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Unlabelled: Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3' untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P<2.3×10(-5)) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role., Significance: Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk., (©2015 American Association for Cancer Research.)

A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10(-17)). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction.

Background: Family studies have served as a cornerstone of genetic research on colorectal cancer., Materials and Methods: The Colorectal Cancer Family Registry (Colon CFR) is an international consortium of six centers in North America and Australia formed as a resource to support studies on the etiology, prevention, and clinical management of colorectal cancer. Differences in design and sampling schemes ensures a resource that covers the continuum of disease risk. Two separate recruitment strategies identified colorectal cancer cases: population-based (incident case probands identified by cancer registries; all six centers) and clinic-based (families with multiple cases of colorectal cancer presenting at cancer family clinics; three centers). At this time, the Colon CFR is in year 10 with the second phase of enrollment nearly complete. In phase I recruitment (1998-2002), population-based sampling ranged from all incident cases of colorectal cancer to a subsample based on age at diagnosis and/or family cancer history. During phase II (2002-2007), population-based recruitment targeted cases diagnosed before the age of 50 years are more likely attributable to genetic factors. Standardized protocols were used to collect information regarding family cancer history and colorectal cancer risk factors, and biospecimens were obtained to assess microsatellite instability (MSI) status, expression of mismatch repair proteins, and other molecular and genetic processes., Results: Of the 8,369 case probands enrolled to date, 2,602 reported having one or more colorectal cancer-affected relatives and 799 met the Amsterdam I criteria for Lynch syndrome. A large number of affected (1,324) and unaffected (19,816) relatives were enrolled, as were population-based (4,108) and spouse (983) controls. To date, 91% of case probands provided blood (or, for a few, buccal cell) samples and 75% provided tumor tissue. For a selected sample of high-risk subjects, lymphocytes have been immortalized. Nearly 600 case probands had more than two affected colorectal cancer relatives, and 800 meeting the Amsterdam I criteria and 128, the Amsterdam II criteria. MSI testing for 10 markers was attempted on all obtained tumors. Of the 4,011 tumors collected in phase I that were successfully tested, 16% were MSI-high, 12% were MSI-low, and 72% were microsatellite stable. Tumor tissues from clinic-based cases were twice as likely as population-based cases to be MSI-high (34% versus 17%). Seventeen percent of phase I proband tumors and 24% of phase II proband tumors had some loss of mismatch repair protein, with the prevalence depending on sampling. Active follow-up to update personal and family histories, new neoplasms, and deaths in probands and relatives is nearly complete., Conclusions: The Colon CFR supports an evolving research program that is broad and interdisciplinary. The greater scientific community has access to this large and well-characterized resource for studies of colorectal cancer.

Genetic susceptibility may play a role in many colorectal cancers (CRCs). Known syndromes such as familial adenomatous polyposis and hereditary nonpolyposis CRC account for <5% of CRCs. The germ-line missense variant of the APC gene, E1317Q, has been proposed to confer a risk for colonic adenomatous polyps (adenomas), but not for CRCs in the general population. These findings are contradictory and controversial. In the present study, 608 cases (377 patients with CRC, 145 patients with 4-100 lifetime adenomas, and 86 with < or =3 lifetime adenomas), and 679 controls (362 spouses and 317 patients with normal colonoscopy) were screened for the APC E1317Q variant. The frequency of heterozygotes for E1317Q among patients with CRC (2.4%), patients with 4-100 adenomas (1.4%), and < or =3 adenomas (3.5%) did not differ from spouse controls (2.8%). When CRC patients were examined by DNA mismatch repair status, age at onset (< or =age 50 versus >50), or family history of CRC, no differences in the frequency of E1317Q were found. The APC variant E1317Q does not appear to be associated with increased risk for colorectal neoplasia in the general population. However, when we used normal colonoscopy controls (E1317Q carrier frequency = 0.3%), the prevalence of E1317Q was significantly increased in CRC patients, in patients with < or =3 adenomas, and in CRC patients with intact mismatch repair status, suggesting a possible role for E1317Q in colorectal tumorigenesis. These results underscore the importance of carefully defining the controls to be used in comparisons of allele frequencies.

The HPC2/ELAC2 gene on chromosome 17p was recently identified as a candidate gene for hereditary prostate cancer (HPC). To confirm these findings, we screened 300 prostate cancer patients (2 affected members/family) from 150 families with HPC for potential germ-line mutations using conformation-sensitive gel electrophoresis, followed by direct sequence analysis. The minimum criteria for our families with HPC was the presence of 3 affected men with prostate cancer. A total of 23 variants were identified, including 13 intronic and 10 exonic changes. Of the 10 exonic changes, 1 truncating mutation was identified, a Glu216Stop nonsense mutation. This nonsense variant was found in 2 of 3 affected men in a single family. The remaining nine alterations included five missense, three silent, and one variant in the 3' untranslated region. To additionally test for potential associations of polymorphic variants and increased risk for disease, we genotyped two common polymorphisms, Ser217Leu and Ala541Thr, in 446 prostate cancer patients from 164 families with HPC and 502 population-based controls. The frequency of the Leu217 variant was similar for patients (32.3%) and controls (31.8%), as was the frequency of the Thr541 variant (5.4% among patients versus 5.2% among controls). In contrast to previous reports, we found no association of the joint effects of Leu271 and Thr541 (odds ratio, 1.04; 95% confidence interval, 0.57-1.89). Overall, our results did not reveal any association between these two common polymorphisms and the risk for HPC. The finding of a nonsense mutation in the HPC2/ELAC2 gene confirms its potential role in genetic susceptibility to prostate cancer. However, our data also suggest that germ-line mutations of the HPC2/ELAC2 are rare in HPC and that the variants Leu217 and Thr541 do not appear to influence the risk for HPC. Cumulatively, these results suggest that alterations within the HPC2/ELAC2 gene play a limited role in genetic susceptibility to HPC.

Two microsatellite instability (MSI) phenotypes have been described in colorectal cancer (CRC): MSI-H (instability at >30% of the loci examined) and MSI-L (MSI at 1-30% of the loci examined). The MSI-H phenotype, observed in both hereditary nonpolyposis colon cancer-associated CRC and approximately 15% of sporadic CRC, generally results from mutational or epigenetic inactivation of the DNA mismatch repair (MMR) genes hMSH2 or hMLH1. The genetic basis for the MSI-L phenotype, however, is unknown. Several other proteins, including hMSH3 and hMSH6, also participate in DNA MMR. Inactivating mutations of MSH6 in yeast and human tumor cell lines are associated with an impaired ability to repair single-base mispairs and small insertion-deletion loops but not large insertion-deletion loops. This suggests that hMSH6 mutations are more likely to be associated with a MSI-L phenotype than a MSI-H phenotype in CRC. To explore this possibility, we screened tumors from 41 patients with MSI-L CRC for hMSH6 mutations with conformation-sensitive gel electrophoresis (CSGE) and for hMSH6 protein expression by immunohistochemistry. Alterations found with CSGE were confirmed by DNA sequencing of normal and tumor tissue. One somatic (Asp389Asn) and 15 germ-line changes were found. Of the 15 germ-line changes, 9 were found in an intron (none involving splice junctions), and 6 were found in an exon (Gly39Glu, Leu395Val, and 4 silent alterations). Immunohistochemical staining for hMSH6 performed on 34 of the 41 tumors revealed strong nuclear hMSH6 expression in all of the cases. Overall, our results suggest that hMSH6 mutations do not play a major role in the development of sporadic CRC with a MSI-L phenotype.

Epidemiological studies have suggested that the breast cancer susceptibility genes, BRCA1 and BRCA2, may be involved in the development of prostate cancer. Several studies have screened prostate cancer populations for the presence of BRCA1 and BRCA2 mutations, with few mutations identified. In this study, 22 high-risk prostate cancer families (at least three cases of prostate cancer) were screened by conformation-sensitive gel electrophoresis (CSGE) for mutations in BRCA1 and BRCA2. To maximize the chance of finding mutations in these two genes, families were also selected for the presence of at least two cases of breast and/or ovarian cancer. We identified one previously reported BRCA2 missense mutation and two previously unreported BRCA2 intron polymorphisms. No BRCA1 or BRCA2 truncating mutations were detected. Thus, BRCA1 and BRCA2 appear to have a limited role in familial prostate cancer, and families with both prostate and breast cancer may result from mutations in other predisposition genes.

Lung cancer (LC) and chronic obstructive pulmonary lung diseases (COPDs; including emphysema and chronic bronchitis) share a common etiology. Despite the known associations of alpha1-antitrypsin deficiency (alpha1AD) with COPD and COPD with LC, few studies examined the association of alpha1AD alleles and LC. We hypothesize that heterozygous individuals who carry a deficient allele of the alpha1AD gene Pi (protease inhibitor locus) are at an increased risk of developing LC. The Pi locus is highly polymorphic with >70 variants reported. There are at least 10 alleles associated with deficiency in alpha1-antitrypsin. Using an exact binomial test, we compared the alpha1AD carrier rate in 260 newly diagnosed Mayo Clinic LC patients to the reported carrier rate in Caucasians in the United States (7%). alpha1AD carrier status, determined by isoelectric focusing assay, was examined with respect to the history of cigarette smoking, COPD, and histological types. Thirty-two of the 260 patients (12.3%; 95% confidence interval, 8.6-16.9%) carried an alpha1AD allele, which was significantly higher than expected (P = 0.002). Twenty-four of the 32 carriers had allele S, 6 had allele Z, and 2 had allele I. Patients who never smoked cigarettes were three times more likely to carry a deficient allele (20.6%; P = 0.008), although smokers had a higher carrier rate (11.1%; P = 0.025) when compared with the 7% rate. Patients with squamous cell or bronchoalveolar carcinoma had a significantly higher carrier rate than expected (15.9% and 23.8%, P < or = 0.01, respectively). Our preliminary findings suggest that individuals who carry an alpha1AD allele may have an increased risk for developing LC, specifically squamous cell or bronchoalveolar carcinoma.

Most colorectal adenomas and carcinomas arise in the setting of chromosomal instability characterized by progressive loss of heterozygosity. In contrast, approximately 15-20% of colorectal neoplasms arise through a distinct genetic pathway characterized by microsatellite instability (MSI) associated with frequent loss of expression of one of the DNA mismatch repair enzymes, most often hMLH1 or hMSH2. These distinct genetic pathways are reflected by differences in tumor histopathology, distribution in the colon, prognosis, and dwell time required for progression from adenoma to carcinoma. To determine whether these two groups of tumors differ in their expression of cyclooxygenase-2 (COX-2), a putative chemopreventative target, immunostaining for this protein was performed in colorectal cancers categorized by the presence (n = 41) and absence (n = 66) of defective mismatch repair. Defective mismatch repair was defined by the presence of tumor microsatellite instability (MSI-H, > or =40% of markers demonstrating instability) and by the absence of protein expression for either hMLH1 or hMSH2. Overall, our results showed that low or absent COX-2 staining was significantly more common among tumors with defective mismatch repair (P = 0.001). Other features predictive of low COX-2 staining included marked tumor infiltrating lymphocytosis, and solid/cribiform or signet ring histological patterns. These observations indicate that colorectal cancers with molecular and phenotypic characteristics of defective DNA mismatch repair express lower levels of COX-2. The clinical implications of this biological distinction remain unknown but should be considered when assessing the efficacy of COX-2 inhibitors for chemoprevention in patients whose tumors may arise in the setting of defective DNA mismatch repair.

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.

Recent studies have demonstrated the presence of microsatellite instability (MSI) in tumors from patients with hereditary nonpolyposis colon cancer and in a subset of patients with sporadic colorectal cancer (CRC). In sporadic CRC, three tumor phenotypes have been defined: microsatellite stable (MSS), low-frequency MSI, and high-frequency MSI (MSI-H). Although defective mismatch repair, consisting primarily of alterations in hMSH2 and hMLH1, is believed to be responsible for the MSI phenotype in the majority of patients with hereditary nonpolyposis colon cancer, the genetic defect responsible for this phenotype in sporadic CRC has yet to be clearly delineated. Somatic or germ-line alterations in these two genes have been identified in only a minority of these cases. Analysis of the protein expression patterns of hMSH2 and hMLH1 in unselected CRC, however, suggests that alterations in hMLH1 may account for a majority of the MSI-H cases. In an effort to explore the underlying molecular basis for these findings, we have examined the methylation status of the presumptive hMLHI promoter region in 31 tumors that vary in regard to their MSI status (MSI-H or MSS), their hMLH1 protein expression (MLH- or MLH+), and their gene mutation (Mut+ or Mut-) status. Hypermethylation of the hMLH1 promoter occurred in all 13 MSI-H/ MLH- tumors that did not have a detectable mutation within the hMLH1 gene. Of those MSI-H tumors containing germ-line or somatic alterations in hMLH1 (n = 7, including 3 frameshift, 1 nonsense, 2 missense mutations, and 1 tumor containing multiple mutations: missense, splice-site alteration, and a frameshift), four had a normal methylation pattern, whereas three others demonstrated hypermethylation of the hMLH1 promoter region. Two of these cases had a missense alteration, the other a frameshift alteration. The single MSI-H/Mut+ tumor that had normal hMLH1 and hMSH2 expression, as well as 9 of the 10 MSS cases, lacked methylation of the hMLH1 promoter. Hypermethylation of the hMSH2 promoter was not observed for any of the cases. These results suggest that hypermethylation of the hMLH1 promoter may be the principal mechanism of gene inactivation in sporadic CRC characterized by widespread MSI.

Recent studies have demonstrated the presence of microsatellite instability (MSI) in tumors from patients with hereditary nonpolyposis colorectal cancer and in a large number of sporadic tumors. To further characterize the type of alterations at these loci and their frequency of involvement in colon cancer, we studied DNA extracted from paraffin-embedded tissue from 508 patients using 11 microsatellites localized to chromosomes 5, 8, 15, 17, and 18. Overall, MSI at each locus varied in character and frequency and was observed with at least one marker in 191 cases (37.6%). Based on the number of markers displaying instability per tumor, three groups of patients were defined: those with <30% of the markers showing instability (MSI-L,, n = 109, 21.5%); those with > or = 30% (MSI-H, n = 82, 16.1%); and those showing no instability (MSS, n = 317, 62.4%). These groups were tested for correlations with a number of clinical and pathological parameters, including age, sex, stage, ploidy status, and site of tumor. Comparing across the three groups and verified by pair-wise comparisons, the MSI-H group was associated with tumor site (proximal colon, P = 0.001), sex (females, P = 0.005), stage (Dukes' B, P = 0.01), and ploidy status (diploid, P = 0.03). No significant differences were noted between the MSI-L and MSS group for any of the parameters tested. An additional 188 consecutive surgical colorectal cancer cases were examined for the presence of MSI and for the immunohistochemical expression of hMLH1 and hMSH2 proteins. Of this group, 129 (68.6%) were classified as MSS, 17 (9.0%) as MSI-L, and 42 (22.3%) as MSI-H. None of the MSS and none of the MSI-L tumors had altered expression of either hMLH1 or hMSH2. However, the majority of MSI-H (40 of 42, 95%) cases demonstrated absence of staining for these proteins. The most frequently altered protein was hMLH1, occurring in 95% of the tumors with altered expression. Cumulatively, these data suggest that the tumor phenotype MSI-H is distinct from tumor phenotypes MSI-L and MSS, with no apparent differences between MSI-L and MSS. Furthermore, altered hMLH1 protein expression appears to be responsible for the mutator phenotype in the vast majority of MSI-H tumors.

To date, at least four genes involved in DNA mismatch repair (MMR) have been demonstrated to be altered in the germline of patients with hereditary nonpolyposis colon cancer: hMSH2, hMLH1, hPMS1, and hPMS2. Additionally, loss of MMR function has been demonstrated to lead to the phenomenon of microsatellite instability (MIN) in tumors from these patients. In this study, we have examined the protein expression pattern of hMSH2 and hMLH1 by immunohistochemistry in paraffin-embedded tumors from 7 patients with MIN+ sporadic cancer, 13 patients with familial colorectal cancer, and 12 patients meeting the strict Amsterdam criteria for hereditary nonpolyposis colon cancer. The relationship between the expression of these two gene products, the presence of germline or somatic mutations, and the presence of tumor MIN was examined. Nineteen of the 28 tumors studied demonstrated MIN, whereas mutations in hMLH1 and hMSH2 were detected in 6 and 2 patients, respectively. Of the eight MIN+/mutation+ cases, the absence of protein expression was observed for the corresponding gene product in all but one case (missense mutation in hMLH1). However, seven MIN+/mutation- cases also showed no expression of either hMLH1 (n = 5), hMSH2 (n = 1), or both (n = 1), whereas four MIN+/mutation- cases demonstrated normal expression for both. None of the MIN-/mutation- cases (n = 9) demonstrated an altered expression pattern for either protein. These data suggest that examination of protein expression by immunohistochemistry may be a rapid method for prescreening tumors for mutations in the MMR genes.

Although prostate cancer is one of the most common malignancies of males in Western countries, relatively little is known about the molecular mechanisms involved in tumor initiation and progression. Allelic loss studies have suggested the involvement of multiple tumor suppressor genes (TSGs), but few detailed studies of all chromosomes have been performed. In an effort to localize and identify candidate TSGs, we performed allelic imbalance (AI) studies on 55 prostate cancers, using 135 polymorphic microsatellite markers. For the entire chromosome. AI ranged from a low of 0% on chromosomes 14 and 20 to a high of 71% on chromosome 8. Chromosomal regions demonstrating at least twice the background frequency of AI (ranging from 20 to 69%) included 5q, 6q, 7q, 8p, 13, l6q, l8q, and 21. In addition, AI was examined for association with a number of clinicopathological parameters. AI on chromosomes 7 and 16 were each associated with greater age at diagnosis (P = 0.009 and 0.001, respectively), and AI on chromosomes 10, 16, and 18 was associated with aneuploidy/tetraploidy (P = 0.037, 0.013, and 0.054, respectively). Furthermore, AI on chromosome 5 was associated with a higher pathological stage (P = 0.021) and on chromosome 8 and 16 with a higher Gleason score (P = 0.027 and 0.041, respectively). No tumor exhibited a phenotype of widespread microsatellite instability. These results indicate that there likely exist multiple sites harboring candidate TSG in prostate cancer, some of which may have important clinical implications, and which argue against widespread microsatellite instability.

The human tumor necrosis factor (TNF) locus is located on chromosome 6p21.3 and contains at least five polymorphic microsatellites. In this study, we compared the allelic frequencies derived from 50 normal controls to 64 patients with colorectal cancer at one of these loci, TNF alpha. No differences in allelic frequencies were observed between these two groups (P = 0.47). However, sequencing of the TNF alpha PCR product revealed two populations of TNF alpha alleles; alleles with the expected DNA sequence (i.e., the expected number of AC/GT repeats) and alleles that contained 8-bp deletions adjacent to the microsatellite repeat. In addition, we also examined paired normal and tumor DNA from the colorectal cancer group for microsatellite alterations at the TNF alpha locus, including allelic loss of heterozygosity and microsatellite instability. Of the 64 tumors examined, 13 (20%) demonstrated microsatellite instability, and 14 (42%) of 33 informative cases demonstrated allelic imbalance. Analysis of 10 additional chromosome 6 loci for allelic loss showed that 23 (47%) of 49 informative cases exhibited allelic imbalance with at least one chromosome 6p marker, 23 (47%) of 49 with at least one 6q marker, and 29 (59%) of 49 with at least one marker on chromosome 6. Examination of tumors for the minimal region of deletion overlap suggests the presence of tumor suppressor genes on both 6p and 6q.

Cytogenetic analyses have demonstrated that chromosome region 7q22-32 is commonly altered in prostate adenocarcinomas. In addition, in recent fluorescence in situ hybridization studies, we have observed that aneusomy of chromosome 7 is frequent in prostate cancer and is associated with higher tumor grade, advanced pathological stage, and early prostate cancer death. These findings suggest that genetic alterations of chromosome 7 play a significant role in the development of prostate cancer. To better define the chromosome 7 alterations, PCR analysis of 21 microsatellite loci was performed on 54 paired prostate cancer and control DNAs. Overall, chromosome 7 allelic imbalance was identified in 16 of 54 cases (30%). Allelic imbalances of loci mapped to 7q were observed in 15 of the 16 cases. The allelic imbalances were classified as losses in 15 tumors (28%) and as gains in 1 (2%) by comparative multiplex PCR analysis. The most common site of allelic loss included loci D7S523 and D7S486 at 7q31.1. A comparison with clinicopathological features of the tested tumors revealed that the allelic loss of 7q31.1 correlated with higher tumor grade (P = 0.012) and lymph node metastasis (P = 0.017). These results indicate that 7q31 may be the site of a putative suppressor gene(s) important for the pathogenesis of prostate carcinoma, and that the genetic alterations at 7q31.1 may participate in tumor progression and metastasis.

Muir-Torre syndrome (MTS) is characterized by the presence of at least one sebaceous tumor and at least one visceral malignancy. Although a wide range of internal malignancies have been reported, the most frequently observed internal neoplasm is colorectal carcinoma. MTS and hereditary nonpolyposis colorectal carcinoma (HNPCC) share many clinical and pathological characteristics and thus may share similar genetic mechanisms of tumorigenesis. Recently, microsatellite instability (MIN) has been reported in tumor tissue from patients with HNPCC. In order to determine if tumors from MTS patients might also show MIN, we examined DNA extracted from paraffin-embedded tissues for the presence of MIN at (CA)n repeats on chromosomes 5q, 15q, 17p, and 18q. Data was obtained on 13 patients, 9 of which had at least one colorectal tumor. Of these, six demonstrated widespread MIN in all sebaceous and colorectal tumors examined, as well as in a transitional cell carcinoma of the renal pelvis, a prostatic adenocarcinoma and a keratoacanthoma. Overall, patients with MIN differed from patients without MIN in several respects, the most important of which include: (a) uniform presence and early onset of colorectal cancer (average age, 40 versus 70 years); (b) prolonged survival following diagnosis of visceral malignancy (median survival, 32 versus 11 years); and (c) a greater number of visceral and skin tumors. These data suggests that patients with MTS may be composed of at least two subgroups, each demonstrating different genetic, pathological and clinical features. Furthermore, the subgroup demonstrating MIN may share similar genetic mechanisms of tumorigenesis with patients having HNPCC, supporting the notion that these syndromes are allelic.

Mutations in the p53 gene are the most common genetic changes in cancer thus far. Many p53 mutations result in a protein product having a prolonged half-life compared to wild-type p53. The mutant protein is frequently detectable immunohistochemically, whereas the wild-type p53 present in normal cells is not. We examined 90 colorectal carcinomas for increased expression of p53 using 3 p53 specific monoclonal antibodies, PAb1801, PAb421, and PAb240. Overall, 70% of the colorectal carcinomas stained for p53. Each tumor's DNA was also assessed for loss of heterozygosity on chromosome 17p, the location of the p53 gene. Of those tumors that reacted with the anti-p53 antibodies, 76% showed loss on chromosome 17p. Tumors with loss of heterozygosity on 17p generally stained with all 3 antibodies, whereas those without loss tended to stain with just one antibody, typically PAb240. Fifteen tumors were examined for the presence of specific p53 mutations. A total of 10 mutations were found, 6 were missense and 2 were deletions, and all but one of the tumors with missense mutations stained for p53.