Clinicopathological differences between familial colorectal cancer type X and sporadic cancer in an isolated area of spain.

AIM: Very few studies have compared the epidemiological characteristics of patients with familial colorectal cancer Type X (FCCTX) with those of sporadic colorectal cancer (S-CRC). The aim of this study was to compare clinicopathological characteristics and survival between FCCTX and S-CRC in patients from a historically isolated geographical region. METHOD: A retrospective study was carried out of patients with S-CRC and FCCTX treated in the Canary Islands. Family and personal history of colorectal cancer (CRC) were recorded, together with genetic (microsatellite instability), immunohistochemical and clinical variables. RESULTS: Forty-eight (10.6%) of 451 patients were classified as FCCTX and the remaining 403 (89.4%) as S-CRC. Age at the diagnosis of tumour was significantly lower in FCCTX than in S-CRC (64.06 ± 12.65 years vs 69.13 ± 10.80 years; P = 0.01; Z = -2.48). Patients with FCCTX had a larger number of synchronous tumours (P = 0.09). Recurrence was significantly higher in FCCTX than in S-CRC (18.7% vs 8.6%; P = 0.01). Survival correlated significantly with the number of first-degree and second-degree relatives with CRC (P = 0.04; OR: 1.368, 95% CI: 1.01-1.84, and P = 0.04; OR: 1.363, 95% CI: 1.08-1.65) and with the total number of cases of CRC in the immediate family (P < 0.01; OR: 1.377, 95% CI: 1.17-1.61). Recurrence-free time was significantly lower in patients with FCCTX (log-rank = 0.01). CONCLUSION: Significant differences were found in several demographic and clinicopathological variables between patients with FCCTX and patients with S-CRC. These included increased tumour presentation under the age of 50 years and a higher recurrence rate in patients with FCCTX, suggesting an increased risk of CRC in this group.

Adrenocortical carcinoma, an unusual extracolonic tumor associated with Lynch II syndrome.

Lynch syndrome (LS) is an autosomal dominant condition that predisposes to colorectal cancer and specific other tumors. Extracolonic tumors occur mainly in the endometrium, stomach, ovary, small intestine and urinary tract. The presence of rare tumors in patients belonging to families who have Lynch syndrome is always interesting, because the question arises whether these tumors should be considered as a coincidence or are related with the syndrome. In this last case, they are also the result of the defect in the mismatch repair system, opening the possibility of extending the tumor spectrum associated with the syndrome. Here we describe a patient from a Lynch syndrome family with a germline mutation c.2063T>G (p.M688R) in the MSH2 gene, who developed an adrenal cortical carcinoma, a tumor not usually associated with LS. We analyzed the adrenocortical tumour for microsatellite instability (MSI), LOH and the presence of the germline c.2063T>G (M688R) mutation. The adrenal cortical carcinoma showed the MSH2 mutation, loss of heterozygosity of the normal allele in the MSH2 gene and loss of immunohistochemical expression for MSH2 protein, but no microsatellite instability. Additionally, the adrenal cortical carcinoma did not harbour a TP53 mutation. The molecular study indicates that this adrenal cortical cancer is probably due to the mismatch repair defect.

Tumour spectrum of non-polyposis colorectal cancer (Lynch syndrome) on the island of Tenerife and influence of insularity on the clinical manifestations.

Colorectal cancer is a complex disease from a genetic point of view because both genetic and environmental factors interact in its development. Only familial adenomatous polyposis (FAP) follows mendelian genetics, in that mutations of the APC gene lead to development of the tumours. Lynch syndrome is the most frequent form of hereditary colorectal cancer and appears to be associated with other types of extracolonic cancers. The genetic basis has been established as a defect in DNA mismatch repair genes, and there is genetic heterogeneity due to the involvement of several genes in this system. Germinal mutations in these genes predispose to appearance of the syndrome. The aim of this study is to describe the tumoral spectrum of 10 families, comprising a total of 488 individuals, from the island of Tenerife (Canary Islands) and to assess whether the geographical isolation of this population has changed any features of the tumoral spectrum of the syndrome in comparison with studies that cover larger geographical areas with more genetic exchange. From our results we can conclude that the genetic drift and consanguinity in this population with a demographic history of isolation did not significantly alter the tumoral spectrum of the syndrome. Our data confirm that families affected by Lynch syndrome are a high-risk population and should be closely monitored, since their careful supervision has been shown to be useful in preventing cancer. We also emphasize the importance of developing a complete family history that permits these families to be identified together with a mutational screening of DNA mismatch repair genes (mainly MLH1 and MSH2 genes) with the aim of a possible identification of members of a family that should be carefully monitored (the carriers of germline mutations in these genes), whereas the remaining members, originally, are no more at risk than the general population.

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.

Prognostic significance of high microsatellite instability in a Spanish series of gastric adenocarcinomas.

In colorectal cancer different levels of microsatellite instability (MSI) have been described. MSI-H (high) characterizes a unique clinical and pathological phenotype known as hereditary non-polyposis colorectal cancer syndrome, whereas MSI-L (low) and MSS (stable) are considered similar phenotypes without pathological implications. MSI has been also described as a frequent genetic alteration in a subset of gastric adenocarcinomas. However, the clinicopathological and prognosis significance of this abnormality in these tumors remains unclear. To investigate the role of genetic instability in gastric carcinogenesis we examined 10 microsatellite loci in 37 patients. MSI-H was found in 37.8% patients. We observed a trend of MSI-H tumors to be associated with elderly patients, intestinal histological type, advanced clinical stages and less aggressiveness with better survival. In conclusion, MSI-H can be considered as a good prognosis factor in a subset of gastric tumors.

Loss of heterozygosity of TP53 is not correlated with clinicopathological variables in sporadic colorectal carcinomas.

We have analyzed the loss of heterozygosity (LOH) of TP53 in a series of 96 sporadic colorectal carcinomas by means of PCR, using two microsatellite sequences (TP53 and Mfd152), to investigate its possible relationship with several clinicopathological variables in the Spanish population. Forty six of the 96 patients (48%) showed loss of one allele of the microsatellite TP53, Mfd152 or both, when compared with normal colorectal mucosae and blood samples of the same patient. This high percentage of LOH seems to corroborate the important role of p53 in sporadic colorectal cancer. However, we have found that LOH on this region is independent of histological grade and tumour location. With regard to tumour Dukes' stage, the fact that a substantial proportion of tumours show LOH on 17p from the first stages of the disease could imply that this alteration is not related with the invasiveness acquisition staging.

Acute megakaryoblastic leukemia in a patient with a familial pericentric inversion of chromosome 8, inv(8)(p23.1q13).

A 7-month-old girl was diagnosed with acute megakaryoblastic leukemia and, at the time of diagnosis, the karyotype was 48-50,XX,+4,+5,del(5)(p13),del(6)(q14), +8,inv(8)(p23.1q13),der(13) t(13;?;?),+19,-20,+21,+22,+mar [cp20]. At relapse, there was clear evidence of her constitutional status as a carrier of the pericentric inversion (8)(p23.1q13). It was a familial inversion affecting the patient's maternal lineage; a history of cancer and bleeding anomalies in carriers of the inversion led us to consider their nonrandom association with these pathologies.

Digestion of human chromosomes by means of the isoschizomers MspI and HpaII.

The isoschizomers MspI and HpaII are four base cutter (C decrease CGG) restriction endonucleases, HpaII being sensitive to methylation of the internal cytosine. Human chromosomes treated with MspI have produced inconsistent results between laboratories, while HpaII has always been described as a nonbanding enzyme when used on human chromosomes. These results have been explained on the basis of both rarity of the CpG doublet in vertebrate genomes and high rate of CpG methylation (5mCpG). We demonstrated consistent banding patterns subsequent to digestions with MspI and HpaII. On euchromatin, MspI (but not HpaII) digests the DNA of R regions and thus R-bands apparently contain many more CCGG sites (mostly methylated) than G-bands. In heterochromatin, extensive digestion of the 9q12 region not only by MspI but also by HpaII reveals a heterochromatic domain with a high frequency of unmethylated CCGG sites, most probably within the satellite 3 DNA fraction. In addition, enzymatic digestions of the Yq12 heterochromatin, when this region is undercondensed by 5-azacytidine, contribute to deepen the insight into the mechanism of action of this cytidine analog and at the same time reinforce the idea of the heterogeneity of this chromosome region where domains with unmethylated CCGG sites may also exist.