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• W105773406 abstract "Occult aspects of tumor proliferation are likely recorded genetically as their microsatellite (MS) loci become polymorphic. However, MS mutations generated by division may also be eliminated with death as noncoding MS loci lack selective value. Therefore, highly polymorphic MS loci cannot exist unless mutation rates are high, or unless mutation losses are inherently minimized. Mutations accumulate differently when cell fates are determined intrinsically before or extrinsically after division. Stem cell (asymmetrical division as in intestinal crypts) and random (asymmetrical and symmetrical division) proliferation, respectively, represent simulated cell fates determined before or after division. Whereas mutations regardless of selection systematically persist once inherited with stem cell proliferation, mutations are eliminated by the symmetrical losses of both daughter cells with random proliferation. Therefore, greater genetic diversity or MS variance accumulate with stem cell compared with random proliferation. MS loci in normal murine intestinal mucosa and xenografts of cancer cell lines accumulated mutations, respectively, consistent with stem cell and random proliferation. Tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) demonstrated polymorphic MS loci. Overall, three of five adenomas and one of six cancers exhibited high MS variances. Assuming mutation rates are not significantly greater in adenomas than in cancers, these studies suggest the stem cell proliferation and hierarchy of normal intestines persists in many HNPCC adenomas and some cancers. An adenoma stem cell architecture can explain the complex polymorphic MS loci observed in HNPCC adenomas and account for many adenoma features. In contrast, cancers may lose intrinsic control of cell fate. These studies illustrate a feasible phylogenetic approach to unravel and describe occult aspects of human tumor proliferation. The switch from predominantly stem cell to random proliferation may be a critical and defining characteristic of malignancy. Occult aspects of tumor proliferation are likely recorded genetically as their microsatellite (MS) loci become polymorphic. However, MS mutations generated by division may also be eliminated with death as noncoding MS loci lack selective value. Therefore, highly polymorphic MS loci cannot exist unless mutation rates are high, or unless mutation losses are inherently minimized. Mutations accumulate differently when cell fates are determined intrinsically before or extrinsically after division. Stem cell (asymmetrical division as in intestinal crypts) and random (asymmetrical and symmetrical division) proliferation, respectively, represent simulated cell fates determined before or after division. Whereas mutations regardless of selection systematically persist once inherited with stem cell proliferation, mutations are eliminated by the symmetrical losses of both daughter cells with random proliferation. Therefore, greater genetic diversity or MS variance accumulate with stem cell compared with random proliferation. MS loci in normal murine intestinal mucosa and xenografts of cancer cell lines accumulated mutations, respectively, consistent with stem cell and random proliferation. Tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) demonstrated polymorphic MS loci. Overall, three of five adenomas and one of six cancers exhibited high MS variances. Assuming mutation rates are not significantly greater in adenomas than in cancers, these studies suggest the stem cell proliferation and hierarchy of normal intestines persists in many HNPCC adenomas and some cancers. An adenoma stem cell architecture can explain the complex polymorphic MS loci observed in HNPCC adenomas and account for many adenoma features. In contrast, cancers may lose intrinsic control of cell fate. These studies illustrate a feasible phylogenetic approach to unravel and describe occult aspects of human tumor proliferation. The switch from predominantly stem cell to random proliferation may be a critical and defining characteristic of malignancy. Abnormal proliferation due to alterations of oncogenes and tumor suppressor genes is a hallmark of cancer. Cell cycle regulatory defects appear to be present in most cancers.1Strauss M Lukas J Bartek J Unrestricted cell cycling and cancer.Nature Med. 1995; 1: 1245-1246Crossref PubMed Scopus (150) Google Scholar However, despite the increasingly detailed understanding of the molecular genetic pathways altered within individual tumor cells, little is known on how individual cells construct tumors. Proliferation represents a balance between cell division and death. Normal intestinal proliferation is characterized by cell division equal to cell loss. Neoplastic proliferation is grossly evident by a net increase in cells. However, the multitude of possible division and death combinations consistent with observed changes in cell number hinder description or classification. For example, the multistep accumulation of mutations in colorectal tumorigenesis is apparently matched by the histological progression from adenomas to cancers.2Kinzler KW Vogelstein B Lessons from hereditary colorectal cancer.Cell. 1996; 87: 159-170Abstract Full Text Full Text PDF PubMed Scopus (4230) Google Scholar Presumably, adenomas have fewer mutations and therefore fewer proliferation abnormalities compared with cancers. Adenomas may persist unchanged in size for years, and only a minority progress to cancer.3Koretz RL Malignant polyps: are they sheep in wolves' clothing?.Ann Internal Med. 1993; 118: 63-68Crossref PubMed Scopus (59) Google Scholar, 4Stryker SJ Wolff BG Culp CE Libbe SD Ilstrup DM MacCarty RL Natural history of untreated colonic polyps.Gastroenterology. 1987; 93: 1009-1013Abstract PubMed Google Scholar, 5Otchy DP Ransohoff DF Wolff BG Waver A Ilstrup D Carlson H Rademacher D Metachronous colon cancer in persons who have had a large adenomatous polyp.Am J Gastroenterol. 1996; 91: 448-454PubMed Google Scholar Proliferation presumably becomes more “abnormal” in cancers. A comprehensive and possible alternative description of occult human tumor proliferation are phylogenetic trees that describe historical relationships between individuals and populations. The clonal evolution model of cancer implies that every tumor cell traces its origin to a common precursor.6Nowell PC The clonal evolution of tumor cell populations.Science. 1976; 194: 23-28Crossref PubMed Scopus (4763) Google Scholar In essence, a tumor represents the physical manifestation of a large phylogenetic tree reflecting numerous divisions, deaths, and mutations. Adjacent cells within a tumor likely share more immediate common ancestors compared with cells from opposite sides (Figure 1). Branch lengths compare genetic differences between individuals. Greater genetic differences imply greater numbers of intervening divisions. Mutation rates in most tumors are too low to allow the accumulation of many mutations.7Loeb LA Mutator phenotype may be required for multistage carcinogenesis.Cancer Res. 1991; 51: 3075-3079PubMed Google Scholar However, tumors lacking DNA mismatch repair (MMR) have elevated mutation rates,8Parsons R Li GM Longley M Fang WH Papadopoulos N Jen J de la Chapelle A Kinzler KW Vogelstein B Modrich P Hypermutability and mismatch repair deficiency in RER+ tumor cells.Cell. 1993; 75: 1227-1236Abstract Full Text PDF PubMed Scopus (957) Google Scholar, 9Shibata D Peinado MA Ionov Y Malkhosyan S Perucho M Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation.Nature Genet. 1994; 6: 273-281Crossref PubMed Scopus (452) Google Scholar, 10Bhattacharyya NP Skandalis A Ganesh A Groden J Meuth M Mutator phenotypes human colorectal carcinoma cell lines.Proc Natl Acad Sci USA. 1994; 91: 6319-6323Crossref PubMed Scopus (403) Google Scholar most notably in microsatellites (MSs), which allow mutations to accumulate after fewer divisions. Therefore, polymorphic MS loci are informative on the number of divisions since the last common ancestor.11Shibata D Navidi W Salovaara R Li ZH Aaltonen LA Somatic microsatellite mutations as molecular tumor clocks.Nature Med. 1996; 2: 676-681Crossref PubMed Scopus (95) Google Scholar Tumor proliferation may be random or chaotic. Individual tumors likely progress along unique phylogenetic pathways and precise trees accounting for every division, and death may be nearly impossible to recreate. However, long-term observations of random events may reveal patterns characteristic of specific proliferation types. Here we sample MS mutations in colorectal adenomas and carcinomas and recreate these measurements with computer simulations and experimental models. These studies illustrate complex mutation patterns and suggest the stem cell architecture of normal intestinal mucosa persists in colorectal adenomas. Adenomas and cancers removed from hereditary nonpolyposis colorectal cancer (HNPCC) patients were fixed in formalin and paraffin embedded. Clinical information was obtained from medical records. Screening intervals are the periods between colonoscopy or surgery. MMR-deficient colorectal cell lines HCT116 and LoVo (American Type Tissue Collection, Rockville, MD) were diluted to single cells and grown in culture for 2 to 4 weeks. Approximately 5 × 106 cells were injected subcutaneously into both flanks of nude mice (BALB/c nu/nu). At various times, the mice were sacrificed and the xenografts were fixed in formalin and paraffin embedded. Data for each time point were obtained from both xenografts present in the same mouse. The initiation of single-cell clones in tissue culture defined day 0. The same approach was used for all tissues. Multiple small tissue regions or dots of approximately 200 to 400 cells were isolated by selective ultraviolet radiation fractionation (SURF)11Shibata D Navidi W Salovaara R Li ZH Aaltonen LA Somatic microsatellite mutations as molecular tumor clocks.Nature Med. 1996; 2: 676-681Crossref PubMed Scopus (95) Google Scholar from microscopic sections (Figure 1B). For human tumors, SURF dots were estimated to contain at least 70% tumor cells. To be included for analysis, at least 35 alleles were amplified from a dot. The DNA in these dots were diluted to essentially single alleles with approximately 20 to 80% of reactions yielding polymerase chain reaction (PCR) products, which were analyzed on 6% denaturing polyacrylamide sequencing gels and a phosphoimager (Molecular Dynamics, Sunnyvale, CA). PCR products were labeled with [33P]dCTP (NEN Research Products, Boston, MA) incorporated during 38 to 43 PCR cycles. Each tissue was examined with at least two different MS loci and with at least two independent microdissections. The CA-dinucleotide repeat MS loci were DXS556, DXS1060, DXS418, DXS453, MIT129, and MIT38 (Research Genetics, Huntsville, AL). Tumor-specific MS alleles were distinguished from germline alleles originating from contaminating normal cells by two methods. A MS distribution separate from the germline allele was assumed to arise by somatic mutation in the tumor cells. In this case, the germline alleles were eliminated by truncation. When MS distributions included germline-sized alleles, some germline alleles must originate from contaminating normal cells. In these cases, up to 30% of all alleles were considered to arise from normal cells, and germline allele frequencies were reduced as far as possible by this number. The remaining alleles were considered tumor-specific MS distributions. Bimodal tumor distributions were observed in a few dots of tumors 3 and 11. The two distributions were considered as two different tumor populations, and variances were calculated for each peak. No corrections were necessary for the xenografts as the human MS primers did not amplify murine DNA. Simulations were performed as previously described.12Tsao JL Davis SD Baker SM Liskay RM Shibata D Intestinal stem cell divisions and genetic diversity: a computer and experimental analysis.Am J Pathol. 1997; 51: 573-579Google Scholar Statistical analysis was performed with Excel 7.0 (Microsoft, Bellevue, WA). Composite variances were calculated by combining the MS distributions of the individual HNPCC tumor dots or by sampling DNA isolated from entire xenograft sections. The stochastic nature of mutation can mask underlying stereotypic proliferation patterns. For example, every branch of Figure 1 may independently accumulate different numbers of MS mutations even if division and death histories were identical. Therefore, the general strategy first simulates two simple but fundamentally distinct proliferation patterns. The simulations are then compared with the MS polymorphisms in experimental models and human tumors. Comparisons between tissues are difficult as tumors vary in size and may be heterogeneous with respect to morphology, age, or cell of origin. To facilitate comparisons between physically disparate tissues, the current approach focuses on similar sized groups of 200 to 400 cells or dots isolated by microdissection and examined genetically by PCR (Figure 1B). Another simplification is the use of X-chromosome MS loci and tumors from male patients. Every MS allele should represent a single cell as MMR-deficient tumors are typically near diploid.13Thibodeau SN Bren G Schaid D Microsatellite instability in cancer of the proximal colon.Science. 1993; 260: 816-819Crossref PubMed Scopus (2773) Google Scholar, 14Lengauer C Kinzler KW Vogelstein B Genetic instability in colorectal cancers.Nature. 1997; 386: 623-627Crossref PubMed Scopus (1626) Google Scholar The focus on small tissue dots requires experimental examination of multiple dots because stochastic variation is increased. However, as noted below, some behaviors become evident when small populations are examined. Somatic mutations that increase the fitness of their cells ensure prevalence due to selection. Noncoding MS mutations must be considered differently as they lack selective value and may be eliminated by chance through death. However, mutations can attain tenure regardless of selection if they occur in cells with systematic renewal. Therefore, MS mutations accumulate differently depending on their cell fates. This analysis concentrates on two fundamentally different proliferation patterns: stem cell or random proliferation (Figure 2). These two models were selected for their functional simplicity and represent fates determined intrinsically before or extrinsically after division. Stem cell proliferation resembles the programmed hierarchy of normal intestinal mucosa,12Tsao JL Davis SD Baker SM Liskay RM Shibata D Intestinal stem cell divisions and genetic diversity: a computer and experimental analysis.Am J Pathol. 1997; 51: 573-579Google Scholar, 15Potten CS Loeffler M Stem cells: attributes, cycles, spirals, pitfalls, and uncertainties. Lessons for and from the crypt.Development. 1990; 110: 1001-1020Crossref PubMed Google Scholar and random proliferation models an unbiased or random elimination of potentially immortal cells in cancers. Stem cell proliferation is asymmetrical division intrinsically programmed to reproduce one stem cell daughter and one mortal daughter. The mortal daughter may continue to divide (three to six times in a normal intestinal crypt),15Potten CS Loeffler M Stem cells: attributes, cycles, spirals, pitfalls, and uncertainties. Lessons for and from the crypt.Development. 1990; 110: 1001-1020Crossref PubMed Google Scholar but her progeny all eventually die. Random proliferation is when asymmetrical and symmetrical (both daughters survive or die) division are equally likely. None of these cells are formally “mortal” because fate is unknown at the time of division and death is determined by extrinsic factors. Whereas every lineage persists with stem cell proliferation, symmetrical loss of both daughter cells can occur with random proliferation. Consequently, MS mutations are sporadically lost with random proliferation but become “fixed” within a stem cell lineage once inherited by a stem cell daughter. With identical mutation and division rates, greater numbers of MS mutations accumulate with stem cell proliferation. These models were simulated assuming constant mutation rates, stepwise mutation, constant cell number, and equal numbers of divisions for all cells. Variables are mutation rates, numbers of divisions, and numbers of immortal cells. Constant mutation rates are generally assumed for phylogenetic analysis. A complex of proteins are required for DNA MMR, and homozygous loss of MLH1 or MSH2 appears to substantially diminish MMR.2Kinzler KW Vogelstein B Lessons from hereditary colorectal cancer.Cell. 1996; 87: 159-170Abstract Full Text Full Text PDF PubMed Scopus (4230) Google Scholar, 6Nowell PC The clonal evolution of tumor cell populations.Science. 1976; 194: 23-28Crossref PubMed Scopus (4763) Google Scholar, 16Marsischky GT Filosi N Kane MF Kolodner R Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair.Genes Dev. 1996; 10: 407-420Crossref PubMed Scopus (491) Google Scholar Cells with heterozygous MLH1 or MSH2 deficiencies are repair proficient, suggesting that loss of the normal allele is primarily responsible for the high mutation frequencies observed in MMR-deficient tumors. Stepwise (single unit additions or deletions) mutation is assumed as most mutations observed in MMR-deficient cell lines are single repeat unit frameshifts.9Shibata D Peinado MA Ionov Y Malkhosyan S Perucho M Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation.Nature Genet. 1994; 6: 273-281Crossref PubMed Scopus (452) Google Scholar, 10Bhattacharyya NP Skandalis A Ganesh A Groden J Meuth M Mutator phenotypes human colorectal carcinoma cell lines.Proc Natl Acad Sci USA. 1994; 91: 6319-6323Crossref PubMed Scopus (403) Google Scholar Cell numbers remain constant in normal mucosa, but growth must occur with neoplasia. However, kinetic studies suggest that most tumor cells die (>90%) as mitotic rates generally exceed growth rates.17Steel GG Growth Kinetics of Tumors. Clarendon, Oxford1977Google Scholar, 18Steel GG Cell loss as a factor in the growth rate of human tumors.Eur J Cancer. 1967; 3: 381-387Abstract Full Text PDF PubMed Scopus (228) Google Scholar Therefore, as an approximation, cell division and death are considered equal between small microdissected tumor dots. Finally, tumors are characterized by defects in cell cycle regulation.1Strauss M Lukas J Bartek J Unrestricted cell cycling and cancer.Nature Med. 1995; 1: 1245-1246Crossref PubMed Scopus (150) Google Scholar Assuming a monoclonal origin, it is likely that adjacent cells will initially have identical MS alleles and divide approximately equally. MS frameshift mutations appear to arise secondary to slippage during replication.19Streisinger G Okada Y Emrich J Newton J Tsugita A Terzaghi E Inouye M Frameshift mutations and the genetic code.Cold Spring Harbor Symp Quant Biol. 1966; 31: 77-84Crossref PubMed Scopus (1071) Google Scholar, 20Strand M Prolla TA Liskay RM Petes TD Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair.Nature. 1993; 365: 274-276Crossref PubMed Scopus (938) Google Scholar Therefore, division and MS mutation should be tightly linked and MS loci become polymorphic with division. The accumulation of mutations were simulated for different numbers of divisions, cells, or mutation rates (Figure 3 and Figure 3 in 12Tsao JL Davis SD Baker SM Liskay RM Shibata D Intestinal stem cell divisions and genetic diversity: a computer and experimental analysis.Am J Pathol. 1997; 51: 573-579Google Scholar). MS diversity is summarized mathematically by the variance of each MS frequency distribution. More polymorphic MS loci have larger variances. Each single trial may yield a different variance, illustrating that small populations with identical proliferation histories stochastically accumulate different numbers of mutations. Therefore, median variance is used to summarize the spread of the variances from multiple trials. As previously noted for stem cell proliferation,12Tsao JL Davis SD Baker SM Liskay RM Shibata D Intestinal stem cell divisions and genetic diversity: a computer and experimental analysis.Am J Pathol. 1997; 51: 573-579Google Scholar median MS variance increases linearly with division, independent of the number of simulated cells, and with the variation expected of stochastic mutation. In contrast, MS variance with random proliferation is limited except with high mutation rates or larger populations. With smaller populations or low mutation rates, random losses of mutations limit increases in variance. Theoretically, high MS diversity in small tissue dots is more consistent with stem cell rather than random proliferation. The simulations were compared with two experimental models. The first examines the accumulation of somatic MS mutations with age in normal intestinal mucosa of mice with germline deficiencies (Pms2) in MMR. These studies (with additional data points) have been previously published12Tsao JL Davis SD Baker SM Liskay RM Shibata D Intestinal stem cell divisions and genetic diversity: a computer and experimental analysis.Am J Pathol. 1997; 51: 573-579Google Scholar and are summarized in Figure 4A. The increases in median variance with age are consistent with simulated stem cell proliferation. The variation of the multiple intestinal dot variances mimics the simulated variation with small numbers of stem cells (<20). Xenografts are considered experimental models of cancer. Cell line daughters are both potentially immortal. However, xenografts do not grow exponentially but rather exhibit Gompertzian kinetics17Steel GG Growth Kinetics of Tumors. Clarendon, Oxford1977Google Scholar characterized by relatively stable tumor sizes after an initial growth spurt. Therefore, cell division is likely balanced by death in macroscopic xenografts. Serial xenografts composed of MMR-deficient colorectal cancer cell lines HCT116 (hMLH1 deficient) and Lovo (hMSH2 deficient) were examined for MS mutations (Figure 4B). There was variation in the MS variances measured from multiple small xenograft dots, consistent with the simulated process of stochastic mutation and cell death. Median variance initially increased but did not further increase with xenograft age (up to 275 days), consistent with simulations of random proliferation with small numbers of cells and mutation rates less than 0.005 (Figure 3B). The numbers of cells destined to further divide (“immortal”) within xenograft dots are less than the total numbers of microdissected cells, and depend on the length of mortal cell survival after division. Assuming equal periods between cell division and death, the number of immortal cells is half of the microdissected cells. Therefore, with one division per day, random proliferation, and 100 to 200 immortal cells per tumor dot, xenograft MS mutation rates are estimated at less than 0.005 per division. This mutation rate is similar to the rate (0.002 to 0.0025) estimated in MMR-deficient murine intestines.12Tsao JL Davis SD Baker SM Liskay RM Shibata D Intestinal stem cell divisions and genetic diversity: a computer and experimental analysis.Am J Pathol. 1997; 51: 573-579Google Scholar Scenarios other than random proliferation may also explain the xenograft data. For example, division may decrease in older xenografts leading to fewer than expected mutations. This possibility seems unlikely as the cell-cycle-associated antigen Ki-6721Gerdes J Lemke H Baisch H Wacker HH Schwab U Stein H Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67.J Immunol. 1984; 133: 1710-1715PubMed Google Scholar was detected in the majority (greater than 75%) of cells regardless of xenograft age (data not shown). In addition, simulations of random proliferation predict variance will progressively increase if larger populations are sampled. When MS alleles were sampled from entire xenograft sections, “composite” variance increased with xenograft age (Figure 5A). Therefore, decreased division does not appear to account for the limited median MS variances observed in older xenograft dots. A succession of clones with increasingly greater selective advantages could also limit genetic diversity as each expansion would homogenize the xenograft. However, the progressive increase of composite MS xenograft variance with age suggests that clonal succession either did not occur or was limited in extent. Small 200- to 400-cell dots accumulate different numbers of mutations with random versus stem cell proliferation. Although MS variances will be initially low after clonal expansion with both types of proliferation, differences arise with division. Based on the experimental and simulated data, median variances over 1.0 appear to distinguish between random and stem cell proliferation when mutations rates are less than 0.005. Specifically, if rates are 0.0025 mutations per division or less, median MS variance will exceed 1.0 after 400 or more stem cell divisions whereas median variance will not exceed 1.0 even after 1000 random divisions. Therefore, high median MS variances (>1.0) in small tumor dots imply either stem cell proliferation and 400 or more divisions or random proliferation with mutation rates greater than 0.0025. With this theoretical and experimental background, the MS mutations in small dots from human mutator phenotype tumors were sampled. Although serial analysis of primary isogenic human tumors is impractical, synchronous and metachronous (asynchronous) tumors in HNPCC patients provide opportunities to minimize confounding factors and observe different tumors arising within the same genetic and similar environmental backgrounds. Primary differences between these tumors should be relative ages (numbers of divisions since the last clonal expansion) and proliferation patterns. Metachronous tumors (a cancer and three adenomas) from a HNPCC patient demonstrated different amounts of MS diversity, as expected from independent tumors of different ages (Table 1 and Figure 6). The adenomas were removed during biennial surveillance colonoscopy. Some of the highly polymorphic and complex topographical MS distributions are illustrated in Figure 7. The different patterns between loci within the same tumor likely reflect independent stochastic mutation- and locus-specific differences in mutation rates. Median variances exceeded 1.0 for the smallest (adenoma 1, <0.5 cm) and largest (adenoma 3, 1.0 cm) adenomas. Median variances were less than 1.0 for adenoma 2 (0.5 cm) and the large carcinoma (number 4).Table 1Summary of HNPCC DataMedian varianceTumorPatientScreening intervalDXS5561060418453ProliferationAdenoma 1, <0.5 CMA (MSH2)24 M1.481.652.240.91SAdenoma 2, 0.5 CM28 M0.470.630.66NDS or RAdenoma 3, 1.0 CM23 M2.581.310.96NDSCancer 4, PD, Dukes' BND0.620.550.60NDS or RAdenoma 5,*Synchronous tumors. 1.0 CMB (MLH1-A)NDND1.262.71NDSCancer 6,*Synchronous tumors. PD, Dukes' CNDND0.340.74NDS or RCancer 7, MD, Dukes' B6 M0.510.330.82NDS or RAdenoma 8,*Synchronous tumors. 0.8 CMC (MLH1-A)46 M0.460.130.400.33S or RCancer 9,*Synchronous tumors. PD, Dukes' A46 M0.420.430.16NDS or RCancer 10, MD, Dukes' BD (MLH1-B)37 M0.350.510.58NDS or RCancer 11, MD, Dukes' BE (MLH1-B)60 M2.001.141.72NDSMS variances of 11 mutator phenotype tumors from five HNPCC patients with germline mutations in hMSH2 (codon 619–620 insertion41Nyström-Lahti M Wu Y Moisio AL Hofstra RM Osinga J Mecklin JP Järvinen HJ Leisti J Buys CHCM de la Chapelle A Peltomäki P DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer.Hum Mol Genet. 1996; 5: 763-769Crossref PubMed Scopus (200) Google Scholar for patient A) and hMLH1 (exon 6 splice site42Nyström-Lahti M Kristo P Nicolaides NC Chang SY Aaltonen LA Moisio AL Järvinen HJ Mecklin JP Kinzler KW Vogelstein B de la Chapelle A Peltomäki P Founding mutations and Alu-mediated recombination in hereditary colon cancer.Nature Med. 1995; 1: 1203-1206Crossref PubMed Scopus (250) Google Scholar for patients B and C (MLH1-A), exon 16 deletion for patients D and E (MLH1-B)).Screening intervals were periods between biopsy and the last previous examination. S, stem cell proliferation; R, random proliferation; ND, no data.* Synchronous tumors. Open table in a new tab Figure 7A: Autoradiographs of the different sized DXS1060 alleles present within small tumor dots. The arrows mark the allele sizes and the solid circles represent the germline alleles. The left is a sample with low variance (final value was 0.34) from cancer 4, and the right is a sample with high variance (final value was 4.08) from adenoma 3. B: Locations of tissue dots and their MS frequency distributions and variances for adenoma 2. The composite graph summarizes the data from all dots. Thex axis indicates repeat unit additions or deletions compared with the germline allele (marked with an arrowhead). The scale is the same for all tumors. C: Locations of tissue dots and their MS frequency distributions and variances for adenoma 3. D: Locations of tissue dots and their MS frequency distributions and variances for adenoma 8.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 7A: Autoradiographs of the different sized DXS1060 alleles present within small tumor dots. The arrows mark the allele sizes and the" @default.
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• W105773406 title "Tracing Cell Fates in Human Colorectal Tumors from Somatic Microsatellite Mutations" @default.
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• W105773406 hasConceptScore W105773406C142724271 @default.
• W105773406 hasConceptScore W105773406C180754005 @default.
• W105773406 hasConceptScore W105773406C501734568 @default.

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