in some studies [25]. Among MSI-H tumors, in which most of the BRAF mutations occur, the presence of a mutation does not have the same adverse prognostic significance [27,28]. ...
... Overall survival (OS) was statistically significantly different between MSI and MSS CRC for right colon cancer, whereas it was not for left colon cancer [20]. KRAS mutations involving either codon 12 or 13 can be identified in 40% of tumors; they were independently associated with a worse prognosis [21][22][23][24][25][26][27], especially G12V [22], which is particularly related to an adverse outcome; also KRAS G12C and G13D were linked with rather poor survival in some studies [25]. Among MSI-H tumors, in which most of the BRAF mutations occur, the presence of a mutation does not have the same adverse prognostic significance [27,28]. ...
... Therefore, these mutations are a negative predictive factor for a biological therapy response [51]. BRAF activating mutations, most of which occur in codon 600 (V600E), happen in less than 10% of sporadic CRCs and are a strong negative prognostic marker for both early-stage and advanced/recurrent non-MSI tumors [10,18,25,26,[52][53][54]. Beyond their prognostic role, RAS and BRAF mutations exhibit reduced responsiveness to standard chemotherapeutic regimens, as these alterations confer resistance mechanisms that compromise the efficacy of therapeutic interventions [22,24]. ...
Citation: Orlandi, E.; Giuffrida, M.; Trubini, S.; Luzietti, E.; Ambroggi, M.; Anselmi, E.; Capelli, P.; Romboli, A. Abstract: Microsatellite Instability (MSI-H) occurs in approximately 15% of non-metastatic colon cancers, influencing patient outcomes positively compared to microsatellite stable (MSS) cancers. This systematic review focuses on the prognostic significance of KRAS, NRAS, and BRAF mutations within MSI-H colon cancer. Through comprehensive searches in databases like MEDLINE, EMBASE, and others until 1 January 2024, we selected 8 pertinent studies from an initial pool of 1918. These studies, encompassing nine trials and five observational studies involving 13,273 patients, provided insights into disease-free survival (DFS), survival after recurrence, and overall survival. The pooled data suggest that while KRAS and BRAF mutations typically predict poorer outcomes in MSS colorectal cancer, their impact is less pronounced in MSI contexts, with implications varying across different stages of cancer and treatment responses. In particular, adverse effects of these mutations manifest significantly upon recurrence rather than affecting immediate DFS. Our findings confirm the complex interplay between genetic mutations and MSI status, emphasizing the nuanced role of MSI in modifying the prognostic implications of KRAS, NRAS, and BRAF mutations in colon cancer. This review underscores the importance of considering MSI alongside mutational status in the clinical decision-making process, aiming to tailor therapeutic strategies more effectively for colon cancer patients.
... However, a high recurrence rate following RFA is the main challenge faced with RFA in CLM [10,11]. Studies have suggested that KRAS is associated with recurrence for colorectal cancer (CRC) [12,13]. In addition, the KRAS gene impacted recurrence after CLM metastases resection had been reported, but their ndings were controversial [14][15][16][17]. ...
... Its mutations can activate the RAS/MAPK signaling pathway that permits the cell to evade apoptosis, promotes growth and proliferation [36,37], Approximately 40% of CRCs harbor KRAS mutations [38]. Large phase II trials [12,13] comprised of 2721 and 4268 patients reported that KRAS mutations were associated with an increased risk of recurrence and death of CRC patients. Meanwhile, some studies suggest otherwise [39,40]. ...
Purpose
KRAS mutation and Primary tumor location are important factors affecting the prognosis of patients with colorectal liver metastases (CLM). However, some studies showed there may be an interaction between the two. We sought to investigate the association of KRAS mutations with recurrence in patients with CLM undergoing radiofrequency ablation (RFA) according to the primary tumor location.
Methods
CLM patients with a known KRAS gene status who underwent RFA were enrolled from January 1, 2012 to December 31, 2018. Clinicopathological data, recurrence, and survival dates were evaluated retrospectively.
Results
164 patients (mean age: 58.0 ± 9.8 years, range: 34–83) who underwent percutaneous RFA of 325 CLM (mean sizes: 2.2 ± 1.0 cm, range: 0.7–5.0) were included in the study; 89 (54.3%) cases were KRAS wild-type and 75 (45.7%) cases had KRAS mutation. Of the patients, 22.0% (36 of 164) had local tumor progression (LTP), and 23 of 75 patients (30.7%) in the KRAS mutation group had LTP, which was significantly higher than in patients with KRAS wild-type (13 of 89 patients (14.6%)) (p = 0.013). Of the 126 (76.8%) patients with recurrence after RFA, 101 (61.6%) had intrahepatic recurrence, while 88 (53.7%) had extrahepatic recurrence. Among patients with left-sided colorectal cancer (CRC), intrahepatic recurrence rates were higher among patients with KRAS mutation than among patients with the wild type KRAS (77.2% vs 52.5%, p = 0.003); the median intrahepatic recurrence-free survival (RFS) was worse in KRAS mutation patients (25 vs 15 months, P = 0.007). In patients with right-sided CRC, there was no significant difference in intrahepatic recurrence between the KRAS wild-type and KRAS mutation groups (P＞0.05). Further, KRAS gene had no impact on extrahepatic recurrence irrespective of the primary tumor site. In the multivariable analysis, KRAS mutation and positive lymph nodes remained independently associated with a worse RFS among patients (HR: 1.526, 95% confidence interval [CI]: 1.056–2.207, P = 0.025; HR: 1.602, 95% CI: 1.008–2.545, P = 0.046).
Conclusions
KRAS status is associated with recurrence of CLM after RFA depending on primary tumor location.
... This pathway is frequently disrupted or excessively activated in human tumors as a result of various factors such as the presence of activated RAS, mutations in the BRAF gene, or overexpression of growth factor receptors [6]. In colorectal cancer, mutant BRAF is found with a 5-12% frequency, and activated RAS is found in approximately 38% of CRC subjects [7,8]. Therefore, blocking this signaling cascade could offer clinical advantages in particular CRC cases. ...
Single-agent regorafenib is approved in Canada for metastatic colorectal cancer (mCRC) patients who have failed previous lines of therapy. Identifying prognostic biomarkers is key to optimizing therapeutic strategies for these patients. In this clinical study (NCT01949194), we evaluated the safety and efficacy of single-agent regorafenib as a second-line therapy for mCRC patients who received it after failing first-line therapy with an oxaliplatin or irinotecan regimen with or without bevacizumab. Using various omics approaches, we also investigated putative biomarkers of response and resistance to regorafenib in metastatic lesions and blood samples in the same cohort. Overall, the safety profile of regorafenib seemed similar to the CORRECT trial, where regorafenib was administered as ≥ 2 lines of therapy. While the mutational landscape showed typical mutation rates for the top five driver genes (APC, KRAS, BRAF, PIK3CA, and TP53), KRAS mutations were enriched in intrinsically resistant lesions. Additional exploration of genomic-phenotype associations revealed several biomarker candidates linked to unfavorable prognoses in patients with mCRC using various approaches, including pathway analysis, cfDNA profiling, and copy number analysis. However, further research endeavors are necessary to validate the potential utility of these promising genes in understanding patients’ responses to regorafenib treatment.
... 36 Indeed, KRAS mutations have a prevalence of 30%-40% in larger series of colorectal cancer trials. 22,23,37 While the prognostic role of mutated KRAS in colorectal cancer remains controversial, 38,39 initial data from small cohorts had suggested, that in patients treated with cetuximab response was only observed in wildtype tumors. 40 This finding was confirmed by in vitro experiments showing lack of response to cetuximab in colon cancer cells Cetuximab in the treatment of colorectal cancer Dovepress submit your manuscript | www.dovepress.com ...
In recent years, the monoclonal epidermal growth factor receptor (EGFR)-targeting antibody cetuximab was introduced into systemic therapy of colorectal cancer and gained an established role in the treatment of this disease. Cetuximab was shown to be active as a single agent in chemorefractory metastatic disease as well as in combination with varying chemotherapies. Recently, randomized trials demonstrated the activity of cetuximab combinations in the first-line setting of metastatic colorectal cancer. Interestingly, the activity of cetuximab was restricted to patients with KRAS wildtype tumors, as was seen with panitumumab, another EGFR antibody. While 60%–70% of tumors harbor KRAS wildtype genes, 30%–40% of tumors express oncogenic KRAS with mutations in codons 12 and 13 causing constitutive activation of signaling cascades downstream of EGFR and resistance to EGFR blockade. Since proof of KRAS wildtype status became a prerequisite for cetuximab treatment, KRAS testing is being established throughout the world. Future trials will address the question which part of the KRAS wildtype cohort will benefit from EGFR inhibition and how to identify those patients. Additionally, new strategies for treatment of KRAS mutated tumors are strongly needed. Recent developments and future strategies will be summarized.
... RAS mutations including KRAS and NRAS mutations are found in about 50% of mCRC and are prognostic for worse outcomes compared with RAS wt Current Treatment Options in Oncology CRC [16,17]. BRAF mutations, most commonly BRAF V600E , occur in about 10% of CRCs, and are detected more frequently in right-sided primary tumors with dMMR. ...
Opinion statement
Standard frontline treatment of metastatic colorectal cancer (CRC) is cytotoxic chemotherapy plus a biologic agent such as an anti-EGFR monoclonal antibody (cetuximab or panitumumab) or anti-VEGF antibody (bevacizumab). Predictive biomarkers include mismatch repair (MMR) status, and RAS and BRAF mutation status; and important factors in treatment selection include primary tumor location, intent of therapy, and potential toxicity, as well as patient age, comorbidities, and patient preference. To date, single-, double-, or triple-agent cytotoxic chemotherapy all have important roles in appropriately selected patients, with the addition of anti-VEGF or anti-EGFR antibody therapy based on the relevant predictive biomarker. Data indicate that patients with proficient MMR, RAS/BRAF wt mCRC are candidates for an anti-EGFR antibody plus doublet chemotherapy if they have a left-sided primary tumor, or for anti-VEGF (bevacizumab) plus doublet or triplet chemotherapy if they have a right-sided primary tumor. Future studies may provide more predictive biomarkers to further personalize therapy for this heterogeneous disease.
... Diğer belirteçlerden EGFR'yi hedefleyen ajanlar için etkinliği predikte eden RAS mutasyonları ve prognostik faktör olarak BRAF mutasyonları potansiyel kullanıma sahiptir. Güncellenmiş American Society for Clinical Pathology (ASCP)/CAP/Association for Molecular Pathology (AMP)/ASCO'nun CRC için moleküler biyobelirteçlere ilişkin kılavuzu aşağıdakileri önermektedir (20,21) Anti-EGFR inhibitörlerine yanıt için prediktif bir moleküler biyobelirteç olarak BRAF V600 mutasyon durumunun kulla- (34). Buna karşın 4268 hastanın incelendiği daha ileri bir analizde kodon 12' deki spesifik mutasyonda sadece nod pozitif hastalarda prognozu olumsuz etkilediği gösterilmiştir (35). ...
This study aims to investigate the long-term prognostic utility of circulating tumour DNA (ctDNA) KRAS mutations in colorectal cancer (CRC) patients and compare this with KRAS mutations in matched tissue samples. Tumour tissue (n = 107) and ctDNA (n = 80) were obtained from patients undergoing CRC resection and were analysed for KRAS mutations. The associations between KRAS mutation and overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were analysed. All outcomes were measured in years (y). A total of 28.8% of patients had KRAS mutations in ctDNA and 72.9% in tumour tissue DNA. The high frequency of KRAS mutations in tissue samples was due to 51.4% of these being a detectable low mutation allele frequency (<10% MAF). Comparing KRAS mutant (KRASmut) to KRAS wild-type (KRASwt) in ctDNA, there was no association found with OS (mean 4.67 y vs. 4.34 y, p = 0.832), CSS (mean 4.72 y vs. 4.49 y, p = 0.747), or RFS (mean 3.89 y vs. 4.26 y, p = 0.616). Similarly, comparing KRASmut to KRASwt in tissue DNA there was no association found with OS (mean 4.23 y vs. 4.61 y, p = 0.193), CSS (mean 4.41 y vs. 4.71 y, p = 0.312), or RFS (mean 4.16 y vs. 4.41 y, p = 0.443). There was no significant association found between KRAS mutations in either tissue or ctDNA and OS, CSS, or RFS.
Importance
The understanding of the association between KRAS sequence variation status and clinical outcomes in colorectal cancer (CRC) has evolved over time.
Objective
To characterize the association of age at onset, tumor sidedness, and KRAS sequence variation with survival among patients diagnosed with CRC.
Design, Setting, and Participants
This cross-sectional study used data extracted from the Surveillance, Epidemiology, and End Results database. Patients diagnosed with adenocarcinoma of the colon or rectum from 2010 through 2015 were included and were classified as having young-onset (YO) cancer if diagnosed between ages 20 to 49 years and late-onset (LO) cancer if diagnosed at age 50 years or older. Data were analyzed from April 2021 through August 2023.
Main Outcomes and Measures
CRC cause-specific survival (CSS) was summarized using Fine and Gray cumulative incidence and Kaplan-Meier curves. Estimation of subdistribution hazard ratios (sHRs) for the association of KRAS status, age at onset, and tumor location with CRC CSS was conducted using the Fine and Gray competing risk model. Cox proportional hazards regression was used to estimate and compare HRs.
Results
Among 21 661 patients with KRAS sequence variation status (mean [SD] age at diagnosis, 62.50 [13.78] years; 9784 females [45.2%]), 3842 patients had YO CRC, including 1546 patients with KRAS variants, and 17 819 patients had LO CRC, including 7311 patients with KRAS variants. There was a significant difference in median CSS time between patients with variant vs wild-type KRAS (YO: 3.0 years [95% CI, 2.8-3.3 years] vs 3.5 years [95% CI, 3.3-3.9 years]; P = .02; LO: 2.5 years [95% CI, 2.4-2.7 years] vs 3.4 years [95% CI, 3.3-3.6 years]; P < .001). Tumors with variant compared with wild-type KRAS were associated with higher risk of CRC-related death (YO: sHR, 1.09 [95% CI, 1.01-1.18]; P = .03; LO: sHR, 1.06 [95% CI, 1.02-1.09]; P = .002). Among patients with YO cancer, mortality hazards increased by location, from right (sHR, 1.02 [95% CI, 0.88-1.17) to left (sHR, 1.15 [95% CI, 1.02-1.29) and rectum (sHR, 1.16 [95% CI, 0.99-1.36), but no trend by tumor location was seen for LO cancer.
Conclusions and Relevance
In this study of patients diagnosed with CRC, KRAS sequence variation was associated with increased mortality among patients with YO and LO tumors. In YO cancer, variant KRAS– associated mortality risk was higher in distal tumors than proximal tumors.
With advances in gene and protein analysis technologies, many target molecules that may be useful in cancer diagnosis have been reported. Therefore, the “Tumor Marker Study Group” was established in 1981 with the aim of “discovering clinically” useful molecules. Later, the name was changed to “Japanese Society for Molecular Tumor Marker Research” in 2000 in response to the remarkable progress in gene-related research. Currently, the world of cancer treatment is shifting from the era of representative tumor markers of each cancer type used for tumor diagnosis and treatment evaluation to the study of companion markers for molecular-targeted therapeutics that target cancer cells. Therefore, the first edition of the Molecular Tumor Marker Guidelines, which summarizes tumor markers and companion markers in each cancer type, was published in 2016. After publication of the first edition, the gene panel testing using next-generation sequencing became available in Japan in June 2019 for insured patients. In addition, immune checkpoint inhibitors have been indicated for a wide range of cancer types. Therefore, the 2nd edition of the Molecular Tumor Marker Guidelines was published in September 2021 to address the need to revise the guidelines. Here, we present an English version of the review (Part 1) of the Molecular Tumor Marker Guidelines, Second Edition.
Ras gene protein products (p21) reacting with the monoclonal antibodies ras 11, DWP, R256 and E184 were studied with an immunohistochemical method which was applied to 17 normal and 79 colorectal adenocarcinoma specimens. Normal colorectal epithelium showed positive staining for ras 11 in 35% of the cases, but not for DWP, R256 and E184. The antibodies showed positive staining in colorectal adenocarcinomas in 76, 53, 29 and 35% of the cases respectively. The degree of staining for ras 11 was significantly related to the grade of differentiation and increased from Dukes stage A to C. Strong staining for ras 11 predicted a significantly shorter recurrence-free interval (p less than 0.001). In Cox's regression analysis, the degree of staining for ras 11 was a prognostic factor independent of the grade of differentiation and Dukes stage (p less than 0.01). The results indicate that the enhanced expression of pan ras p21 may provide an important biological marker for determining prognosis in colorectal adenocarcinomas.
One hundred and nine samples comprising carcinomas, adenomas, dysplastic, inflamed and normal mucosa from patients with sporadic colon cancer and ulcerative colitis (UC) were analysed for c-Ki-ras mutations. DNA was extracted from archival paraffin-embedded material, amplified using the polymerase chain reaction (PCR) and the PCR products analysed using restriction enzyme digestion. Forty-two per cent (14/33) of the sporadic carcinoma controls contained Ki-ras codon 12 mutations in contrast to 24% (8/33) of ulcerative colitis carcinomas. A significantly higher c-Ki-ras mutation rate was observed in rectal carcinomas (72%) in comparison to colonic carcinomas (28%) in control patients (P less than 0.04), while the opposite was observed in UC patients. The difference between the incidence of c-Ki-ras mutations in rectal carcinomas in UC (9%) and in sporadic rectal carcinomas (72%) was also significant (P less than 0.01). This lower prevalence rate and different site distribution of c-Ki-ras mutations in UC carcinomas compared to sporadic carcinomas suggests that specific genetic differences may underlie the causation of carcinomas arising in these situations.
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To set the basis for a precise assessment of new therapeutic approaches, the prognosis of patients with colorectal cancer should be evaluated with the highest precision. The recent discovery, in tumor cells, of somatically acquired genetic alterations believed to be instrumental in tumor behavior may provide new independent prognostic factors. In the present study, the usual prognostic factors and a set of genetic alterations, i.e., Ki-ras mutations, DNA content, and allelic losses on chromosome 17p, 18q, 5q, and 1p, were investigated in 109 colorectal carcinomas. Univariate analysis for correlation with 5-year survival showed the following significant associations, histological staging (P < 0.00001), preoperative serum carcinoembryonic antigen concentration (P < 0.002), DNA content (P < 0.009), and allelic loss on the short arm of chromosome 17 (P < 0.002) and 1 (P < 0.03). In multivariate analysis, only histological staging and allelic loss on the short arm of chromosome 17 were found to be independently associated with shorter survival (P < 0.0001 and P < 0.004, respectively). Loss of 17p alleles in colorectal carcinoma thus appears to be a marker of tumor aggressiveness. Its monitoring may lead to an improved classification of patients when adjuvant chemotherapy is considered.
Objective:
To establish whether specific K-ras alterations are predictive of less aggressive tumor behavior and subsequently those patients who are most likely to benefit from resection of hepatic metastases from colorectal carcinoma.Design:
Evaluation of long-term survivors of hepatic resection for metastases of colorectal carcinoma (median survival, 85 months).Results:
DNA, extracted from 26 paraffin-embedded hepatic metastases from 19 patients, was analyzed using single-strand conformation polymorphism and direct sequence analysis of codons 12 and 13 of the K-ras gene. Seven of 19 patients were found to harbor K-ras mutations. A similar frequency and spectrum of K-ras mutational events was detected in 14 patients with short-term survival following pathologic diagnosis of hepatic metastasis.Conclusions:
Neither the presence of a K-ras mutational event nor the precise nucleotide change are predictive of less aggressive tumor behavior, and genetic alterations at this locus alone cannot be used to select patients undergoing resection of hepatic metastases from colorectal carcinoma.(Arch Surg. 1995;130:9-14)
Clinical and pathological associations with molecular genetic alterations were studied in colorectal carcinomas from 83 patients. Fractional allelic loss, a measure of allelic deletions throughout the genome, and allelic deletions of specific chromosomal arms (the short arm of 17 and long arm of 18) each provided independent prognostic information by multivariate analysis when considered individually with Dukes'classification. Distant metastasis was significantly associated with high fractional allelic loss and with deletions of 17p and 18q. Mutations of ras proto-oncogenes and deletions of 5q had no prognostic importance. Statistically significant associations were also found between allelic losses and a family history of cancer, left-sided tumor location, and absence of extracellular tumor mucin. Allelic deletion analysis thus identified subsets of colorectal carcinoma with increased predilection for distant metastasis and cancer-related death. Further studies may define a subset of genetic alterations that can be used clinically to help assess prognosis.
(JAMA. 1989;261:3099-3103)
Human colorectal carcinoma tissue sampled from 37 patients, routinely graded into Dukes' stages A, B and C and histologically examined for the level of differentiation, were analyzed for the presence of point mutations in the K-ras oncogene. Seventeen cases out of the 37 analyzed were found to have a mutation in either the 12th or the 13th codon of the K-ras gene, giving an overall frequency of mutation of 46%. The incidence of mutations in Dukes' stages A, B and C was 33, 46 and 58% respectively. Although the frequency of mutation appears to be similar to that reported for the USA population, the spectrum of point mutations in codons 12 and 13 of the K-ras gene in the Yugoslav population appears to differ significantly. G-to-T trans-versions make up 77% of all mutations present, with the distribution as follows: 18% at the first base and 59% at the second base of codons 12 and 13. G-to-A transitions at the second base is the only other mutation identified, occurring mainly in codon 13 in colorectal tumors of all 3 stages.
Material from paraffin sections of 109 human colorectal carcinomas, mostly obtained at autopsy, was analyzed for the presence of K-ras point mutations at codon 12, position 2. Mutations at this position were found in 23 cases (21.1%). Aneuploid colorectal carcinomas showed a significantly higher prevalence of K-ras point mutations than diploid tumors, suggesting an involvement of ras mutations in the development of aneuploidy. No differences in the prevalence of K-ras mutations were observed with respect to the patients' age, sex and tumor type. In metastases, the type of ras gene mutation was always identical to that of the respective primary tumor. Mutations were not found in metastases from primary tumors devoid of ras mutations. This renders a clonal selection of K-ras mutated cells from a wild-type primary tumor during the metastatic process unlikely. However, nearly twice as many ras gene mutations were seen in metastatic than in non-metastatic primary tumors.
To set the basis for a precise assessment of new therapeutic approaches, the prognosis of patients with colorectal cancer should be evaluated with the highest precision. The recent discovery, in tumor cells, of somatically acquired genetic alterations believed to be instrumental in tumor behavior may provide new independent prognostic factors. In the present study, the usual prognostic factors and a set of genetic alterations, i.e., Ki-ras mutations, DNA content, and allelic losses on chromosome 17p, 18q, 5q, and 1p, were investigated in 109 colorectal carcinomas. Univariate analysis for correlation with 5-year survival showed the following significant associations: histological staging (P less than 0.00001), preoperative serum carcinoembryonic antigen concentration (P less than 0.002), DNA content (P less than 0.009), and allelic loss on the short arm of chromosome 17 (P less than 0.002) and 1 (P less than 0.03). In multivariate analysis, only histological staging and allelic loss on the short arm of chromosome 17 were found to be independently associated with shorter survival (P less than 0.0001 and P less than 0.004, respectively). Loss of 17p alleles in colorectal carcinoma thus appears to be a marker of tumor aggressiveness. Its monitoring may lead to an improved classification of patients when adjuvant chemotherapy is considered.
Ras oncogene mutations are found in a significant number of human colonic carcinomas. Correlation between patient survival and ras mutations was explored and compared with other clinical parameters. Colonic carcinoma embedded in paraffin was subjected to the polymerase chain reaction using primers to amplify codon 12 of the K-ras oncogene. Oligonucleotide probes to six mutations were used to identify mutated genes. A total of 71 cases were successfully amplified. Some 54% of the cases had mutations. There was no correlation between presence of a mutation and age. Patients in Stage D, patients with a family history of carcinoma, and males have a greater incidence of ras mutations. Patients in Stage C had a lower incidence of mutations. Presence of the mutation did not correlate with decreased survival except in Stage D. Some 61% of long-term survivors with colon carcinoma living for more than 6 yr had ras mutations. The absence of K-ras mutations did not identify long-term survivors.