Massive juvenile polyposis of the stomach in a family with SMAD4 gene mutation.

Relatively little is known on the genotype-phenotype correlations between SMAD4 gene mutations, juvenile polyposis of the intestine and Hereditary Hemorrhagic Teleangectasia. We describe a family in which the proband (a 46-year old woman) had massive polyposis of the stomach-leading to surgery-with high-grade dysplasia at histology. Molecular analysis was carried out using Next Generation sequencing techniques with Miseq Illumina Platforms and a minimal coverage of 40 reads. In the proband, the analysis showed the presence of a truncating mutation in the SMAD4 gene (c.1213dupC, a variant previously associated with juvenile polyposis and Hereditary Hemorrhagic Teleangectasia). The same mutation was detected in two other members of the family (father and brother of the proband), who showed massive polypoid involvement of the stomach at gastroscopy. By taking the family history, subtle evidence of Hereditary Teleangectasia was found (nasal bleeding and arterovenous malformations) in the three gene carriers. Colonoscopy showed polyp occurrence in all three affected members with SMAD4 mutation, with prevalence of adenomatous lesions in one (father), of hamartomas in the brother, and of a mix of histological types in the proband. The main features of the family can be summarized as follows: (A) In hereditary juvenile polyposis, lesions of different histology can be detected at colonoscopy; (B) In the gene carriers of SMAD4 mutations, lesions of the stomach require careful surveillance and, when necessary, surgical interventions; (C) Signs and symptoms of Hereditary Hemorrhagic Teleangectasia should be suspected (and searched) in individuals with SMAD4 constitutional mutations.

Attenuated polyposis of the large bowel: a morphologic and molecular approach.

Attenuated polyposis could be defined as a variant of familial adenomatous polyposis (FAP) in which synchronous polyps of the large bowel range between 10 and 99. We analysed all cases of attenuated polyposis observed over the last 30 years with the objectives: (A) to classify the disease according to different type and proportion of polyps; (B) To ascertain the contribution of APC and MutYH genes; (C) to discover features which could arise the suspicion of mutations; (D) To obtain indications for management and follow-up. 84 individuals in 82 families were studied. Polyps were classified into four groups as adenoma, hyperplastic, other serrated lesions or others; APC and MutYH mutations were assessed. Mean age at diagnosis was 54 ± 14 years in men and 48 ± 13 in women (P = 0.005). Polyps were more numerous in women (37 ± 26 vs 29 ± 22). Sixty % of patients underwent bowel resection, mainly for cancer; the remaining were managed through endoscopy. A total of 2586 polyps were detected at diagnostic endoscopy: 2026 (80 %) were removed and analysed. Adenomas were diagnosed in 1445 (70 %), hyperplastic polyps in 541 (26 %), other serrated lesions in 61 (2.9 %). Adenomas and hyperplastic lesions were detected in the majority of patients. In 68 patients (81 %) in whom studies were executed, APC mutations were found in 8 and MutYH mutations in 10. Genetic variants were more frequent in women (12 vs 6, P = 0.039). Taking into consideration the prevalent (>50 %) histology and presence of mutations, patients could be subdivided into four groups: (1) APC mutated polyposis (AFAP), when adenomas were >50 % and APC mutations detected (no. 8, 10 %); (2) MutYH mutated polyposis (MAP), adenomas >50 % and biallelic MutYH mutations (no. 10, 12 %); (1) attenuated polyposis without detectable mutations, prevalence of adenomas, 48 cases (57 %); (1) hyperplastic-serrated polyposis, with prevalence (>50 %) of hyperplastic/other serrated lesions and no constitutional mutation (no. 18, 21 %). Aggregation of tumors, cancer in probands, distribution of polyps and other clinical characteristics showed no difference among the four groups. In conclusions, AFAP and MAP, the polyposis labeled by constitutional mutations, represented about 25 % of all attenuated polyposis. Mutation-associated cases showed an earlier age of onset of polyps and were more frequent in the female sex.

Clinical features of colorectal cancer patients in advanced age: a population-based approach.

In the immediate future, the number of geriatric patients will continue to rise; consequently we should expect an increase of colorectal cancer, a disease of the elderly population. Through the data of a Cancer Registry, we examined (a) the effect of ageing on the main features of colorectal cancer; (b) changes in management, especially for individuals older than 80 years; and (c) changes in prognosis and survival in subgroups of patients with different age. The Registry provided information on colorectal cancer up to 2010 (27 years). A total of 5293 patients were registered; these were divided into three groups: A (0-64 years), B (65-79) and C (80 or more). Three periods of observation were chosen: 1 (1984-1992), 2 (1993-2001) and 3 (2001-2010). Group A included 1571 patients (29 %), Group B 2539 (48 %) and Group C 1183 (22.3 %). The fraction of old individuals increased during the 27 years of the investigation. In these patients, tumours were predominantly localized to the right colon (42.6 %). The rate of surgery and ratio between curative and palliative approaches were similar among the three groups (p < 0.38). There was disparity (p < 0.002) in the administration of chemotherapy (5.8 % of the elderly vs 34.4 % in remaining patients). Survival increased over time in all three groups. In the elderly, average 5-year survival was 31 % in period 1 and 55 % in period 3. These data show that in Western countries, the standard of care for colorectal cancer diagnosed in geriatric patients has improved over the last 30 years.

The perception of health-related quality of life in colon cancer patients during chemotherapy: differences between men and women.

There is a need for more information on the quality of life (QoL) in patients undergoing chemotherapy. We wanted to investigate the perception of health status in colon cancer patients before, 3 and 6 months after chemotherapy. A secondary purpose was to assess the different perceptions of QoL between men and women during and after adjuvant or palliative therapy. We investigated 100 patients throughout chemotherapy for colon cancer. Data were collected through the SF-36 questionnaire. The score of all variables analyzed in the study group was lower than in the control group, which indicates a lower performance status, more marked in the female sex. Patients were then subdivided by the state of disease (localized or metastatic) and the variables, were evaluated before, 3 and 6 months after therapy. In patients treated with adjuvant treatment, there was a worsening of the performance status, followed by an increase after 6 months. We found that after 3 months of therapy, affected male patients perceived more limitations in carrying out their work, other daily activities and social relationships, owing to both their emotional state and their physical health. In metastatic patients the values of the eight variables decreased dramatically after 6 months, indicating a worsening of the QoL. In patients who received adjuvant treatment there was a certain worsening of the health status at 3 months, followed by a general improvement after 6 months. This improvement was not observed in patients undergoing palliative therapy. Several differences were observed between men and women in performance status after treatment.

What clinicians wish to know about benign colorectal polyps: an operative classification.

INTRODUCTION: In recent years we assisted to a real "boom" of colorectal polyps, mainly due to the diffusion of screening procedures and of colonoscopy. This new "Polyp Epidemic" raises a series of problems and challenges. It became clear that many syndromes are defined by the number, histological type and location of polyps, together with extraintestinal manifestations and, in most cases, specific molecular changes. This paper discusses some of the above mentioned points, focusing on the relative role of endoscopists and pathologists. The objective is to reach an operative classification of the most common polyps observed in daily practice which might be of help for the identification of inherited syndromes. METHODS AND RESULTS: Six main histological types of polyps are defined and underlined: Adenoma, hyperplastic/serrated, hamartoma, ganglioneuroma, mixed, inflammatory. The importance of a brief description, in pathology reports, of each type of polyps is fundamental for a correct diagnosis. Each of the defined polyps is associated with inherited syndromes whose genetic basis has recently been elucidated. Relevant information should be given, and separated from additional (and not strictly necessary) information. RECOMMENDATIONS: A correct polyp analysis is a valuable element for identifying specific inherited syndromes. Polyps represent a precious tool for planning screening and follow-up in a given individual. In addition, these lesions focus the interest of clinicians toward syndrome which were considered as rare diseases; indeed, the explosion of molecular biology and the diffusion of colonoscopy revealed that these conditions are frequent and amenable of treatment.

MUTYH-associated polyposis (MAP): evidence for the origin of the common European mutations p.Tyr179Cys and p.Gly396Asp by founder events.

MUTYH-associated polyposis (MAP) is an autosomal recessive adenomatous polyposis caused by biallelic germline mutations of the base-excision-repair gene MUTYH. In MAP patients of European origin, the combined allele frequency of the mutations p.Tyr179Cys and p.Gly396Asp ranges between 50 and 82%, while these mutations have not been identified in Far Eastern Asian populations, supporting the hypothesis that a founder effect has occurred at some point in European history. To investigate the natural history of the two common European MUTYH alleles, we genotyped six gene-flanking microsatellite markers in 80 unrelated Italian and German MAP patients segregating one or both mutations and calculated their age in generations (g) by using DMLE+2.2 software. Three distinct common haplotypes, one for p.Tyr179Cys and two for p.Gly396Asp, were identified. Estimated mutation ages were 305 g (95% CS: 271-418) for p.Tyr179Cys and 350 g (95% CS: 313-435) for p.Gly396Asp. These results provide evidence for strong founder effects and suggest that the p.Tyr179Cys and p.Gly396Asp mutations derive from ancestors who lived between 5-8 thousand years and 6-9 thousand years B.C., respectively.

Morphological and quantitative analysis of BCL6 expression in human colorectal carcinogenesis.

The aim of the present study was to determine whether BCL6 is expressed during malignant transformation of the large bowel and to assess whether, and to what extent, immunoreactivity is related to the different stages of neoplastic progression. Samples of normal colorectal mucosa (n=22), microadenomas (n=22) and colorectal cancer (n=22), were analyzed by immunohistochemistry, immunofluorescence coupled with confocal microscopy and western blotting. Our results clearly outlined the marked increase occurring in both intensity and density of BCL6 protein expression in the normal mucosa-microadenoma-carcinoma sequence. Immunohistochemistry and immunofluorescence analyses showed that BCL6 is expressed at low levels in normal mucosa and increases in microadenoma and in cancer with statistical significance. These results were confirmed by western blotting data. The increasing expression of BCL6 in human colorectal cancer development suggests the involvement of BCL6 in tumor progression, from the earliest stages of carcinogenesis with significant increase in cancer. The enhanced understanding of the biological role of BCL6, previously shown to exert a key role in lymphomagenesis, may lead to a re-evaluation of this protein and may highlight the importance of performing further studies in order to identify novel therapeutic targets for colorectal cancer.

Th inducing POZ-Kruppel Factor (ThPOK) is a key regulator of the immune response since the early steps of colorectal carcinogenesis.

We purposed to evaluate the role of Th inducing POZ-Kruppel Factor (ThPOK), a transcriptional regulator of T cell fate, in tumour-induced immune system plasticity in colorectal carcinogenesis. The amounts of CD4+, CD8+ and CD56+ and ThPOK+ cells infiltrate in normal colorectal mucosa (NM), in dysplastic aberrant crypt foci (microadenomas, MA), the earliest detectable lesions in colorectal carcinogenesis, and in colorectal carcinomas (CRC), were measured, and the colocalization of ThPOK with the above-mentioned markers of immune cells was evaluated using confocal microscopy. Interestingly, ThPOK showed a prominent increase since MA. A strong colocalization of ThPOK with CD4 both in NM and in MA was observed, weaker in carcinomas. Surprisingly, there was a peak in the colocalization levels of ThPOK with CD8 in MA, which was evident, although to a lesser extent, in carcinomas, too. In conclusion, according to the data of the present study, ThPOK may be considered a central regulator of the earliest events in the immune system during colorectal cancer development, decreasing the immune response against cancer cells.

Duodenal carcinoma in a 37-year-old man with Cowden/Bannayan syndrome.

A 37-year-old man was hospitalised because of anaemia and fatigue due to an infiltrating adenocarcinoma of the Treitz angle (duodenum), together with gastric, duodenal and colorectal polyps. After the operation, removal of colorectal lesions revealed the presence of ganglioneuromatosis of the large bowel. Further investigations showed lack of MLH1 protein expression and microsatellite instability in the duodenal neoplasm, while the gene was normally expressed in the polyps. MLH1 sequence and Multiple Ligation-dependent Probes Amplification analysis (from constitutional DNA) were normal. Analysis of the PTEN gene revealed the presence of a constitutional mutation (c.510 T>A; p.Ser170Arg) which had been associated with the Cowden phenotype. Further detailed clinical investigations revealed macrocephaly (63 cm), melanotic spots of the penis, small angiomas, millimetric trichilemmomas in the nose and multiple lipomas, which led to the diagnosis of Cowden/Bannayan disease. The unusual appearance of a duodenal carcinoma as the first symptom rendered the identification of the syndrome extremely difficult.

MSH3 protein expression and nodal status in MLH1-deficient colorectal cancers.

PURPOSE: Patients with colorectal cancers (CRC) and high microsatellite instability (MSI) have a better outcome than their chromosome-unstable counterpart. Given the heterogeneity of microsatellite-unstable CRCs, we wanted to see whether any MSI-associated molecular features are specifically associated with prognosis. EXPERIMENTAL DESIGN: One hundred and nine MSI-high CRCs were typed for primary mismatch repair (MMR) defect and for secondary loss of MMR proteins. Frameshifts at seven target genes, mutations in the RAS pathway, and methylation at MLH1/CDKN2A promoters were also searched. The interplay of molecular findings with clinicopathologic features and patient survival was analyzed. RESULTS: Of 84 MLH1-deficient CRCs, 31 (36.9%) had MSH3 and 11 (13.1%) had MSH6 loss (P < 0.001), biallelic frameshift mutations at mononucleotide repeats accounting for most (78%) MSH3 losses. As compared with MSH3-retaining cancers, MLH1-deficient tumors with MSH3 loss showed a higher number of mutated target genes (3.94 ± 1.56 vs. 2.79 ± 1.75; P = 0.001), absence of nodal involvement at pathology [N0; OR, 0.11; 95% confidence interval (CI), 0.04-0.43, P < 0.001], and better disease-free survival (P = 0.06). No prognostic value was observed for KRAS status and for MLH1/CDKN2A promoter methylation. The association between MSH3 loss and N0 was confirmed in an independent cohort of 71 MLH1-deficient CRCs (OR, 0.23; 95% CI, 0.06-0.83, P = 0.02). CONCLUSIONS: MLH1-deficient CRCs not expressing MSH3 have a more severe MSI, a lower rate of nodal involvement, and a better postsurgical outcome.

Clinical and molecular characterization of colorectal cancer in young Moroccan patients.

BACKGROUND/AIMS: Early-onset colorectal cancers are relatively rare. About 20% of colorectal cancers are familial or hereditary. Two autosomal dominantly inherited cancer syndromes are more studied: Lynch syndrome accounts for 2-5% of colorectal cancers and familial adenomatous polyposis represents 1% of total colorectal cancers. Unlike the familial adenomatous polyposis syndrome, there are no clinical features that help in easily recognizing Lynch syndrome. The young age of cancer occurrence could be a criterion that should raise a suspicion of Lynch syndrome. In Morocco, the average age at diagnosis of colorectal cancers according to the register of cancers of Casablanca is 56 years, which is 10 years earlier than in European countries. Our study aimed to assess the frequency and molecular characteristics of the Lynch syndrome in Moroccan early-onset colorectal cancers patients. MATERIALS AND METHODS: The population analyzed included 70 patients. The criteria for inclusion of patients in this study were a colorectal cancers before age 50 and the exclusion of familial adenomatous polyposis. We started by searching for microsatellite instability, first by immunohistochemistry of 3 mismatch repair proteins (MLH1, MSH2 and MSH6) and with second confirmation using 4 monomorphic markers (BAT25, BAT26, NR21, and CAT25). RESULTS: We found instability in 10/70 (15%) of the cases. The loss of expression affects more often the MLH1 protein, with 8 cases, versus 2 cases of altered MSH2. None of the 70 patients of the series fulfilled the Amsterdam II criteria, indicative of Lynch syndrome. CONCLUSIONS: Further work needs to be done to discriminate hereditary cases from sporadic ones, but testing for microsatellite instability as a first step is important.

Analysis of mismatch repair gene mutations in Turkish HNPCC patients.

Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) is caused by the inheritance of a mutant allele of a DNA mismatch repair gene. We aimed to investigate types and frequencies of mismatch repair (MMR) gene mutations in Turkish patients with HNPCC and to identify specific biomarkers for early diagnosis of their non-symptomatic kindred's. The molecular characteristics of 28 Turkish colorectal cancer patients at high-risk for HNPCC were investigated by analysis of microsatellite instability (MSI), immunohistochemistry and methylation-specific PCR in order to select tumors for mutation analysis. Ten cases (35.7%) were classified as MSI (+). Lack of expression of the main MMR proteins was observed in MSI (+) tumors. Hypermethylation of the MLH1 promoter region was observed in one tumor. Nine Lynch syndrome cases showed novel germ-line alterations of the MMR gene: two frame-shifts (MLH1 c.1843dupC and MLH1 c.1743delG) and three missense mutations (MLH1 c.293G>C, MLH1 c.954_955delinsTA and MSH2 c.2210G>A). Unclassified variants were evaluated as likely to be pathogenic by using the in-silico analyses. In addition, the MSH2 c.2210G>A alteration could be considered as a founder mutation for the Turkish population due to its identification in five different Lynch syndrome families and absence in control group. The present study adds new information about MMR gene mutation types and their role in Lynch syndrome. This is the first detailed research on Turkish Lynch syndrome families.

Clinical features and colorectal cancer survival: an attempt to explain differences between two different Italian regions.

UNLABELLED: AIMS OF THE STUDY AND METHODS: Recent studies suggested the existence of significant regional variations, in Italy, for cancer survival. For most neoplasms, survival rates tended to be lower in Southern regions versus Northern areas; for colorectal tumours, 5-year survival was 60% in Northern regions, but ranged between 40% and 50% in the South. Main purpose of the present study was to find out possible reasons which might explain such differences. To reach this objective, we compared the main epidemiological and clinical data in two areas covered by cancer registration: Modena, in the North, and Naples in the South of Italy. RESULTS: The results of the study suggest that differences in colorectal cancer survival can be mainly attributed to a different stage at diagnosis, which was less favourable in a larger fraction of cases diagnosed in Southern Italy. This could be the consequence of an insufficient diffusion of screening procedures. Type of surgery, medical treatment and follow-up seem to play little or no role. The study also shows that incidence rates of colorectal cancer are significantly higher in the North than in the South of the country, and that the excess of cases seen in Modena is limited to the age group 55-75+ years, while age-specific incidence is virtually identical in the younger age classes. CONCLUSION: This high-resolution study confirms the paramount importance of stage at diagnosis in the management of colorectal cancer, and suggests that social and economic factors are of relevance, even in Western countries, for reducing inequalities in cancer care.

Survival, surgical management and perioperative mortality of colorectal cancer in the 21-year experience of a specialised registry.

BACKGROUND AND AIMS: A general improvement of colorectal cancer prognosis has been observed. Reasons of this more favourable trend are diffusion of screening, advancements in molecular biology, new developments in chemotherapy and surgical techniques. Through the data of a colorectal cancer registry, we purposed to evaluate changes in surgical procedures for colorectal neoplasms and to analyse trends of perioperative mortality. PATIENTS AND METHODS: Patients with colorectal cancer were registered from 1984 to 2004. The main surgical procedures were recorded and classified. Perioperative mortality was defined as death of patients within 1 month since the operation. RESULTS: Regression analysis showed an increase over time of right and left hemicolectomy. Both colectomy and endoscopic polypectomy showed significant rise over time. In contrast, abdominoperineal operations dropped during the study period. A similar decrease was observed for palliative surgery. Perioperative mortality declined from 7-11% to 3-6% of all operations; main factors associated with perioperative mortality were presence of comorbidities, increasing age and advanced stage. CONCLUSION: The better prognosis of patients with colorectal cancer was associated with changes of surgical techniques, with a tendency to prefer large operations over limited resections. Perioperative mortality showed a gradual decrease and is at present in the order of 3% to 6% of all operations.

Prognostic relevance of MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer patients.

AIMS AND BACKGROUND: Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. METHODS: A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. RESULTS: Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). CONCLUSIONS: Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal carcinoma patients depends on the associated constitutional mismatch repair genotype.

Genotype-phenotype correlations in individuals with a founder mutation in the MLH1 gene and hereditary non-polyposis colorectal cancer.

OBJECTIVE: A unique mutation of the MLH1 gene was recently reported in six families living in a small area of Northern Italy. The mutation consists in the insertion of a T base between nucleotides 2269 and 2270 (2269-2270insT), causing the synthesis of an unstable polypeptide. The mutation was not reported by other investigators or outside this small geographic area, thus suggesting a possible founder effect. The main purpose of this investigation was to investigate whether patients (and families) with the 2260-2270insT mutation show relevant clinical differences when compared with individuals with other MLH1 or MSH2 gene alterations. MATERIAL AND METHODS: We identified hereditary non-polyposis colorectal cancer (HNPCC) families through the specialized colorectal cancer registry following a previously described multistep approach. In all, 58 HNPCC families were identified; of these, 38 were detected through the registry, and 20 were referred from other areas in Italy. RESULTS: Small differences were found in the main clinical and pathologic features; however, tumour burden per family tended to be higher in kindred sharing the founder mutation; in addition, multiple primaries (four or five different tumours in some subjects) were significantly more frequent in patients with the 2269-2270insT than in individuals with MSH2, MLH1 gene mutations or sporadic colorectal neoplasms. No significant difference in prognosis was found between patients with the founder mutation and those with other MLH1 or MSH2 mutations. Regardless of the type of mutation, neoplasms of the colon-rectum, stomach and endometrium represented nearly 80% of the tumour burden in families with HNPCC. CONCLUSIONS: A proclivity to multiple tumours arising in the same subject and a higher tumour burden per family were the most relevant findings observed in affected patients with the founder mutation compared with other MLH1 or MSH2 mutations. In general, the results of the study underline the difficulty in discriminating between Lynch I and Lynch II syndromes on the basis of specific molecular changes.

Prognostic significance of histological features and biological parameters in stage I (pT1 and pT2) colorectal adenocarcinoma.

Patients with stage I colorectal cancer have a good prognosis, however, a small fraction of them die of local or distant recurrence after curative resection. The aggressive behavior reflects some biological properties of these tumors. In this study, we evaluated the prognostic role of some histopathological and biological parameters in stage I colorectal carcinomas. From the Colorectal Cancer Registry of Modena, we selected two series of patients; the first included all patients who had died of disease progression, the second included patients with a favorable outcome. The histopathological parameters assessed were grade of differentiation, growth pattern at the invasive tumor front, peritumoral lymphocytic infiltration, tumor budding and vascular invasion. The biological variables were proliferative activity (using Ki-67 nuclear antigen), overexpression of p53 protein and altered expression of the mismatch repair proteins (MLH1 and MSH2). The results showed that an infiltrating growth pattern, absent or sparse peritumoral lymphocytic infiltration, the presence of tumor budding and vascular invasion are significantly related to the risk of recurrence. Among the biological parameters, p53 overexpression was significantly correlated with a poor clinical outcome. Our study showed that the histopathologial features are relevant prognostic indicators and might be used as markers for an appropriate treatment strategy in patients with stage I carcinomas.

Investigation of APC mutations in a Turkish familial adenomatous polyposis family by heterodublex analysis.

PURPOSE: Familial adenomatous polyposis is an autosomal dominant disease characterized by the presence of 100 or more colorectal adenomatous polyps. Mutations in the adenomatous polyposis coli gene are primarily responsible for the development of this disease. This study was designed to investigation of adenomatous polyposis coli (APC) gene mutations in members of familial adenomatous polyposis family to identify individuals at risk of the disease. METHODS: We examined one patient with familial adenomatous polyposis and 21 family members including one affected person from familial adenomatous polyposis and 20 nonsymptomatic persons. We studied E, D, F, and G segments of exon 15 of the adenomatous polyposis coli gene by heteroduplex analysis. RESULTS: We used silver staining method for staining. We found a mutation for five persons at segment F of exon 15 of the adenomatous polyposis coli gene. Two of them were affected by colorectal cancer, one of whom was the proband, and the other three were nonsymptomatic family members. The pathogenetic mutation was a T deletion at codon 1172, causing a frameshift in the adenomatous polyposis coli gene, as a result of the sequencing analysis of these cases. CONCLUSIONS: Investigation of adenomatous polyposis coli gene mutations is very important for the identification of genetic susceptibility to colorectal cancer and for the definition of tumor developing at an early stage. Furthermore, the identification of this mutation for the first time in a Turkish family will be useful to foster further studies on familial adenomatous polyposis in Turkey.