Biomedical subjects

S R Hamilton

Publications and source records attributed to S R Hamilton.

At least 55 records · Page 3Linked to original sources

PubMed1999

Genetic epidemiology of mutated K-ras proto-oncogene, altered suppressor genes, and microsatellite instability in colorectal adenomas.

BACKGROUND: The genetic epidemiology of colorectal adenomas has not been studied prospectively in colonoscopy patients without cancer. AIMS: To study genetic alterations in colorectal adenomas and correlate these with patient demographics and adenoma characteristics. METHODS: Mutations and allelic deletions in 201 adenomas from 60 patients were compared with demographic features, adenoma characteristics, and family history. RESULTS: The most common alteration was K-ras proto-oncogene mutation, present in 35% of adenomas and 65% of patients. Patients 65 years of age and older had a decreased probability of K-ras mutations (26% versus 45%). Overexpression of p53 gene product was present in only 6% of adenomas but was more frequent in villous or tubulovillous adenomas (19% versus 3%). Allelic loss of chromosome 18q was present in only 2% of adenomas and was significantly less frequent than p53 overexpression. DNA replication errors (RER) were present in 7% of adenomas and 15% of patients, including multiple adenomas in four patients (two with hereditary non-polyposis colorectal cancer syndrome). Only 36% of RER positive adenomas had alteration of BAT-26 alleles, none had alteration of BAT-25, and only one (8%) had mutation in the transforming growth factor beta type II receptor gene. RER positive adenomas were more likely to have a K-ras mutation. In patients with multiple adenomas, there was concordance of p53 overexpression and RER but not of K-ras mutations. CONCLUSIONS: Genetic progression in colorectal adenomas is heterogeneous, involving factors related to patient age and the presence of RER for the occurrence of ras mutations, but different intraindividual characteristics for the occurrence of p53 alterations and RER.

Adenoma↗

PubMed1999

Rectal epithelial apoptosis in familial adenomatous polyposis patients treated with sulindac.

BACKGROUND: Sulindac regresses colorectal adenomas in patients with familial adenomatous polyposis (FAP), although the mechanism of polyp regression is unclear. AIMS: To determine whether differences occur in alteration of rectal epithelial apoptotic index and expression of apoptosis related proteins in FAP patients treated with sulindac compared with placebo. PATIENTS: Twenty one FAP patients; 12 had not undergone colectomy. METHODS: Patients with FAP were treated with sulindac 150 mg orally twice a day for three months (n=10) or placebo (n=11). Colorectal polyp number was determined and biopsies of the normal rectal mucosa were performed before and after three months of treatment. Response to treatment and alteration of the apoptotic ratio (index in base of crypt divided by index in surface epithelium) were evaluated. Bcl-2, bax, p21/WAF-1, and p53 proteins were assessed semiquantitatively by immunohistochemistry. RESULTS: Significant decreases in polyp number and in the apoptotic ratio were seen in patients treated with sulindac compared with controls. The mean percentage change in polyp number from baseline was -46% in the sulindac group and +13% in the placebo group (p=0.005). Mean percentage change in the apoptotic ratio was -8% and +25% in the sulindac and placebo treated patients, respectively (p=0.004). No differences in expression or compartmentalisation of apoptosis related proteins were noted between treatment groups. CONCLUSIONS: Sulindac regression of colorectal adenomas is accompanied by alteration of the rectal epithelial apoptotic ratio with relative increase in apoptosis in surface cells compared with the deeper crypt. The utility of the apoptotic ratio as an intermediate biomarker for colorectal tumorigenesis deserves further study.

Adenomatous Polyposis Coli↗

PubMed1999

Colon cancer testing and screening.

Laboratory testing has the potential to favorably affect the outcome of patients with neoplasia by applications in screening, risk identification, surveillance, diagnosis, prognosis, prediction of tumor response or resistance to therapies, and prediction of toxic effects from therapies. Molecular testing directed at colorectal neoplasia is currently in use for diagnosis and characterization of rare, highly penetrant inherited syndromes due to germline mutation of the APC suppressor gene or DNA nucleotide mismatch repair genes. Routine application of molecular assays of colorectal tumors as prognostic and predictive markers is likely to occur in the near future, but major advances in technology are needed to begin to move molecular testing into screening of the general population and surveillance of subjects at increased risk. It seems certain that molecular methods will become increasingly important in improving the outcome of patients with colorectal neoplasia and in contributing to continued decline of the death rate from this common cancer.

Biomarkers, Tumor↗

PubMed1998

Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by intestinal hamartomatous polyps, mucocutaneous melanin deposition, and increased risk of cancer. Families with PJS from the Johns Hopkins Polyposis Registry were studied to identify the molecular basis of this syndrome and to characterize the pathogenesis of gastrointestinal hamartomas and adenocarcinomas in PJS patients. Linkage analysis in the family originally described by Jeghers in 1949 and five other families confirmed linkage to 19p13.3 near a recently identified gene responsible for PJS. Germ-line mutations in this gene, STK11, were identified in all six families by sequencing genomic DNA. Analysis of hamartomas and adenocarcinomas from patients with PJS identified loss of heterozygosity (LOH) of 19p markers near STK11 in 70% of tumors. Haplotype analysis indicated that the retained allele carried a germ-line mutation, confirming that STK11 is a tumor suppressor gene. LOH of 17p and 18q was identified in an adenocarcinoma but not in hamartomas, implying that allelic loss of these two regions corresponds to late molecular events in the pathogenesis of cancer in PJS. The adenocarcinomas showing 17p LOH also demonstrated altered p53 by immunohistochemistry. None of the 18 PJS tumors showed microsatellite instability, LOH on 5q near APC, or mutations in codons 12 or 13 of the K-ras proto-oncogene. These data provide evidence that STK11 is a tumor suppressor gene that acts as an early gatekeeper regulating the development of hamartomas in PJS and suggest that hamartomas may be pathogenetic precursors of adenocarcinoma. Additional somatic mutational events underlie the progression of hamartomas to adenocarcinomas, and some of these somatic mutations are common to the later stages of tumor progression seen in the majority of colorectal carcinomas.

Adenocarcinoma↗

PubMed1998

A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.

In December 1997, the National Cancer Institute sponsored "The International Workshop on Microsatellite Instability and RER Phenotypes in Cancer Detection and Familial Predisposition," to review and unify the field. The following recommendations were endorsed at the workshop. (a) The form of genomic instability associated with defective DNA mismatch repair in tumors is to be called microsatellite instability (MSI). (b) A panel of five microsatellites has been validated and is recommended as a reference panel for future research in the field. Tumors may be characterized on the basis of: high-frequency MSI (MSI-H), if two or more of the five markers show instability (i.e., have insertion/deletion mutations), and low-frequency MSI (MSI-L), if only one of the five markers shows instability. The distinction between microsatellite stable (MSS) and low frequency MSI (MSI-L) can only be accomplished if a greater number of markers is utilized. (c) A unique clinical and pathological phenotype is identified for the MSI-H tumors, which comprise approximately 15% of colorectal cancers, whereas MSI-L and MSS tumors appear to be phenotypically similar. MSI-H colorectal tumors are found predominantly in the proximal colon, have unique histopathological features, and are associated with a less aggressive clinical course than are stage-matched MSI-L or MSS tumors. Preclinical models suggest the possibility that these tumors may be resistant to the cytotoxicity induced by certain chemotherapeutic agents. The implications for MSI-L are not yet clear. (d) MSI can be measured in fresh or fixed tumor specimens equally well; microdissection of pathological specimens is recommended to enrich for neoplastic tissue; and normal tissue is required to document the presence of MSI. (e) The "Bethesda guidelines," which were developed in 1996 to assist in the selection of tumors for microsatellite analysis, are endorsed. (f) The spectrum of microsatellite alterations in noncolonic tumors was reviewed, and it was concluded that the above recommendations apply only to colorectal neoplasms. (g) A research agenda was recommended.

Colorectal Neoplasms↗

PubMed1998

Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma.

Inactivation of the genes involved in DNA mismatch repair is associated with microsatellite instability (MSI) in colorectal cancer. We report that hypermethylation of the 5' CpG island of hMLH1 is found in the majority of sporadic primary colorectal cancers with MSI, and that this methylation was often, but not invariably, associated with loss of hMLH1 protein expression. Such methylation also occurred, but was less common, in MSI- tumors, as well as in MSI+ tumors with known mutations of a mismatch repair gene (MMR). No hypermethylation of hMSH2 was found. Hypermethylation of colorectal cancer cell lines with MSI also was frequently observed, and in such cases, reversal of the methylation with 5-aza-2'-deoxycytidine not only resulted in reexpression of hMLH1 protein, but also in restoration of the MMR capacity in MMR-deficient cell lines. Our results suggest that microsatellite instability in sporadic colorectal cancer often results from epigenetic inactivation of hMLH1 in association with DNA methylation.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Size-dependent increase in prostanoid levels in adenomas of patients with familial adenomatous polyposis.

Recent studies indicate that nonsteroidal anti-inflammatory drugs have a chemopreventive effect against colorectal neoplasia. Nonsteroidal anti-inflammatory drugs inhibit cyclooxygenases, principal enzymes that mediate the formation of prostanoids. To determine whether prostanoids are involved in the pathogenesis of colorectal adenomas, we compared the levels of five major stable metabolic products of the cyclooxygenase pathway in the normal-appearing mucosa and in adenomas of patients with familial adenomatosis polyposis. Of 12 patients tested, 6 had elevated levels of at least one prostanoid in the adenomas. More importantly, the relative levels of three prostanoids [prostaglandin (PG)D2, PGE2, and 6-keto-PGF1alpha] were elevated in adenomas compared to normal-appearing mucosa from the same patients, and the resulting ratios were correlated with the size of the adenoma. These results suggest a role for prostanoids in progression of colorectal polyposis in familial adenomatosis polyposis patients.

6-Ketoprostaglandin F1 alpha↗

PubMed1998

Molecular detection of genetic alterations in the serum of colorectal cancer patients.

We have searched for the presence of genetic alterations in serum DNA obtained from 44 colorectal cancer patients. Microsatellite analysis using highly polymorphic markers revealed loss of heterozygosity and/or microsatellite instability in 35 of 44 (80%) primary tumors. No alterations were detected in the paired serum DNA. We next used an oligonucleotide-mediated mismatch ligation assay to detect tumor specific gene mutations in the serum. Among the 16 cases with a K-ras gene mutation in the tumor, the same mutation was detected in three paired serum samples. In the 10 cases with a p53 mutation in the tumor, the identical mutation was detected in seven corresponding serum samples. Comparison of the molecular analysis with clinical diagnosis of these patients revealed that none of the seven Dukes' stage B patients with a K-ras mutation in their tumors demonstrated a mutation in the serum. In contrast, five of seven stage B patients with a p53 mutation in the tumor demonstrated a mutation in the paired serum (P = 0.01, Fisher's exact test). Taken together, either a K-ras or p53 mutation was detected in the serum in 40% of the 25 patients (95% confidence interval, 21-61%), whose primary tumors contained a mutation and in 23% of the 44 patients (95% confidence interval, 12-38%) with colorectal cancer. The frequent detection of p53 mutation in the serum of patients with early stage tumors suggests a possible use of this approach for clinical prognosis and cancer monitoring of colorectal cancer patients.

Alleles↗

PubMed1998

Genetics of colorectal cancer.

Recent years have brought great advances in the understanding of the pathogenesis of colorectal cancers. The elucidation of the underlying genetic alterations that produce these cancers has made it possible to broadly categorize this disease into two major types, hereditary and sporadic. The hereditary cancers have been divided further into recognized syndromes, mainly familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. These syndromes have unique clinical pictures and different prognoses in addition to their different genetic bases. Sporadic cancers have been found to have analogous genetic alterations which propel them along the progression from normal tissue to benign adenoma/dysplasia to malignancy. These advances in genetics can potentially lead to clinically useful advances in detection, treatment, and, ultimately, prevention of colorectal cancer.

Adenoma↗

PubMed1998

Genetic alterations in Barrett esophagus and adenocarcinomas of the esophagus and esophagogastric junction region.

The incidence of esophageal adenocarcinoma has increased markedly in the past two decades, but the genetic alterations in this cancer and its precursor, Barrett mucosa, have not been characterized extensively. DNA replication errors and allelic losses of chromosomes 17p, 18q, and 5q were studied in 36 resected adenocarcinomas arising in the esophagus and esophagogastric junction, 56 Barrett adenocarcinomas, and 11 dysplasias in Barrett esophagus. The results were compared with clinical and pathological characteristics, including patient survival. Replication error positive cancer was rare (5.4%) in esophageal adenocarcinomas and was not found in Barrett mucosa. There was an increase in the prevalence of chromosomal losses in the Barrett mucosa-columnar dysplasia-adenocarcinoma sequence: 17p loss occurred in 14% of Barrett mucosae, 42% of low-grade dysplasias, 79% of high-grade dysplasias, and 75% of adenocarcinomas, respectively; loss of 18q in 32%, 42%, 73%, and 69%; and loss of 5q in 10%, 21%, 27%, and 46%. Clinical stage was a very strong prognostic factor for survival, and adenocarcinomas with allelic loss of both 17p and 18q had worse survival than cancers with no or one allelic loss (P = 0.002). Our results indicate that accumulation of genetic alterations follows the dysplasia-adenocarcinoma sequence in the esophagus and that losses of 18q and 17p occur earlier than 5q loss. Allelic loss of both 17p and 18q in esophageal adenocarcinoma identifies patients with poor prognosis.

Adenocarcinoma↗

PubMed1998

Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences.

A subset of hereditary and sporadic colorectal carcinomas is defined by microsatellite instability (MSI), but the spectra of gene mutations have not been characterized extensively. Thirty-nine hereditary nonpolyposis colorectal cancer syndrome carcinomas (HNPCCa) and 57 sporadic right-sided colonic carcinomas (SRSCCa) were evaluated. Of HNPCCa, 95% (37/39) were MSI-positive as contrasted with 31% (18/57) of SRSCCa (P < 0.000001), but instability tended to be more widespread in SRSCCa (P = 0.08). Absence of nuclear hMSH2 mismatch repair gene product by immunohistochemistry was associated with germline hMSH2 mutation (P = 0.0007). The prevalence of K-ras proto-oncogene mutations was similar in HNPCCa and SRSCCa (30% (11/37) and 30% (16/54)), but no HNPCCa from patients with germline hMSH2 mutation had codon 13 mutation (P = 0.02), and two other HNPCCa had multiple K-ras mutations attributable to subclones. 18q allelic deletion and p53 gene product overexpression were inversely related to MSI (P = 0.0004 and P = 0.0001, respectively). Frameshift mutation of the transforming growth factor beta type II receptor gene was frequent in all MSI-positive cancers (85%, 46/54), but mutation of the E2F-4 transcription factor gene was more common in HNPCCa of patients with germline hMSH2 mutation than in those with germline bMLH1 mutation (100% (8/8) versus 40% (2/5), P = 0.04), and mutation of the Bax proapoptotic gene was more frequent in HNPCCa than in MSI-positive SRSCCa (55% (17/31) versus 13% (2/15), P = 0.01). The most common combination of mutations occurred in only 23% (8/35) of evaluable MSI-positive cancers. Our findings suggest that the accumulation of specific genetic alterations in MSI-positive colorectal cancers is markedly heterogeneous, because the occurrence of some mutations (eg, ras, E2F-4, and Bax genes), but not others (eg, transforming growth factor beta type II receptor gene), depends on the underlying basis of the mismatch repair deficiency. This genetic heterogeneity may contribute to the heterogeneous clinical and pathological features of MSI-positive cancers.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Prostaglandin levels in human colorectal mucosa: effects of sulindac in patients with familial adenomatous polyposis.

Recent evidence suggests that nonsteroidal antiinflammatory drugs (NSAIDs) may prevent colorectal cancer. The mechanism of action of NSAIDs in chemoprevention is unknown but may be linked to their effect on mucosal prostaglandin levels. Levels of five major prostaglandin metabolites were measured by gas chromatography-mass spectrometry in biopsy specimens of flat rectal mucosa from four patients with familial adenomatous polyposis (FAP) before and after sulindac therapy and from five healthy individuals. The prostaglandin present at highest concentration in rectal mucosa from FAP and control subjects was prostaglandin E2. The concentration of thromboxane B2 alone was significantly elevated in FAP patients compared to controls (P = 0.016). In FAP patients treated with sulindac, all prostaglandin metabolite levels were significantly reduced compared to pretreatment levels (P < 0.05) except prostaglandin D2 (P = 0.07). Prostaglandins D2, E2, F2alpha, and 6-keto-F1alpha levels also were significantly reduced in FAP patients on sulindac compared to healthy controls (P < 0.05). However, interpatient heterogeneity of response to sulindac was evident with changes ranging from +19% to -89%, and the patient with the greatest reductions after sulindac developed colorectal cancer after 35 months of therapy. Sulindac treatment, at drug doses shown to regress colorectal adenomas in FAP patients, has heterogeneous effects on the level of major prostaglandins in their rectal mucosa and may not prevent colorectal cancer due to uncoupling of prostaglandin levels and carcinogenesis.

Adenomatous Polyposis Coli↗

PubMed1998

Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability.

Loss of imprinting (LOI) is an epigenetic alteration of some cancers involving loss of parental origin-specific expression of imprinted genes. We observed LOI of the insulin-like growth factor-II gene in twelve of twenty-seven informative colorectal cancer patients (44%), as well as in the matched normal colonic mucosa of the patients with LOI in their cancers, and in peripheral blood samples of four patients. Ten of eleven cancers (91%) with microsatellite instability showed LOI, compared with only two of sixteen tumors (12%) without microsatellite instability (P < 0.001). Control patients without cancer showed LOI in colonic mucosa of only two of sixteen cases (12%, P < 0.001) and two of fifteen blood samples (13%, P < 0.001). These data suggest that LOI in tumor and normal tissue identifies most colorectal cancer patients with microsatellite instability in their tumors, and that LO! may identify an important subset of the population with cancer or at risk of developing cancer.

Colon↗

PubMed1998

Inhibition of DNA cytosine methyltransferase by chemopreventive selenium compounds, determined by an improved assay for DNA cytosine methyltransferase and DNA cytosine methylation.

The organoselenium compounds benzyl selenocyanate (BSC) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC), as well as sodium selenite, are effective chemopreventive agents for various chemically induced tumors in animal models at both the initiation and postinitiation stages. The mechanisms involved at the postinitiation stage are not clear. Because several lines of evidence indicate that inhibition of excess DNA (cytosine-5)-methyltransferase (Mtase) may be a sufficient factor for the suppression or reversion of carcinogenesis, we examined the effects of sodium selenite, BSC, p-XSC and benzyl thiocyanate (BTC), the sulfur analog of BSC, on Mtase activity in nuclear extracts of human colon carcinomas, and of p-XSC on the Mtase activity of HCT116 human colon carcinoma cells in culture. For this purpose, we developed an improved Mtase assay, in which the incorporation of the methyl-[3H] group from S-adenosyl[methyl-3H]methionine into deoxycytidine of poly(dI-dC)-poly(dI-dC), is specifically determined by HPLC with radioflow detection after enzymatic hydrolysis, enhancing specificity and reliability. In a variation, using SssI methyltransferase and labeled S-adenosylmethionine, the overall methylation status of DNA in various tissues can also be compared. Selenite, BSC and p-XSC inhibited Mtase extracted from a human colon carcinoma with IC50s of 3.8, 8.1 and 5.2 microM, respectively; BTC had no effect. p-XSC also inhibited the Mtase activity and growth of human colon carcinoma HCT116 cells, with an IC50 of approximately 20 microM. The improved Mtase assay should prove to be a reliable method for screening potential Mtase inhibitors, especially using cells in culture. We suggest that inhibition of Mtase may be a major mechanism of chemoprevention by selenium compounds at the postinitiation stage of carcinogenesis.

Adenocarcinoma↗

PubMed1998

Malignant tumors in the rectum simulating solitary rectal ulcer syndrome in endoscopic biopsy specimens.

Patients with solitary rectal ulcer syndrome (SRUS) frequently present with a mass that can be misinterpreted as cancer. In contrast, the occurrence and characteristics of SRUS-like histopathology produced by underlying malignancy have not been reported in detail. We report seven patients whose rectal mass that was induced by infiltrating carcinoma showed only histopathologic changes of SRUS on initial mucosal biopsy specimens. Carcinoma was evident in subsequent specimens after one to five repeat biopsies with delay in diagnosis from 1 week to 18 months in six patients. In one patient, infiltrating carcinoma was suggested on the first biopsy specimen by immunohistochemistry for cytokeratin. Three of the patients had primary rectal adenocarcinoma, two had metastatic carcinoma from stomach or ovary, and two had direct invasion of anal squamous cell carcinoma or prostatic adenocarcinoma. We conclude that the histopathology of SRUS may occasionally represent a characteristic but nonspecific mucosal reactive change to a deeper seated malignancy. The terminology "solitary rectal ulcer syndrome/mucosal prolapse changes" with a cautionary note may be useful for reporting biopsy results to emphasize the possibility of underlying primary or metastatic malignancy in the differential diagnosis.

Adenocarcinoma↗

PubMed1998

Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis.

Fundic gland polyps (FGPs) of the stomach are regarded as hamartomatous or hyperplastic/functional polyps that occur sporadically but at increased frequency in patients with familial adenomatous polyposis syndrome (FAP). There is controversy about the histopathology of FGPs, including occurrence of dysplasia. We, therefore, studied dysplasia in 270 sporadic FGPs from 216 patients and 49 FGPs from 24 patients with FAP. We evaluated dysregulation of epithelial proliferation manifested by loss of the normal inverse topographic distribution of Ki-67 proliferation marker and the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) using immunohistochemistry in 27 sporadic FGPs and in 22 FGPs from patients with FAP. Dysplasia in foveolar and surface epithelia occurred in 12 of 49 (25%) FGPs in patients with FAP but in only 3 of 270 (1%) of sporadic FGPs (p < 0.000001). Fourteen of 49 (29%) of FGPs from patients with FAP were indefinite for dysplasia, as contrasted with 8 of 270 (3%) sporadic FGPs (p < 0.00001). The normal inverse topographic distribution of Ki-67 and p21(WAF1/CIP1) was maintained in 20 of 22 (91%) of FGPs negative for dysplasia but was lost in all (8 of 8) FGPs with dysplasia and in 11 of 19 (58%) FGPs that were indefinite for dysplasia (p = 0.00001). The results indicate that dysplasia can occur in foveolar and surface epithelia of FGPs, especially in patients with FAP, and often is preceded by dysregulation of epithelial proliferation when the morphologic abnormalities are indefinite for dysplasia.

Adenomatous Polyposis Coli↗

PubMed1998

Prognostic significance of DNA replication errors in young patients with colorectal cancer.

OBJECTIVE: To determine the DNA replication error (RER) status in young patients with colorectal cancer (CRC), and to compare the clinical and pathologic characteristics of RER-positive and RER-negative cases. SUMMARY BACKGROUND DATA: Recent studies suggest that patients with RER-positive CRC have an improved prognosis. Further data are required to confirm this observation in young CRC patients. METHODS: All patients 40 years of age and younger with CRC admitted to the National Naval Medical Center between 1970 and 1992 were considered for inclusion in the study. After review, 36 patients for whom the original archived pathology specimen could be retrieved served as the study population. The RER status was determined using a previously described polymerase chain reaction-based assay. The clinical and pathologic features and survival data were compared to RER status. RESULTS: RER-positive tumors were found in 17 cases (47%). There was no significant difference in Dukes' stage or histologic grade at the time of diagnosis between patients with RER-positive tumors compared to RER-negative tumors. Patients with RER-positive tumors were found to have an improved prognosis: the 5-year survival probability for patients with RER-positive tumors was 68%, as compared to 32% for patients with RER-negative tumors (p < 0.05). CONCLUSIONS: RER-positive tumors are common in young patients with CRC, and patients with RER-positive tumors have a significantly improved prognosis. Because of their young age, survival data and prognosis play an important role in the overall treatment plan of young patients with CRC. Therefore, knowledge of RER status could affect initial therapy, postoperative chemotherapy, and follow-up.

Adult↗

PubMed1998

Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene.

BACKGROUND: Germline mutation in the adenomatous polyposis coli (APC) gene on chromosome 5 causes familial adenomatous polyposis. "Attenuated" phenotype has been reported with mutation in the 5' end of the gene (5' to codon 158), but genotype-phenotype relations at the 3' end (3' to codon 1596) have not been described fully. AIMS: To describe and compare colorectal and extracolonic phenotypes in a case series of families with mutation in the 3' end of the APC gene. METHODS: Thirty one at risk or affected members from four families with a mutation in the APC gene located at codon 1979 or 2644 were evaluated. RESULTS: Variable intrapedigree colorectal phenotype was observed: some members at older age had oligopolyposis (fewer than one hundred colorectal adenomas) whereas other members had classic polyposis at young age. Colorectal cancer was diagnosed at older mean age (50 (7) years) in the four families than in classic FAP pedigrees (39 (14) years). Extracolonic lesions characteristic of FAP occurred with 3' APC mutations, but variability in intrapedigree and interpedigree extracolonic phenotype and dissociation of severity of extracolonic manifestations from number of colorectal polyps was noted. CONCLUSIONS: Families with 3' mutations of the APC gene exhibit variable intrapedigree phenotype similar to the heterogeneity noted in families with proximal 5' mutations. Genotyping of FAP and oligopolyposis pedigrees can guide appropriate surveillance of the upper and lower gastrointestinal tract in affected members.

Adenomatous Polyposis Coli↗