Preoperative serum levels of the carcinoembryonic antigen in hereditary non-polyposis colorectal cancer compared to levels in sporadic colorectal cancer.

BACKGROUND: Carcinoembryonic antigen (CEA) serves as the most widely used and most cost-effective tumor marker in colorectal cancer for almost 30 years. Recent publications about serum CEA levels are based on patient groups without definite differentiation between hereditary and non-hereditary forms of colorectal cancer. PATIENTS AND METHODS: We compared preoperative CEA serum levels from 105 patients with hereditary non-polyposis colorectal cancer (HNPCC) and 107 patients with sporadic colorectal cancer including influences of age and Dukes stage. CEA values in cases of HNPCC were correlated to the findings of microsatellite analyses, mutation analyses of the MMR genes (MLH1, MSH2) and respective immunohistochemistries. RESULTS: Thirty-three HNPCC patients (31%) and 37 patients with sporadic CRC (34%) revealed elevated CEA levels higher than 5 ng/ml. The mean preoperative CEA level in all Dukes stages of HNPCC patients was lower with 31.7 +/- 180 ng/ml than in sporadic colorectal cancer with 68.3 +/- 424 ng/ml, but without significance (p = 0.72). HNPCC tumors with signs of de-differentiation (G3 and G4) revealed significantly higher CEA values with 62.2 +/- 262 ng/ml in comparison to well-differentiated tumors (G1 and G2) with 5.0 +/- 9.6 ng/ml (p = 0.02). HNPCC patients with "classical characteristics" (high microsatellite instability (MSI), MMR gene mutation, loss of MMR protein expression) had lower preoperative CEA serum levels than those without equivalent genetic alterations, but without reaching statistical significance. CEA levels of HNPCC tumors increased significantly under occurrence of metastases with mean values of 170.3 +/- 343 (p < 0.02). CONCLUSIONS: Normal preoperative serum CEA levels do not have the same validity for all colorectal cancer patients. Low CEA levels in HNPCC patients could occur due to well-differentiated tumors and should be considered more critically than in sporadic CRC patients. Further studies including comparison of postoperative CEA development are necessary to elucidate the importance of these results.

Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer.

Mutations in DNA MMR genes, mainly MSH2 and MLH1, account for the majority of HNPCC, an autosomal dominant predisposition to colorectal cancer and other malignancies. The evaluation of many questions regarding HNPCC requires clinically and genetically well-characterized HNPCC patient cohorts of reasonable size. One main focus of this multicenter study is the evaluation of the mutation spectrum and mutation frequencies in a large HNPCC cohort in Germany; 1,721 unrelated patients, mainly of German descent, who met the Bethesda criteria were included in the study. In tumor samples of 1,377 patients, microsatellite analysis was successfully performed and the results were applied to select patients eligible for mutation analysis. In the patients meeting the strict Amsterdam criteria (AC) for HNPCC, 72% of the tumors exhibited high microsatellite instability (MSI-H) while only 37% of the tumors from patients fulfilling the less stringent criteria showed MSI-H; 454 index patients (406 MSI-H and 48 meeting the AC of whom no tumor samples were available) were screened for small mutations. In 134 index patients, a pathogenic MSH2 mutation, and in 118 patients, a pathogenic MLH1 mutation was identified (overall detection rate for pathogenic mutations 56%). One hundred sixty distinct mutations were detected, of which 86 are novel mutations. Noteworthy is that 2 mutations were over-represented in our patient series: MSH2,c.942+3A>T and MLH1,c.1489_1490insC, which account for 11% and 18% of the MSH2 and MLH1 mutations, respectively. A subset of 238 patients was screened for large genomic deletions. In 24 (10%) patients, a deletion was found. In 72 patients, only unspecified variants were found. Our findings demonstrate that preselection by microsatellite analysis substantially raises mutation detection rates in patients not meeting the AC. As a mutation detection strategy for German HNPCC patients, we recommend to start with screening for large genomic deletions and to continue by screening for common mutations in exon 5 of MSH2 and exon 13 of MLH1 before searching for small mutations in the remaining exons.

Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder that predisposes to predominantly colorectal and endometrial cancers due to germline mutations in DNA mismatch repair genes, mainly MLH1, MSH2 and in families with excess endometrial cancer also MSH6. In this population-based study, we analysed the mutation spectrum of the MLH1, MSH2 and MSH6 genes in a cohort of patients with microsatellite unstable double primary tumours of the colorectum and the endometrium by PCR, DHPLC and sequencing. Fourteen of the 23 patients (61%) had sequence variants in MLH1, MSH2 or MSH6 that likely affect the protein function. A majority (10/14) of the mutations was found among probands diagnosed before age 50. Five of the mutations (36%) were located in MLH1, 3 (21%) in MSH2 and 6 (43%) in MSH6. MSH6 seem to have larger impact in our population than in other populations, due to a founder effect since all of the MSH6 families originate from the same geographical area. MSH6 mutation carriers have later age of onset of both colorectal cancer (62 vs. 51 years) and endometrial cancer (58 vs. 48 years) and a larger proportion of endometrial cancer than MLH1 or MSH2 mutation carriers. We can conclude that patients with microsatellite unstable double primary cancers of the colorectum and the endometrium have a very high risk of carrying a mutation not only in MLH1 or MSH2 but also in MSH6, especially if they get their first cancer diagnosis before the age of 50.