Insights into disparities observed with COVID-19.

The onset of human disease by infection with SARS-CoV-2 causing COVID-19 has revealed risk factors for disease severity. There are four identified factors that put one at high risk for infection and/or mortality creating a disparity: age, co-morbidities, race/ethnicity and gender. Data indicate that the older a person is, and/or the presence of obesity and diabetes, cardiovascular disease and chronic kidney disease place one at higher risk for COVID-19. In the United States, specific race/ethnicities, particularly African Americans and Native Americans, are strong COVID-19 risk components. Male gender has also emerged as a severity risk factor. For age and racial/ethnicities, the accumulation of health co-morbidities is common precipitating mechanisms. In particular, underlying socio-economic structures in the United States likely drive development of co-morbidities, putting affected populations at higher risk for severe COVID-19. Sudden cardiac death triggered by a common sodium channel variant in African Americans with COVID-19 has not been evaluated as a cause for racial disparity. There is no evidence that racial/ethnic differences for COVID-19 are caused by ABO blood groups, use of angiotensin-converting enzyme (ACE) inhibitors or from amino acid substitutions in the SARS-CoV-2 spike protein. There is growing evidence that androgen-enabled expression of ACE2 receptors and the serine protease TMPRSS2, two permissive elements engaging the SARS-CoV-2 spike protein for infection, may contribute to severe COVID-19 in men. Overall, COVID-19 has generated disparities for who is infected and the severity of that infection. Understanding the mechanisms for the disparity will help nullify the differences in risk for COVID-19.

Age, Gender, and Liver Enzyme Impact Hospital Stay in COVID-19 Minority Patient with Cancer in the USA: Does Race Matters in the Pandemic?

Patients with cancer are known to have a poor prognosis when infected with SARS-CoV-2 infection. We aimed in this study to assess health outcomes in COVID-19 patients with different cancers in comparison to non-cancer COVID-19 patients from different centers in the United States (US). We evaluated medical records of 1,943 COVID-19 Cancer patients from 3 hospitals admitted between December 2019 to October 2021 and compared them with non-cancer COVID-19 patients. Among 1,943 hospitalized COVID-19 patients, 18.7% (n=364) have an active or previous history of cancer. Among these 364 cancer patients, 222 were African Americans (61.7%) and 121 were Caucasians (33.2%). Cancer patients had significantly longer hospitalization compared to controls (8.24 vs 6.7 days). Overall, Lung cancer is associated with high mortality. Patients with a previous history of cancer were more prone to death (p=0.04) than active cancer patients. In univariate and multivariate analyses, predictors of death among cancer patients were male sex, older age, presence of dyspnea, elevated troponin, elevated AST (0.001) and ALT (0.05), low albumin (p=0.04) and mechanical ventilation (p=0.001). Patients with a previous history of cancer were more prone to death when compared to active cancer COVID-19 patients. Early recognition of cancer COVID-19 patients' death-associated risk factors can help determine appropriate treatment and management plans for better prognosis and outcome.

Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N'-nitro-N-nitrosoguanidine.

The phenomenon of alkylation tolerance has been observed in cells that are deficient in some component of the DNA mismatch repair (MMR) system. An alkylation-induced cell cycle arrest had been reported previously in one MMR-proficient cell line, whereas a MMR-defective clone derived from this line escapes from this arrest. We examined human cancer cell lines to determine if the cell cycle arrest were dependent upon the MMR system. Growth characteristics and cell cycle analysis after MNNG treatment were ascertained in seven MMR-deficient and proficient cell lines, with and without confirmed mutations in hMLH1 or hMSH2 by an in vitro transcription/translation assay. MMR-proficient cells underwent growth arrest in the G2 phase of the cell cycle after the first S phase, whereas MMR-deficient cells escaped an initial G2 delay and resumed a normal growth pattern. In the HCT116 line corrected for defective MMR by chromosome 3 transfer, the G2 phase arrest lasted more than five days. In another MMR-proficient colon cancer cell line, SW480, cell death occurred five days after MNNG treatment. A competent MMR system appears to be necessary for G2 arrest or cell death after alkylation damage, and this cell cycle checkpoint may allow the cell to repair damaged DNA, or prevent the replication of mutated DNA by prohibiting clonal expansion.

Symptomatic colonic spirochaetosis in an immunocompetent patient.

Spirochaetes are organisms that can infect the colon of people with normal or compromised immune systems. Infected patients can present with a variety of gastrointestinal symptoms, including diarrhoea and rectal bleeding. However, some report a lack of association between specific symptoms and the presence of spirochaetes. It is therefore unclear whether the spirochaetes colonising the colon are true pathogens. Diagnosis is typically made by histological examination, with the biopsy specimen showing a band-like growth of spirochaetes adherent to the colonic luminal surface, giving an accentuated brush-border appearance. A course of metronidazole can eliminate the spirochaetes, but treatment might not lead to improvement of symptoms. Owing to the lack of a definite association between symptoms and the presence of spirochaetes, observation without specific antibiotic treatment can be pursued in most patients.

Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N'-nitro-N-nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation.

The human colon tumor cell line HCT 116 is known to have a homozygous mutation in the mismatch repair gene hMLH1 on human chromosome 3, to exhibit microsatellite instability, and to be defective in mismatch repair. In order to determine whether the introduction of a normal copy of hMLH1 gene restores mismatch repair activity and corrects microsatellite instability, a single human chromosome 3 from normal fibroblasts was transferred to HCT 116 cells via microcell fusion. As a control, human chromosome 2 was also transferred to HCT 116 cells. Two HCT 116 microcell hybrid clones that received a single copy of chromosome 2 (HCT 116 + ch2) and two that received a single copy of chromosome 3 (HCT 116 + ch3) were isolated and characterized. A G-G mismatch in M13-derived heteroduplex DNA was efficiently repaired in cell extracts from HCT 116 + ch3 cells, but not in those of parent HCT 116 cells or HCT 116 + ch2 cells. Microsatellite alterations at the D5S107 locus containing CA repeats were seen in 8 of 80 subclones from HCT 116 cells, and in 13 of 150 subclones from HCT 116 + ch2 cells. In contrast, none of the 225 subclones derived from mismatch repair-proficient HCT 116 + ch3 cells showed alterations in the microsatellite at the same locus. The effect of introducing chromosome 3 on the sensitivity of HCT 116 cells to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was examined, since enhanced tolerance to MNNG is accompanied by loss of mismatch repair activity in several cell lines. Within 3 days after treatment with 5 microM MNNG, HCT 116 + ch3 cells became morphologically flat and stopped growing. Their colony-forming ability, determined 10 days after treatment, was reduced 200-fold when compared to MNNG-treated parental HCT 116 and HCT 116 + ch2 cells. These results support the hypothesis that mutations in both alleles of the hMLH1 gene are necessary for the manifestation of defective mismatch repair and microsatellite instability and for enhanced MNNG tolerance. The results also suggest that the mismatch repair system contributes to the process that causes growth arrest in response to DNA damage by alkylating agents.

Genetic pathways in the evolution of morphologically distinct colorectal neoplasms.

Colorectal adenomas can be morphologically classified as exophytic or flat. Polypoid cancers and cancers arising de novo (ie., without any adenomatous component) might be the results of genetic progression from exophytic and flat adenomas, respectively. In this study, we examined 94 morphologically distinct neoplastic specimens for mutations in K-RAS and analyzed 10 microsatellite loci tightly linked to the tumor suppressor genes APC, p53, DCC/SMAD4, hMSH2, and hMLH1. K-RAS mutations were significantly associated with exophytic adenomas [11 of 21 (52%)] compared to flat adenomas [2 of 13(15%), P < 0.03] and polypoid cancers [17 of 25 (68%)] compared to cancers arising de novo [7 of 25 (28%), P < 0.01]. Two polypoid cancer cases demonstrated three and four different K-RAS mutations, respectively, suggesting multiple areas of clonal expansion. Cancers arising de novo were significantly associated with loss of heterozygosity (LOH) at chromosome 3p compared to pol ypoid cancers [6 of 18(33%) versus 1 of 20(5%), P < 0.03], whereas the prevalence of LOH at chromosomes 2p, 5q, 17p, and 18q and microsatellite instability were not different between the groups. For all cancers, LOH at chromosomes 17p and 18q occurred in 47 and 51%, respectively. However, LOH at 17p and 18q occurred in 0 and 16% of benign lesions, respectively, suggesting their role in malignant transformation. There was no difference in LOH at chromosomes 17p and 18q between exophytic and flat lesions. These findings suggest that (a) mutant K-RAS is associated with the exophytic growth of colonic neoplasms, and that (b) some colorectal cancers arising de novo lose chromosome 3p during their evolution, which is not seen in polypoid cancers. Half of all cancers lose chromosomes 17p and 18q at or near the malignant transition of benign lesions as reported previously, irrespective of morphology. There may be more than one genetic avenue for colorectal cancer formation, and this correlates with the morphological characteristics.

Genetic heterogeneity in familial juvenile polyposis.

Juvenile polyposis syndrome (JPS) is an autosomal dominant syndrome characterized by multiple gastrointestinal hamartomatous polyps in the absence of the extraintestinal features that are classic for other hamartomatous polyposis syndromes, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden disease (CD). About 50% of BRRS and >80% of CD demonstrate germ-line mutations in the tumor suppressor and dual phosphatase, PTEN. Germ-line mutation of PTEN as a cause for JPS in a child is controversial because extraintestinal manifestations that would exclude JPS could appear after adolescence, altering the clinical diagnosis. Here, we investigated a family in which the 55-year-old father, who lacks thyroid or skin findings characteristic of CD, demonstrated a germ-line mutation in PTEN that was passed to identical twin daughters, who both manifested JPS. The mutation was a deletion of five bases beginning seven bases from the start of exon 4 of PTEN, which caused aberrant transcripts by reverse transcription-PCR that were absent from a normal individual. Thus, mutations in PTEN are associated with JPS in addition to CD and some BRRS families, although the incidence of PTEN germ-line mutations in JPS might be more rare than that reported for SMAD4, a gene found to be mutated in approximately one-half of the JPS families investigated.

Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint.

The human colon tumor cell line HCT116 is deficient in wild-type hMLH1, is defective in mismatch repair (MMR), exhibits microsatellite instability, and is tolerant to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Transferring a normal copy of hMLH1 on chromosome 3 into the cell line restores MMR activity, stabilizes microsatellite loci, and increases the sensitivity of the cell to MNNG. Previous studies in other cell lines tolerant to alkylating agents such as MNNG or N-methylnitrosourea have shown cross-tolerance to 6-thioguanine (6TG), leading to a hypothesis that tolerance to MNNG or 6TG may be the result of MMR deficiency. To test this hypothesis, we studied the effects of 6TG on the MNNG-tolerant, MMR-deficient HCT116 cell line and its MNNG-sensitive, MMR-proficient, MNNG-tolerant, and MMR-deficient derivatives. Continuous exposure to low doses of 6TG (0.31-1.25 micrograms/ml) had no apparent effect on colony-forming ability (CFA) in MNNG-tolerant, MMR-deficient cells, whereas MNNG-sensitive, MMR-proficient cells exhibited a dose-dependent decrease in CFA. Growth kinetics and cell cycle analysis revealed that the growth of 6TG-treated HCT116 + chr3 cells was arrested at G2 after exposure to low dose of 6TG. In contrast, the same exposure to 6TG did not induce G2 arrest but rather a G1 delay in HCT116 and HCT116 + chr2. To obtain further evidence for the role of MMR on 6TG and MNNG toxicity, we isolated an MNNG-resistant revertant clone, M2, from the MNNG-sensitive, MMR-proficient HCT116 + chr3 cell line and characterized the MMR activity, hMLH1 status, and 6TG response. The results showed that M2 cells lost MMR activity as well as the previously introduced normal hMLH1 gene. Restoration of the CFA of M2 and an absence of G2 arrest were observed after treatment with low doses of 6TG. These results suggest that the mismatch repair system interacts with the G2 checkpoint in response to 6TG or MNNG-induced DNA lesions. The results further suggest that any agent that induces DNA mispairs will cause G2 arrest in MMR-proficient cells but not in MMR-deficient cells.

Absence of PTEN/MMAC1 germ-line mutations in sporadic Bannayan-Riley-Ruvalcaba syndrome.

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare hamartomatous polyposis condition with features of macrocephaly, intestinal juvenile polyposis, developmental delay, lipomas, and pigmentation spots of the male genitalia. An autosomal dominant pattern of inheritance exists in some families, but others appear as sporadic cases. Germ-line mutations in PTEN, a tyrosine phosphatase and putative tumor suppressor gene, have been demonstrated in two families with BRRS, and chromatin loss at the PTEN gene locus on chromosome 10q23 has been demonstrated in two BRRS patients. Germ-line mutations in PTEN have also been described in Cowden disease and in a small number of patients with juvenile polyposis syndrome. In an attempt to assess the nature of PTEN mutations in BRRS, we analyzed three sporadic BRRS patients for chromosome 10q23 deletion or PTEN germ-line mutations. All 3 patients demonstrated no loss of parental alleles at 15 chromosome 10q23 markers that encompassed the region of PTEN. In addition, analysis of mRNA and genomic DNA revealed no nonsense, missense, or insertion/deletion mutations of PTEN. Thus, other mechanisms besides mutation of PTEN must have occurred to cause BRRS in these patients. We speculate that BRRS and juvenile polyposis syndrome may have a heterogeneous etiology to cause their syndromes.

Antisense inhibition of hMLH1 is not sufficient for loss of DNA mismatch repair function in the HCT116+chromosome 3 cell line.

We have reported that transfer of chromosome 3 (Chr3) containing a single wild-type copy of the hMLH1 gene into HCT116 colon cancer cells, a cell line deficient in DNA mismatch repair (MMR) activity attributable to inactivating hMLH1 mutations, corrects all of the aspects of the MMR repair-deficient phenotype. We inhibited the expression of the wild-type hMLH1 gene using antisense RNA in HCT116+Chr3 cells to determine if this would result in reversion to the MMR-deficient phenotype. Despite profound inhibition of hMLH1 expression, DNA MMR activity and alkylation sensitivity were not impaired in the antisense-transfected HCT116+Chr3 cells. Additionally, arrest of the cell cycle at the G2 phase with alkylation damage occurs in these cells, a phenotype associated with MMR proficiency. These results indicate that even with a reduction in the expression of hMLH1 protein below the limits of detection by Western blotting, DNA MMR activity remained fully functional (by direct DNA MMR activity assay). We would speculate that hMLH1 is expressed in substantially greater abundance than would be minimally necessary for DNA MMR and that minor reductions in the expression of this protein would not be sufficient to permit DNA MMR dysfunction. Alternatively, Chr3 may contain a second hMLH1 homologue that might overlap with the function of hMLH1.

Human pancreatic adenocarcinomas express parathyroid hormone-related protein.

PTH-related protein (PTHrP) is expressed in many common malignancies such as breast and prostate cancer and can regulate their growth. Little is known, however, about the role of PTHrP in pancreatic adenocarcinoma. To study PTHrP in pancreatic exocrine cancer, we studied its expression in pancreatic cancer cell lines and surgical specimens. Eight human pancreatic adenocarcinoma cell lines were evaluated: AsPC-1, BxPC-3, Capan-1, CFPAC-1, MIA PaCa-2, PANC-1, PANC-28, and PANC-48. Murine monoclonal antibodies to the amino-terminal (1-34), mid-region (38-64), and carboxyl-terminal peptides (109-141) of PTHrP were used to identify cellular PTHrP and secreted PTHrP, including Western blotting and immunocytochemical staining for PTHrP from each cell line. Cellular PTHrP was detected in all cell line extracts by both Western blotting and immunoassay. CFPAC-1, derived from a pancreatic liver metastasis, had the highest concentration of PTHrP, and MIA PaCa-2, derived from primary pancreatic adenocarcinoma, had the lowest. PTHrP was localized by immunocytochemical staining in the cytoplasm in all but one cell line, and both nuclear and cytoplasmic immunostaining were observed in the MIA PaCa-2 and PANC-1 cells. Secretion of PTHrP into cell medium was also observed for each cell line and paralleled intracellular PTHrP levels. Evidence for differential processing of PTHrP expression was provided by studies demonstrating different patterns of PTHrP among the cell lines when assessed by PTHrP immunoassays directed against different PTHrP peptides. In specific, PTHrP secretion measured by a PTHrP-(38-64) assay was highest for BxPC-3, whereas the highest levels of secreted PTHrP-(109-141) occurred in CFPAC-1 and PANC-1. Growth of AsPC-1 cells was stimulated in a dose-dependent manner by PTHrP-(1-34). Immunostaining from archival tissue of patients with pancreatic adenocarcinoma revealed strong PTHrP expression in all 14 specimens. All patients were eucalcemic preoperatively. These results demonstrate that PTHrP is commonly expressed in pancreatic cancer. Our data suggest that PTHrP may have growth-regulating properties in pancreatic adenocarcinoma cells, but further studies are required.

Mutations of transforming growth factor beta 1 type II receptor, BAX, and insulin-like growth factor II receptor genes in microsatellite unstable cell lines.

Inactivation of the DNA mismatch repair (MMR) system allows the genome to accumulate mutations because of failure to correct mispairing of nucleotides and slippage mistakes at microsatellite sequences (termed microsatellite instability ¿MSI¿). While most mutations are acquired in noncoding regions by virtue of its larger share of DNA, mutations may occur in exons of genes that contain microsatellite sequences. The type II receptor for TGF beta 1 (TGF beta RII), the insulin-like growth factor II receptor (IGFIIR), and the proapoptotic gene BAX have been shown to contain mononucleotide microsatellites, and in MSI tumors, mutations may occur in these sequences late in the multistep carcinogenesis pathway. Here, we characterize 9 cell lines for MSI and mutations in TGF beta RII, BAX, and IGFIIR by PCR-based assays. The MMR-proficient cell lines SW480 and HT29 demonstrate stability at microsatellite sequences and do not have mutations in TGF beta RII, BAX, or IGFIIR. The MMR-deficient cell lines LoVo, SW48, LS174t, and HCT116 all demonstrate MSI and have only mutant alleles of TGF beta RII. Additionally, SW48 cells were heterozygous for wild-type and mutant IGFIIR. While LoVo and LS174t cells possessed only mutant BAX alleles, HCT116 was heterozygous and SW48 had only the wild-type allele. The MMR-deficient ovarian cell line 2774 demonstrated MSI, but showed only wild-type TGF beta RII, IGFIIR, and BAX alleles. In HCT116+ch2 cells, there was no genotypic change from the hMLH1-mutated HCT116 cells. In HCT116+ch3 cells, MSI was corrected, and this cell line became heterozygous for mutant and wild-type TGF beta RII because wild-type hMLH1 and TGF beta RII are both located on chromosome 3. Thus, the presence of a defective MMR system correlates with MSI, and the wild-type allele of TGF beta RII was absent in all microsatellite unstable colon cell lines, whereas the absence of wild-type BAX occurred in only two colon cell lines. In ovarian cancer cells with MSI, mutations in TGF beta RII, BAX, and IGFIIR may be unimportant in the genesis of this tumor.

Flanking sequence specificity determines coding microsatellite heteroduplex and mutation rates with defective DNA mismatch repair (MMR).

The activin type II receptor (ACVR2) contains two identical microsatellites in exons 3 and 10, but only the exon 10 microsatellite is frameshifted in mismatch repair (MMR)-defective colonic tumors. The reason for this selectivity is not known. We hypothesized that ACVR2 frameshifts were influenced by DNA sequences surrounding the microsatellite. We constructed plasmids in which exons 3 or 10 of ACVR2 were cloned +1 bp out of frame of enhanced green fluorescent protein (EGFP), allowing -1 bp frameshift to express EGFP. Plasmids were stably transfected into MMR-deficient cells, and subsequent non-fluorescent cells were sorted, cultured and harvested for mutation analysis. We swapped DNA sequences flanking the exon 3 and 10 microsatellites to test our hypothesis. Native ACVR2 exon 3 and 10 microsatellites underwent heteroduplex formation (A(7)/T(8)) in hMLH1(-/-) cells, but only exon 10 microsatellites fully mutated (A(7)/T(7)) in both hMLH1(-/-) and hMSH6(-/-) backgrounds, showing selectivity for exon 10 frameshifts and inability of exon 3 heteroduplexes to fully mutate. Substituting nucleotides flanking the exon 3 microsatellite for nucleotides flanking the exon 10 microsatellite significantly reduced heteroduplex and full mutation in hMLH1(-/-) cells. When the exon 3 microsatellite was flanked by nucleotides normally surrounding the exon 10 microsatellite, fully mutant exon 3 frameshifts appeared. Mutation selectivity for ACVR2 lies partly with flanking nucleotides surrounding each microsatellite.

The cellular and molecular pathogenesis of colorectal cancer.

The development of colorectal neoplasia originates from normal colonic mucosa, progresses to the adenomatous polyp, and later may evolve into carcinoma. This procession of histologic change can be defined by a series of successive waves of clonal expansion that contain certain genetic alterations. These genetic alterations include mutations in the K-ras oncogene and mutation in the one allele coupled with loss of the second allele for the tumor suppressor genes APC, DCC, and p53. The normal forms of these genes encode for proteins that regulate cell growth, cell-to-cell adhesion, and cell cycle checkpoints. Information on the function of these genes, as well as a proposed model of sequential mutation and loss of these regulatory genes during colorectal tumorigenesis are presented.

Racial and ethnic factors in the genetic pathogenesis of colorectal cancer.

Colorectal cancer can develop by two distinct pathogenic mechanisms: one involving chromosomal breakage and aneuploidy (called chromosomal instability) and one involving mutations at DNA micro-satellite sequences (termed micro-satellite instability). Relatively few reports consider these mechanisms of colorectal cancer development across racial or ethnic groups. Available data indicate a moderate increase in colorectal cancer risk among Ashkenazi Jews who have a mutational polymorphism at codon 1307 in the APC gene. In American blacks, there is evidence for a higher prevalence of right-sided colonic tumors and an earlier age of onset of colorectal cancer. In addition, blacks have the highest colon cancer incidence in the United States among ethnic groups and have poorer 5-year survival rates compared with whites. While some differences may be attributed to health care access and socioeconomic differences, these do not completely explain all the variances. In the chromosomal instability pathway, there are polymorphisms within the P53 gene that are more prevalent in blacks, but the significance of these polymorphisms is not fully known. Blacks are more likely to demonstrate micro-satellite instability in their tumors; however, the mechanism for this phenomenon in blacks is unexplored. Differences in diet among racial and ethnic groups and polymorphic variations in drug metabolizing or acetylation genes have not been adequately cataloged. Identification of genetic and environmental factors among racial and ethnic groups should offer some insights into the observed epidemiologic data and advance opportunities to better understand the control and development of colorectal cancer.

Intramural duodenal hematoma presenting as a complication of peptic ulcer disease.

We report the first case in the English literature of an intramural duodenal hematoma presenting as a complication of Helicobacter pylori-induced peptic ulcer disease. Intramural duodenal hematomas have been previously described in patients-usually in the setting of blunt trauma, postendoscopic biopsy, gastrostomy placement, and hemostatic therapy and in patients with a coagulopathy or bleeding diathesis-but not as a presentation of peptic ulcer disease. It is important to recognize this complication, as surgical management may benefit patients with a duodenal hematoma.

Massive secretory diarrhea and pseudo-obstruction as the initial presentation of Crohn's disease.

We report large-volume secretory diarrhea and intestinal pseudo-obstruction in a man whom ultimately proved to have Crohn's disease that responded to sulfasalazine and steroids with resolution of all his symptoms. Although this is an unusual presentation, Crohn's disease should be included in the differential diagnosis in patients whose initial symptoms are intestinal pseudo-obstruction and secretory diarrhea.

Localization of the Bannayan-Riley-Ruvalcaba syndrome gene to chromosome 10q23.

BACKGROUND & AIMS: Bannayan-Riley-Ruvalcaba syndrome is a congenital syndrome with characteristic features of macrocephaly, cognitive and motor dysfunction, subcutaneous and visceral lipomas and hemangiomas, and intestinal juvenile polyposis. It has been suggested that Bannayan-Riley-Ruvalcaba syndrome may be a variant of juvenile polyposis coli because of the shared features of intestinal juvenile polyps. The aim of this study was to precisely map loss of DNA from 2 patients with intestinal juvenile polyposis and karyotypic abnormalities involving chromosome 10q. METHODS: DNA was extracted from peripheral leukocytes drawn from each patient and each patient's biological parents. The DNA was amplified by polymerase chain reaction using primers specific for microsatellites located on chromosome 10q. RESULTS: Precise mapping localized a maximal distance of 1.0 cM that was commonly deleted from each patient's genome, between D10S541 and D10S1735. This area overlaps the region for Cowden disease, a distinct hamartomatous intestinal polyposis syndrome with increased risk of breast and thyroid carcinoma. CONCLUSIONS: The three hamartomatous polyposis syndromes, Bannayan-Riley-Ruvalcaba syndrome, juvenile polyposis coli, and Cowden disease, may share the same genetic defect because of their common map localization to chromosome 10q23.

Genetic instability and chromosomal aberrations in colorectal cancer: a review of the current models.

Our understanding of the pathogenesis of cancer has undergone a revolution over the past decade. Tumors develop by the accumulation of damage to genes that regulate cell growth. Many of the genes responsible for disregulation of cell growth have been identified, as have the processes that lead to the genetic damage. One of the most important concepts that has facilitated our understanding of carcinogenesis is that of genetic or "genomic" instability, which is required to permit a sufficient amount of genetic damage to accumulate to permit the neoplastic phenotype to emerge and evolve. Two mechanisms that lead to genomic instability--one of which involves the loss of chromosomal fragments from the nucleus, and a second which is characterized by microsatellite instability--are discussed.