Panitumumab and irinotecan very 3 weeks is an active and convenient regimen for secondline treatment of patients with wild-type K-RAS metastatic colorectal cancer

PURPOSE: To evaluate the efficacy and safety profile of the combination of panitumumab and irinotecan every 3 weeks in a phase II trial as second-line treatment in patients with advanced wild-type (WT) K-RAS colorectal cancer (CRC). METHODS: Fifty-three patients received 9 mg/kg of panitumumab followed by 350 mg/m(2) of irinotecan every 21 days until disease progression, unacceptable toxicity or consent withdrawal. RESULTS: Median age of patients included was 67 years. All patients had previously received 5-fluorouracil, 84 % oxaliplatin and 8 % irinotecan as first-line treatment. Patients received a median of five infusions of panitumumab and irinotecan. On an intention-to-treat analysis, 12 patients (23 %) achieved partial responses and 22 patients (41 %) achieved disease stabilization. Median progression-free survival and overall survival were 4.5 and 15.1 months, respectively. The most frequent treatment-related severe toxicities per patient were diarrhoea (35.8 %), followed by skin rash (32.1 %), asthenia (18.9 %) and neutropenia (13.2 %). A significant association between clinical response and incidence and grade of skin toxicity was observed (p = 0.0032). CONCLUSION: This study shows that the administration of panitumumab plus irinotecan every 3 weeks is safe, active and feasible as second-line treatment in patients with advanced WT K-RAS CRC (AU)

Panitumumab and irinotecan every 3 weeks is an active and convenient regimen for second-line treatment of patients with wild-type K-RAS metastatic colorectal cancer.

PURPOSE: To evaluate the efficacy and safety profile of the combination of panitumumab and irinotecan every 3 weeks in a phase II trial as second-line treatment in patients with advanced wild-type (WT) K-RAS colorectal cancer (CRC). METHODS: Fifty-three patients received 9 mg/kg of panitumumab followed by 350 mg/m(2) of irinotecan every 21 days until disease progression, unacceptable toxicity or consent withdrawal. RESULTS: Median age of patients included was 67 years. All patients had previously received 5-fluorouracil, 84 % oxaliplatin and 8 % irinotecan as first-line treatment. Patients received a median of five infusions of panitumumab and irinotecan. On an intention-to-treat analysis, 12 patients (23 %) achieved partial responses and 22 patients (41 %) achieved disease stabilization. Median progression-free survival and overall survival were 4.5 and 15.1 months, respectively. The most frequent treatment-related severe toxicities per patient were diarrhoea (35.8 %), followed by skin rash (32.1 %), asthenia (18.9 %) and neutropenia (13.2 %). A significant association between clinical response and incidence and grade of skin toxicity was observed (p = 0.0032). CONCLUSION: This study shows that the administration of panitumumab plus irinotecan every 3 weeks is safe, active and feasible as second-line treatment in patients with advanced WT K-RAS CRC.

A genotype-directed phase I-IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer.

BACKGROUND: Infusional fluorouracil/leucovorin (FU/LV) plus irinotecan (FOLFIRI) is one of the standard first-line options for patients with metastatic colorectal cancer (mCRC). Irinotecan is converted into 7-ethyl-10-hydroxycamptothecin (SN-38) by a carboxylsterase and metabolised through uridine diphosphate glucuronosyl transferase (UGT1A1). The UGT1A1*28 allele has been associated with the risk of developing severe toxicities. The present trial was designed to define the maximum tolerated dose according to UGT1A1 genotype. This report focuses on the results of tolerance to different escalated doses of FOLFIRI first-line of chemotherapy. PATIENTS AND METHODS: Patients undergoing first-line treatment for mCRC and eligible for treatment with FOLFIRI were classified according to UGT1A1 genotype. A total of 94 patients were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 180 mg m(-2) for the *1/*1, 110 mg m(-2) for the *1/*28 and 90 mg m(-2) for the *28/*28 genotypes. RESULTS: The dose of irinotecan was escalated to 450 mg m(-2) in patients with the *1/*1 genotype, to 390 mg m(-2) in those with the *1/*28 genotype and to 150 mg m(-2) in those with the *28/*28 genotype. Neutropenia and diarrhoea were the most common grade 3 or 4 toxicities. CONCLUSIONS: Our results demonstrated that the recommended dose of 180 mg m(-2) for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated for patients with the UGT1A1 *1/*1 and *1/*28 genotypes. The maximum tolerable dose (MTD) in patients with a high-risk UGT1A1 *28/*28 genotype is 30% lower than the standard dose of 180 mg m(-2).

UGT1A and TYMS genetic variants predict toxicity and response of colorectal cancer patients treated with first-line irinotecan and fluorouracil combination therapy.

BACKGROUND: The impact of thymidylate synthase (TYMS) and UDP-glucoronosyltransferase 1A (UGT1A) germline polymorphisms on the outcome of colorectal cancer (CRC) patients treated with irinotecan plus 5-fluorouracil (irinotecan/5FU) is still controversial. Our objective was to define a genetic-based algorithm to select patients to be treated with irinotecan/5FU. METHODS: Genotyping of TYMS (5'TRP and 3'UTR), UGT1A1(*)28, UGT1A9(*)22 and UGT1A7(*)3 was performed in 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy enrolled in a randomised phase 3 study. Their association with response, toxicity and survival was investigated by univariate and multivariate statistical analysis. RESULTS: TYMS 3TRP/3TRP genotype was the only independent predictor of tumour response (OR=5.87, 95% confidence interval (CI)=1.68-20.45; P=0.005). UGT1A1(*)28/(*)28 was predictive for haematologic toxicity (OR=6.27, 95% CI=1.09-36.12; P=0.04), specifically for neutropenia alone (OR=6.40, 95% CI=1.11-37.03; P=0.038) or together with diarrhoea (OR=18.87, 95% CI=2.14-166.67; P=0.008). UGT1A9(*)1/(*)1 was associated with non-haematologic toxicity (OR=2.70, 95% CI=1.07-6.82; P=0.035). Haplotype VII (all non-favourable alleles) was associated with non-haematologic toxicity (OR=2.11, 95% CI=1.12-3.98; P=0.02). CONCLUSION: TYMS and UGT1A polymorphisms influence on tumour response and toxicities derived from irinotecan/5FU treatment in CRC patients. A genetic-based algorithm to optimise treatment individualisation is proposed.

Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study.

BACKGROUND: Irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI) is accepted as a reference treatment for the first-line treatment of patients with metastatic colorectal cancer (MCRC). The aim of this study was to demonstrate that a regimen without leucovorin (LV) (FUIRI) is not inferior to the standard FOLFIRI (response rate). PATIENTS AND METHODS: Chemotherapy-naive patients with MCRC were randomized to receive either irinotecan (180 mg/m(2) on day 1) + 5-fluorouracil (5-FU) (400 mg/m(2) bolus and 600 mg/m(2) 22-h infusion) + LV (200 mg/m(2) on days 1-2) (FOLFIRI) every 2 weeks or irinotecan (80 mg/m(2)) + 5-FU (2.250 mg/m(2) 48-h infusion) (FUIRI) weekly. RESULTS: In all, 346 patients were included, 173 in each arm. In the intention-to-treat analysis, the response rates for FOLFIRI and FUIRI were 57% [95% confidence interval (CI) 49% to 64%] and 51% (95% CI 43% to 59%), respectively (P = 0.2809). No statistically significant differences were observed between FOLFIRI and FUIRI regarding median progression-free survival (8.3 versus 8.4 months; P = 0.4339) nor median overall survival (21.6 versus 19.2 months; log-rank test P = 0.2941). Grade 3/4 neutropenia was significantly more frequent on FOLFIRI arm (27% versus 9%), while the proportion of diarrhea was higher on FUIRI arm (21% versus 42%). CONCLUSION: FUIRI represents a valid alternative without LV to the FOLFIRI regimen as MCRC first-line treatment.

Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy.

To determine whether molecular parameters could be partly responsible for resistance or sensitivity to oxaliplatin (OX)-based chemotherapy used as first-line treatment in advanced colorectal cancer (CRC). We studied the usefulness of the excision repair cross-complementing 1 (ERCC1), xeroderma pigmentosum group D (XPD), XRCC1 and GSTP1 polymorphisms as predictors of clinical outcome in these patients. We treated 126 CRC patients with a first-line OX/5-fluorouracil chemotherapeutic regimen. Genetic polymorphisms were determined by real-time PCR on an ABI PRISM 7000, using DNA from peripheral blood. Clinical response (CR), progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. In the univariate analysis for CR, ERCC1-118 and XPD 751 polymorphisms were significant (P=0.02 and P=0.05, respectively). After adjustment for the most relevant clinical variables, only ERCC1-118 retained significance (P=0.008). In the univariate analysis for PFS, ERCC1-118 and XPD 751 were significant (P=0.003 and P=0.009, respectively). In the multivariant analysis, only the XPD 751 was significant for PFS (P=0.02). Finally, ERCC1-118 and XPD 751 polymorphisms were significant in the univariate analysis for OS (P=0.006 and P=0.015, respectively). Both genetic variables remained significant in the multivariate Cox survival analysis (P=0.022 and P=0.03). Our data support the hypothesis that enhanced DNA repair diminishes the benefit of platinum-based treatments.

Transcription factor-binding sites in the thymidylate synthase gene: predictors of outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin?

The identification of clinical and genetic parameters to predict the outcome in advanced colorectal cancer is a key issue in the management of this disease. We ascertained whether the clinical determinants of survival defined in a large cohort of patients treated with 5-fluorouracil (5-FU) (European Organization for the Research and Treatment of Cancer, EORTC model) also apply to 109 colorectal cancer patients receiving a therapy including oxaliplatin/5-FU as their first-line treatment. Our results confirm the considerable discriminatory power of the clinical model proposed in patients treated with a combined chemotherapy regimen. With the aim of identifying additional genetic prognostic parameters, we determined whether the polymorphisms in the promoter region of the thymidylate synthase (TS) gene that modifies the number of operative binding sites of a transcription factor (USF) could predict the clinical outcome of our patients and complement the EORTC clinical model. Our results indicate that this new genetic parameter (the number of USF-binding sites) could be considered when evaluating the role of TS genotype in the efficacy of the 5-FU-based regimens. Further, confirmatory studies aimed at evaluating the effect of the number of binding sites of transcription factors for selecting 5-FU-treated patients are warranted.

Methylenetetrahydrofolate reductase gene polymorphisms: genomic predictors of clinical response to fluoropyrimidine-based chemotherapy?

Fluorouracil (5-FU) is widely used in the treatment of colorectal cancer. Methylenetetrahydrofolate reductase (MTHFR) may play a central role in the action of 5-FU, an inhibitor of thymidylate synthase, by converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The aim of this study was to ascertain whether two polymorphisms in the MTHFR gene (677C>T and 1298 A>C) could be used as genomic predictors of clinical response to fluoropyrimidine-based chemotherapy (in combination with irinotecan or oxaliplatin). Ninety-four patients diagnosed with metastatic colorectal cancer and undergoing 5-FU-containing chemotherapy as a first line treatment were studied. The results suggest that the MTHFR genotype cannot be considered as an independent factor of outcome in colorectal cancer patients under 5-FU-based chemotherapy.

UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer.

SN-38 is the active metabolite of irinotecan and it is metabolised through conjugation by uridine diphosphate glucuronosyl transferase (UGT1A1). The major toxicity of irinotecan therapy is diarrhoea, which has been related to the enzymatic activity of UGT1A1. We examined the influence of the UGT1A1 gene promoter polymorphism in the toxicity profile, in the response rate and in the overall survival (OS) in 95 patients with metastatic colorectal cancer treated with an irinotecan-containing chemotherapy. Genotypes were determined by analysing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Clinical parameters and genotypes were compared by univariate and multivariate statistical methods. The more frequent adverse effects were asthenia (34 patients), diarrhoea (29 patients) and neutropenia (20 patients). Severe diarrhoea was observed in 7/10 homozygous (70%) and 15/45 heterozygous (33%) in comparison to 7/40 (17%) wild-type patients (P=0.005). These results maintained the statistical significance in logistic regression analysis (P=0.01) after adjustment for other clinical relevant variables. The presence of severe haematological toxicity increased from wild-type patients to UGT1A1(*)28 homozygotes, but without achieving statistical significance. No relationship was found between the UGT1A1(*)28 genotypes and infection, nausea or mucositis. In univariate studies, patients with the UGT1A1(*)28 polymorphism showed a trend to a poorer OS (P=0.09). In the multivariate analysis, the genotype was not related to clinical response or to OS. The role of the UGT1A1 genotype as a predictor of toxicity in cancer patients receiving irinotecan demands the performance of a randomized trial to ascertain whether genotype-adjusted dosages of the drug can help to establish safe and effective doses not only for patients with the UGT1A1(*)28 homozygous genotype but also for those with the most common UGT1A1 6/6 or 6/7 genotype.

Phase I/II trial of irinotecan plus high-dose 5-fluorouracil (TTD regimen) as first-line chemotherapy in advanced colorectal cancer.

BACKGROUND: We conducted a phase I/II study of weekly irinotecan [30 min intravenous (i.v.) infusion] combined with 5-fluorouracil (5-FU 3 g/m(2) weekly 48 h i.v. infusion, TTD regimen) as first-line chemotherapy for patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: The maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) in the treatment of gastrointestinal solid tumors (in phase I), and the antitumor activity and toxicity of the recommended phase I dose (in phase II) were determined. RESULTS: Diarrhea was the DLT, and irinotecan 80 mg/m(2) plus 5-FU 3 g/m(2) was the recommended phase I dose. In phase II, the confirmed response rate was 44% [95% confidence interval (CI) 29% to 59%] and the median overall survival was 23.8 months. However, grade 3/4 diarrhea affected 59% of patients and led to withdrawal of three patients. A second cohort of patients studied using the same schedule but with a reduced 5-FU starting dose of 2.25 g/m(2) showed improved tolerance (the incidence of grade 4 diarrhea decreased from 28% to 11% and overall grade 3/4 diarrhea to 56%, with no patient withdrawals) but the confirmed response rate was 28% (95% CI 14% to 45%) and median overall survival was 17.2 months. CONCLUSIONS: We found weekly irinotecan 80 mg/m(2) plus TTD regimen (5-FU 2.25 g/m(2) given as 48-h i.v. infusion) to be a feasible and active combined chemotherapy for the first-line treatment of advanced colorectal cancer.

Irinotecan (CPT-11) in metastatic colorectal cancer patients resistant to 5-fluorouracil (5-FU): a phase II study.

The efficacy and toxicity of irinotecan (CPT-11) 350 mg/m(2) i.v. once every 3 weeks was assessed in 60 patients with advanced colorectal cancer (CRC) showing failure to 5-fluorouracil (5-FU) treatment. The overall objective response rate was 13.6% (1 complete response and 4 partial responses) and 25 patients (42.4%) showed stable disease; the median time to disease progression was 4.4 months and the median survival was 10.5 months. The main non-hematological toxicities were alopecia (80.3% of patients), diarrhea (75.0%), and nausea/vomiting (71.7%); neutropenia was the main hematological toxicity. Grade 3 or 4 diarrhea appeared in 21 of 131 cycles (16.1%), whereas grade 3 or 4 neutropenia appeared in 78 cycles (25.0%). In conclusion, the present phase II study confirms that CPT-11 350 mg/m(2) every 3 weeks is active and well tolerated as second-line chemotherapy for CRC in 5-FU resistant patients.

Management and prognosis of transitional cell carcinoma superficial recurrence in muscle-invasive bladder cancer after bladder preservation.

PURPOSE: To assess the bladder preservation rate and cancer-specific survival after conservative treatment of superficial relapses in invasive tumors after bladder preservation. MATERIAL AND METHODS: Fifty-one patients with invasive bladder tumor (T2) were treated using transurethral resection (TUR) followed by three cycles of systemic chemotherapy (carboplatin-vinblastine). After three weeks, an endoscopic reappraisal was made including deep TUR of the site of the original tumor and multiple cold cup biopsies. Forty-two patients retained their bladder (33 complete responses and 9 partial responses). RESULTS: With a median follow-up of 63 months, 18 patients recurred as superficial TCC tumor (43%). Fourteen patients with high grade superficial recurrence were treated with TUR and Bacillus Calmette-Guerin (BCG) instillations; two patients (G2-3 T1) with TUR as well as endovesical mytomicine, and two patients with low grade recurrence with only TUR. With a median follow-up of 44 months after TUR of first superficial relapse, there was only one case with progression of the disease without any evidence of bladder tumor. Two cystectomies were made due to carcinoma in situ (Cis) persistence and high grade superficial recurrence. Eighty-three percent of the patients who had superficial recurrence retained their bladders, with 94% cancer-specific survival. CONCLUSIONS: A very strict follow-up is mandatory due to the high rate of superficial relapses (43%). Cis is the most frequent type of superficial recurrence. Superficial recurrences in bladder preservation may be treated with TUR and BCG instillations when they are high grade and and/or associated with Cis. Superficial recurrences do not imply a worse prognosis for bladder preservation or cancer-specific survival.

Phase II multicentre study of docetaxel plus cisplatin in patients with advanced urothelial cancer.

A multicentre phase II trial was undertaken to evaluate the activity and toxicity of docetaxel plus cisplatin as first-line chemotherapy in patients with urothelial cancer. Thirty-eight patients with locally advanced or metastatic transitional-cell carcinoma of the bladder, renal pelvis or ureter received the combination of docetaxel 75 mg m(-2) and cisplatin 75 mg m(-2) on day 1 and repeated every 21 days, to a maximum of six cycles. The median delivered dose-intensity was 98% (range 79-102%) of the planned dose for both drugs. There were seven complete responses and 15 partial responses, for and overall response rate of 58% (95% CI, 41-74%). Responses were even seen in three patients with hepatic metastases. The median time to progression was 6.9 months, and the median overall survival was 10.4 months. Two patients who achieved CR status remain free of disease at 4 and 3 years respectively. Grade 3-4 granulocytopenia occurred in 27 patients, resulting in five episodes of febrile neutropenia. There was one toxic death in a patient with grade 4 granulocytopenia who developed acute abdomen. Grade 3-4 thrombocytopenia was rare (one patient). Other grade 3-4 toxicities observed were anaemia (three patients), vomiting (five patients), diarrhoea (four patients), peripheral neuropathy (two patients) and non-neutropenic infections (seven patients). Docetaxel plus cisplatin is an effective and well-tolerated regimen for the treatment of advanced urothelial cancer, and warrants further investigation.

Redefining the significance of aneuploidy in the prognostic assessment of colorectal cancer.

The aberrant content of DNA, or aneuploidy, is a hallmark of tumor cells and may be associated with malignant potential. Based on the hypothesis that aneuploidy, as a form of genetic instability, results in an increased capability to generate cell heterogeneity, we investigated whether a comprehensive assessment of aneuploidy extent and degree might be a reliable indicator of tumor aggressiveness. DNA content was determined by flow cytometry in the infiltrating front of 131 paraffin-embedded primary colorectal carcinomas collected in a prospective design. Enrichment of tumor cells by sample microdissection resulted in neoplastic cell contents above 75%. An estimate of aneuploidy, the aneuploidy index (AI), was calculated as the tumor DNA content adjusted by the percentage of diploid and aneuploid cells in G0/G1. Thirty-nine tumors were diploid, 90 hyperdiploid, and 2 hypodiploid. The mean AI in aneuploid tumors was 1.20+/-0.17 and correlated with Dukes' stage and metastasis (p < 0.05). A high AI (receiver operating characteristic curve cutoff value greater than 1.14) predicted a poorer outcome in univariate (p = 0.004) and multivariate (p = 0.01) analyses. Based on these results, we postulate that aneuploidy is the molecular engine of progression in a subset of colorectal cancers, in which the AI seems to be a sensible and independent gauge of malignant potential. The AI determination may have prognostic application in colorectal cancer, especially in low-grade tumors, which might benefit from coadjuvant therapies.

K-ras and p16 aberrations confer poor prognosis in human colorectal cancer.

PURPOSE: Mutations in the K-ras gene are frequent in human cancer. ras activation in primary cells results in a cellular senescence phenotype that is precluded by inactivation of p16. At the clinical level, this may imply a differential behavior for tumors with alternative or cooperative activation of K-ras function and impairment of p16 pathways. PATIENTS AND METHODS: We have determined the presence of mutations in the K-ras gene and the methylation status of p16 promoter in a series of 119 prospectively collected colorectal carcinomas. p53 mutations and p14 alternative reading frame methylation status were also assessed. Associations with survival were investigated. RESULTS: K-ras mutations were present in 44 (38%) of 115 cases, and p16 methylation was present in 42 (37%) of 113 cases. p53 mutations were detected in 50% (56 of 115) and p14 methylation in 29% (32 of 112) of cases. K-ras and p16 alterations were independent genetic events. Presence of K-ras or p16 genetic alterations (analyzed independently) was associated with shorter survival, although differences were not statistically significant. Cox analysis of the two variables combined showed a diminished survival as the results of an interaction between p16 and K-ras. Alternative alteration of K-ras and p16 genes was an independent prognostic factor in human colorectal cancer in univariate and multivariate analysis. Differences were maintained when cases undergoing radical surgery and without distant metastases were considered. CONCLUSION: These results suggest that the combined K-ras and p16 analyses may be of prognostic use in human colorectal cancer.

Standardized approach for microsatellite instability detection in colorectal carcinomas.

BACKGROUND: Ubiquitous mutations in microsatellite DNA sequences define a specific type of genetic instability, termed microsatellite instability (MSI). Various approaches have been used to identify the presence and degree of MSI. To define standard diagnostic criteria for MSI, we developed and tested a mathematical model. METHODS: We designed an algorithm for the efficient characterization of MSI and used it to analyze data on six microsatellite markers in colorectal carcinoma and normal tissues from 415 patients. Theoretical models considering one, two, or three populations were tested against the data collected. RESULTS: The observed frequencies of MSI in our series of samples best fit a two-population model, stable and unstable, defined by instability in two or more of four to six markers analyzed. MSI was observed in 7.5% of the tumors. The misclassification rate was less than 5% when any four loci were analyzed and less than 1% when the six markers were used. A stepwise strategy, consisting first of a bulk screening of two loci and then a second screening of two to four additional markers, provided excellent sensitivity (>/=97%) and specificity (100%). Tumors with MSI had distinctive genetic and clinicopathologic features, including better patient survival. CONCLUSION: To assess the presence of MSI in colorectal cancer, we have developed a simple, sensitive, and specific approach based on the apparent good fit of the data to a two-population model. Its application to a prospective series of patients with colorectal carcinomas demonstrates that the presence of MSI characterizes a subset of less aggressive tumors.

[Identification of 2 families with hereditary nonpolyposis colonic cancer (HNPCC) and the Amsterdam criteria. Relevance of the genealogic tree and follow-up]. / Identificación de dos familias con cáncer de colon hereditario no polipósico (CCHNP) y criterios de Amsterdam. Relevancia del árbol genealógico y las medidas de seguimiento.

Hereditary nonpolyposis colorectal cancer (HNPCC) diagnosis is based either on the so-called "Amsterdam 1 criteria" or "Amsterdam 2 criteria", which includes extracolonic neoplasms associated with Lynch II syndrome. Many families are suspected of having a hereditary predisposition to cancer and may benefit from close surveillance. We describe a family (family 1) with suspected HNPCC at the beginning who fulfilled the Amsterdam 1 criteria over the course of its follow-up. We also describe an Amsterdam 2 family (family 2) with a very young affected individual. Both of them received genetic counseling and screening recommendations. A total colonoscopy was done to an asymptomatic member of family 1 and he was diagnosed with an early-stage colon cancer. He underwent subtotal colectomy because of the high risk of metachronous lesion. Screening recommendations must be the same in Amsterdam 2 families as in Amsterdam 1. Both families show the importance of considering the family history when hereditary criteria are suspected.

Intron splice acceptor site polymorphism in the hMSH2 gene in sporadic and familial colorectal cancer.

A polymorphism in hMSH2 gene has been associated with an increased susceptibility to develop colorectal cancer (CRC). Here we show that it is a genetic risk factor for CRC in the Spanish population. However, its presence does not apparently affect hMSH2 function.

Prospective assessment of allelic losses at 4p14-16 in colorectal cancer: two mutational patterns and a locus associated with poorer survival.

Previous studies have shown that allelic losses in a locus mapping to the chromosomal region 4p14-16 are indicative of poor prognosis in colorectal cancer. To further characterize the region involved and to confirm earlier observations, we have analyzed losses of heterozygosity (LOH) in nine microsatellite markers spanning this region in a prospective series of 181 colorectal carcinomas. The extent and the nature of the allelic imbalance were also ascertained by comparative genomic hybridization analysis of selected cases. The minimum common deleted region was confined to marker D4S2397 (LOH in 35% of the informative cases). Surrounding markers displayed LOH in 13-25% of informative cases and (other than the D4S2397 marker itself) showed a higher rate of allelic imbalances in association with mutations in the p53 tumor suppressor gene. Tumors with lymph node invasion also displayed increased rates of LOH in most markers. Regarding patient outcome, LOH solely at the D4S2397 locus was indicative of a shorter disease-free survival (P = 0.027). In consequence, two patterns of allelic loss are defined within the 4p14-16 region: (a) gross losses associated with tumor progression and probably attributable to the genomic instability related to the inactivation of the p53 tumor suppressor gene; and (b) specific losses limited to the D4S2397 locus (within an estimated fragment of 2 Mb) and associated with increased tumor aggressiveness. The presence of one or more putative tumor suppressor genes in this region is postulated.