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Arndt Hartmann

Publications and source records attributed to Arndt Hartmann.

At least 19 recordsLinked to original sources
PubMed2026

Integrating NECTIN4 Amplification With Membranous Nectin-4 Expression to Develop a Scoring System for Predicting Enfortumab Vedotin Response in Urothelial Carcinoma.

PURPOSE: Enfortumab vedotin (EV) is standard therapy for metastatic urothelial carcinoma (mUC), yet the predictive relevance of NECTIN4 expression-especially membranous versus cytoplasmic-remains unclear. Here, we sought to extend previous findings on NECTIN4 gene amplification in parallel with a systematic subcellular evaluation of NECTIN4 expression. EXPERIMENTAL DESIGN: We retrospectively analyzed 179 EV-treated mUC patients. NECTIN4 amplification was assessed by FISH and NECTIN4 protein levels by IHC. A four-tier membranous scoring algorithm (0,1+,2+,3+) adapted from CAP HER2 gastric guidelines was benchmarked against H-score. We integrated amplification status with membranous staining to refine predictive stratification and compared associations with objective response rate (ORR) to EV-301 data. RESULTS: Combining membranous and cytoplasmic compartments resulted in a median composite H-score of 260 (78.2% &#x2265;150), closely matching NECTIN4 expression prevalence reported in EV-301 (median 250; 82.6% &#x2265; 150). A &#x2265;150 cut-off enriched for EV responders in both cohorts; in EV-301 with ORR of 45.8% vs. 20% (P = 0.001). High membranous expression based on the scoring (2+/3+) predicted response (ORR 55.1% vs. 25.5%; P < 0.001), with longer PFS (7.1 vs. 2.9 months; HR 0.45) and OS (12.3 vs. 6.9 months; HR 0.57), whereas cytoplasmic expression lacked predictive value. NECTIN4-amplified tumors showed particularly favorable outcomes (PFS 12.2 months; OS 30.1 months). An integrated three-tier model-amplified, non-amplified/high-membranous, and non-amplified/low-membranous-yielded ORRs of 77.2%, 42.9%, and 26.1% and separated survival outcomes. CONCLUSIONS: Our NECTIN4 scoring system integrating NECTIN4 amplification with membranous NECTIN4 expression accurately predicts outcomes, supporting combined genomic and membranous assessment as complementary biomarkers for optimizing EV selection.

Journal Article↗
PubMed2025

Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.

BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (&#x2264;3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Journal Article↗
PubMed2007

Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations.

Multifocal hyperplasia of interstitial cells of Cajal (ICC hyperplasia) is a precursor of hereditary gastrointestinal stromal tumors (GISTs) in patients with germline mutations of c-KIT or PDGFRA, but precursor lesions of sporadic GISTs have not been defined yet. Small hyalinizing stromal tumors of the proximal stomach (referred to in this study as GIST tumorlets) were collected prospectively from 98 consecutive autopsies and additional cases were retrieved from surgical pathology files (total n=57). GIST tumorlets were grossly detectable in 22.5% consecutive autopsies performed in individuals older than 50 years. All lesions were located in the cardia, fundus, or proximal body, and ranged in size from 1 to 10 mm (4 mm). Similar lesions were not detected in the antrum, duodenum, and the remainder of the bowel. Histologically, the spindle cell subtype comprised all cases, with hyalinization and calcification in 57% of cases. The spindle cells were immunohistochemically positive for vimentin, CD117, and CD34. Twenty-four cases yielded sufficient DNA for subsequent molecular analysis, which showed c-KIT mutations in 11 cases (46%) and PDGFRA mutations in 1 case (4%). Sporadic GIST tumorlets of the proximal stomach are common in the general population over the age of 50 years and frequently show somatic c-KIT mutations. GIST tumorlets probably represent the grossly recognizable counterpart of sporadic ICC hyperplasia caused by somatic c-KIT or PDGFRA mutations. Early hyalinization and calcification seems to confer limited growth potential, and complete regression of such lesions is common. GIST tumorlets likely represent preclinical (preneoplastic) lesions that need additional stimuli to evolve into clinical GISTs, raising the possibility of a hyperplasia-neoplasia sequence in the development of sporadic GISTs.

Adult↗
PubMed2007

Role of the STK15 Phe31Ile polymorphism in renal cell carcinoma.

The search of inherited cancer susceptibility factors is an important subject in cancer epidemiology. Analyses of single nucleotide polymorphisms (SNP) in various genes revealed a correlation between the presence of specific allelic variants and cancer predisposition in diverse malignancies. STK15 is an important protein in control of the integrity of the mitotic spindle apparatus and genomic stability. We analysed the distribution of the functionally important T91A SNP in the STK15 gene in a cohort of renal cell carcinoma (RCC) patients and compared it to the distribution in a control group without malignancies. DNA from formalin-fixed, paraffin-embedded healthy renal tissue (RCC patients) or peripheral blood samples (control group) was isolated according to standard protocols. Allelic variant of STK15 nucleotide 91 was determined using restriction fragment length polymorphism (RFLP) analysis. Overall, 156 RCC patients and 158 patients without any malignancy were analysed. The distribution of the STK15 SNP in RCC patients (T/T, 58.97%; A/T, 36.53%; A/A, 4.49%) did not significantly differ from that of the control group (T/T, 51.27%; A/T, 41.14%; A/A, 7.59%). There was also no correlation between genotype and tumour grade or stage or other histopathological characteristics of the tumours. This first analysis of the STK15 T91A SNP in RCC patients revealed no correlation between a certain allelic variant and an increased risk for RCC.

Aurora Kinase A↗
PubMed2006

FGFR3 mutations in benign skin tumors.

Activating FGFR3 germline mutations cause skeletal dysplasia and craniosynostosis syndromes. Somatic FGFR3 mutations have been identified in several cancer entities such as urothelial carcinoma and multiple myeloma. Recently, the same FGFR3 mutations known from skeletal dysplasia syndromes and urothelial carcinoma have been shown to cause benign human skin tumors such as seborrheic keratoses and epidermal nevi. The underlying mechanisms for the somatic FGFR3 mutations in the epidermis are unknown so far, as well as details of the involved signaling pathways in the mutant keratinocytes leading to the formation of acanthotic skin tumors. Herein we discuss potential mechanisms and functional consequences of activating FGFR3 mutations in human skin. Further studies are required to provide insights in the pathogenesis of benign skin tumors caused by FGFR3 mutations. These studies will add to new non-invasive therapeutical strategies for benign acanthotic skin tumors in dermatology.

Abnormalities, Multiple↗
PubMed2006

Chromosome 9 deletions are more frequent than FGFR3 mutations in flat urothelial hyperplasias of the bladder.

Flat urothelial hyperplasias (FUHs) in patients with papillary bladder tumours frequently show deletions of chromosome 9, suggesting that FUH could be the first neoplastic step in the development of papillary bladder cancer. FGFR3 mutations are frequent in non-invasive papillary tumours with low risk of progression. Our aim was to investigate the frequency of FGFR3 mutations and deletions of chromosomes 9p/q and 8p/q in FUH. Thirty FUH and 9 simultaneous or consecutive tumours were detected by 5-ALA-based photodynamic cystoscopy. DNA was isolated from frozen sections and whole genome amplification was done by I-PEP-PCR, followed by LOH analysis on chromosomes 8p/q and 9p/q. FGFR3 mutations were detected by SNaPshot analysis. LOH analysis on FUH revealed deletions at 9p/q (11/30, 37%) and 8p/q (3/30, 10%). FGFR3 mutations were found in 7/30 FUH (23%). Only 2 FUH showed an FGFR3 mutation without deletions of chromosome 9. In contrast, 6 FUH revealed chromosome 9 deletions but wild type FGFR3 (p = 0.03). These results suggest that chromosome 9 deletions are the earliest genetic alterations in bladder cancer. The detection of FGFR3 mutations in FUH further supports the role of this lesion as precursor of papillary bladder cancer.

Adult↗
PubMed2006

Validation of the diagnostic value of NMP22 BladderChek test as a marker for bladder cancer by photodynamic diagnosis.

OBJECTIVES: The aim of the present study was to validate the sensitivity and specificity of the new "point-of-care" NMP22 BladderChek test compared to photodynamic diagnosis (PDD). METHODS: Voided urine samples from 100 patients with suspicion of bladder cancer were collected to perform the NMP22 BladderChek test and voided urinary cytology. The nuclear matrix protein 22 (NMP22) levels were measured by a lateral flow immunochromatographic qualitative assay, using 10 U/ml as the cut-off value. Subsequently patients underwent PDD, using 5-aminolevulinic acid or hexyl-aminolevulinate; previous bladder washings for cytology were collected. Sensitivity and specificity of the NMP22 BladderChek test were compared with cytology and PDD. RESULTS: Forty of the 100 patients had urothelial malignancies (22 pTa, 4 pT1, 3 pT2, 9 carcinoma in situ, 2 pTx; 16 G1, 6 G2, 18 G3). The sensitivity was 65% for the NMP22 BladderChek test, 44% for voided cytology, 75% for washing cytology, and 93% for PDD. Specificity rates were 40%, 78%, 62%, and 43%, respectively. Positive predictive values were 0.42, 0.58, 0.53, and 0.52 and the negative predictive values 0.63, 0.68, 0.82, and 0.9, respectively. CONCLUSIONS: The results demonstrate that the NMP22 BladderChek is an easily applied test, giving diagnostic findings within 30 min. However, validated by the highly sensitive PDD, the NMP22 BladderChek test demonstrates poor specificity and sensitivity and, therefore, cannot be recommended for screening or surveillance in daily clinical routine use. Further studies with careful patient selection are necessary to identify the patient population that might benefit from the NMP22 BladderChek test.

Aged↗
PubMed2006

Elevated microsatellite alterations at selected tetranucleotides (EMAST) and mismatch repair gene expression in prostate cancer.

Elevated microsatellite alterations at selected tetranucleotides (EMAST), a new form of microsatellite instability (MSI) affecting tetranucleotide repeats, was recently described to be frequent in several tumor types (e.g., bladder, lung, ovarian, and skin cancers). EMAST was found as a form of microsatellite alteration distinct from the MSI phenotype in hereditary nonpolyposis colorectal cancer (HNPCC)-related tumors which mostly affects mono- and dinucleotide repeats. To date, no study has investigated the role of EMAST in prostate cancer. We therefore analyzed 81 prostate tumors using 10 markers frequently detecting EMAST in other cancer types and the National Cancer Institute-consensus panel for HNPCC detection plus BAT40. In addition, we investigated p53 gene alterations [loss of heterozygosity (LOH)] and the expression of p53 and the mismatch repair (MMR) genes hMLH1 and hMSH2 on tissue microarrays. EMAST was detected in 4/81 (5%) cases and MSI in 6/79 (7.6%) cases. LOH of p53 was found in 9/45 (20%) informative cases. There was no correlation between MSI status and the histopathological or molecular characteristics of the tumors. Immunohistochemistry revealed p53 positivity in 5/61 (8%) tumors. There was a significant correlation between tumors showing a recurrence within 3 years after treatment and p53 positivity (p=0.029). Reduced hMLH1 expression, but no complete loss, was detected in 9/41 (22%) tumors without any correlations to histopathological or clinical features. Analysis of hMSH2 expression was available from 58/81 (72%) tumors. Staining intensity was as follows: negative in 7/58 (12%), weak staining in 16/58 (27.5%) samples, moderate staining in 19/58 (33%) samples, and strong staining in 16/58 (27.5%) samples. When negative/weak staining and moderate/strong staining were considered as two groups, there was a significant association between hMSH2 expression and tumor recurrence (p=0.039). In conclusion, our data show that MSI and EMAST are infrequent but distinct patterns of MSI in prostate tumors not related to MMR defects, p53 alterations, and histopathological characteristics. p53 positivity and moderate to strong hMSH2 expression of prostate tumors are correlated with early disease recurrence and indicate an unfavorable clinical course of the disease. These two genes could be useful biomarkers for the prediction of patients' outcome and should be analyzed in prospective studies.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Molecular profiling of laser-microdissected matched tumor and normal breast tissue identifies karyopherin alpha2 as a potential novel prognostic marker in breast cancer.

PURPOSE: The aim of the present study was to identify human genes that might prove useful in the diagnosis and therapy of primary breast cancer. EXPERIMENTAL DESIGN: Twenty-four matched pairs of invasive ductal breast cancer and corresponding benign breast tissue were investigated by a combination of laser microdissection and gene expression profiling. Differential expression of candidate genes was validated by dot blot analysis of cDNA in 50 pairs of matching benign and malignant breast tissue. Cellular expression of candidate genes was further validated by RNA in situ hybridization, quantitative reverse transcription-PCR, and immunohistochemistry using tissue microarray analysis of 272 nonselected breast cancers. Multivariate analysis of factors on overall survival and recurrence-free survival was done. RESULTS: Fifty-four genes were found to be up-regulated and 78 genes were found to be down-regulated. Dot blot analysis reduced the number of up-regulated genes to 15 candidate genes that showed at least a 2-fold overexpression in >15 of 50 (30%) tumor/normal pairs. We selected phosphatidic acid phosphatase type 2 domain containing 1A (PPAPDC1A) and karyopherin alpha2 (KPNA2) for further validation. PPAPDC1A and KPNA2 RNA was up-regulated (fold change >2) in 84% and 32% of analyzed tumor/normal pairs, respectively. Nuclear protein expression of KPNA2 was significantly associated with shorter overall survival and recurrence-free survival. Testing various multivariate Cox regression models, KPNA2 expression remained a highly significant, independent and adverse risk factor for overall survival. CONCLUSIONS: Gene expression profiling of laser-microdissected breast cancer tissue revealed novel genes that may represent potential molecular targets for breast cancer therapy and prediction of outcome.

Biomarkers, Tumor↗
PubMed2006

High frequency of FGFR3 mutations in adenoid seborrheic keratoses.

FGFR3 germline mutations cause autosomal dominant skeletal disorders including achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans, and Crouzon syndrome. Somatic mutations of FGFR3 have been identified in bladder cancer, multiple myeloma, and other neoplasms. FGFR3 mutations have also been detected in 40% of seborrheic keratoses (SKs) of the hyperkeratotic and acanthotic subtype, which are very common benign skin tumors. Using a multiplex SNaPshot assay that covers 11 activating FGFR3 mutations, we investigated a series of 27 SKs of the adenoid subtype. Mutations were detected in 23 of 27 (85%) adenoid SKs. R248C mutations were the most frequent mutation type. In two SKs, the A393E mutation was found, which has not been described in acanthotic and hyperkeratotic SKs so far. Three adenoid SKs displayed two simultaneous FGFR3 mutations. Adenoid SKs seem to be characterized by a higher frequency of FGFR3 mutations than hyperkeratotic and acanthotic SKs. The mechanism for the high rate of somatic FGFR3 mutations in these benign skin tumors remains elusive, but UV light exposure may play a potential role, especially in the R248C mutations.

Aged↗
PubMed2006

Nuclear and cytoplasmic Maspin expression in primary non-small cell lung cancer.

AIM: To investigate whether nuclear and cytoplasmic Maspin expression is associated with distinct clinicopathological parameters and TP53 expression in a representative series of primary non-small cell lung cancer (NSCLC). METHODS: Tissue microarrays (n=487) were used to immunohistochemically analyse expression of Maspin and TP53. Cytoplasmic and nuclear expression of Maspin was scored on the basis of the percentage of positive tumour cells. Univariate analysis of clinicopathological variables potentially affecting tumour-specific survival was performed. RESULTS: Immunohistochemical Maspin expression (nuclear and cytoplasmic) was informative in 72.3% (352/487) of cases. Cytoplasmic and nuclear Maspin immunoreactivity in >or=10% of tumour cells was detected in 37.8% (133/352) and 65.3% (230/352) of informative cases, respectively. Nuclear and cytoplasmic Maspin staining was observed more frequently in primary squamous cell carcinomas than in other lung cancer types. Only nuclear Maspin immunoreactivity was significantly associated with positive TP53 staining. Cytoplasmic or nuclear Maspin expression was not associated with tumour-specific survival. CONCLUSION: Maspin expression was found both in the nucleus and the cytoplasm of NSCLC, more frequently in squamous cell carcinomas. However, no association with tumour-specific survival could be demonstrated.

Biomarkers, Tumor↗
PubMed2006

Expression of peroxisome proliferator activated receptor gamma and cyclo-oxygenase 2 in primary and recurrent ovarian carcinoma.

AIM: Peroxisome proliferator-activated receptor gamma (PPARgamma) has emerged as a potential therapeutic target in several types of cancer. In ovarian carcinomas, limited and conflicting data on PPARgamma protein expression have been reported. METHODS: The immunoexpression of PPARgamma and its putative target cyclo-oxygenase 2 (COX2) was investigated in tumour tissues from 80 patients with primary and corresponding recurrent ovarian serous carcinomas after conventional platinum-based chemotherapy. RESULTS: PPARgamma expression was observed in 29% of primary and recurrent carcinomas. In the recurrent tumours, PPARgamma expression inversely correlated with COX2 overexpression in both chemosensitive (p = 0.02) and chemoresistant (p = 0.04) carcinomas. CONCLUSIONS: The data indicate that PPARgamma may represent a potential target for second-line treatment in ovarian cancers.

Adult↗
PubMed2006

Elevated microsatellite instability at selected tetranucleotide repeats does not correlate with clinicopathologic features of bladder cancer.

INTRODUCTION: The aim of the present study was to evaluate whether elevated microsatellite instability (MSI) at selected tetranucleotide repeats (EMAST) is associated with clinicopathologic and molecular parameters in urinary bladder cancer (BC). METHODS: A consecutive series of 117 nonselected urothelial BCs was studied. Microsatellite analysis and detection of loss of heterozygosity (LOH) was performed after microdissection by using 12 markers selected for sensitive detection of EMAST. Furthermore, five markers (BAT25, BAT26, D2S123, APC, and D17S250) of the Bethesda consensus panel for detection of colorectal cancer within the hereditary non-polyposis colon cancer syndrome (HNPCC) were analyzed. Expression of TP53 and mismatch repair (MMR) proteins hMSH2, hMLH1, and hMSH6 was investigated by immunohistochemistry. RESULTS: EMAST was detected in 10 of 117 patients (8.5%), whereas MSI in the HNPCC panel was found in one of 114 cases (0.9%). LOH in EMAST markers was seen in six of 114 (5.3%) cases. All tumours showed normal expression of hMSH2 and hMLH1. Overexpression of TP53 was observed in nine of 117 evaluated cases (7.7%). No association of EMAST and TP53 expression could be demonstrated. None of the clinicopathologic or molecular parameters were associated with EMAST. CONCLUSIONS: EMAST is another distinct form of MSI in urothelial BC. However, EMAST seems to be a rare event in non-selected urothelial BC and does not seem to be associated with commonly used clinicopathologic and clinical features in patients with BC.

Humans↗
PubMed2006

Nuclear Maspin expression is associated with response to adjuvant 5-fluorouracil based chemotherapy in patients with stage III colon cancer.

Maspin, a member of the Serpin protease inhibitor family, is overexpressed in poorly differentiated colorectal tumors and more frequently found in tumors with microsatellite instability. Immunohistochemical nuclear Maspin staining is predominantly seen in tumor cells at the invasion front of such cancers, suggesting that this molecule is associated with local tumor cell infiltration and aggressiveness. In a retrospective study, we studied nuclear Maspin expression as a potential prognostic tool in a total of 172 primary stage III colon cancers by immunohistochemistry. Of those 172 patients, 76 were treated by surgery only, and 96 patients received additional adjuvant 5-fluorouracil (5-FU) based chemotherapy. Nuclear Maspin expression was an independent adverse prognostic factor for overall survival in our patient cohort (hazard ratio 2.08; 95% CI, 1.13-3.81; p = 0.018). However, patients with primary tumors expressing Maspin in the nucleus showed a significant treatment benefit from 5-FU chemotherapy (hazard ratio 0.384; 95% CI, 0.188-0.784; p = 0.009) compared to adjuvantly treated patients whose tumors did not express this molecule. Nuclear Maspin expression is highly predictive of 5-FU chemotherapy response in patients with advanced stage colon cancer. Patients with negative immunohistochemical Maspin expression do not benefit from 5-FU treatment and may be candidates for an alternative (non-5-FU based) adjuvant therapy regime.

Aged↗
PubMed2006

Serological pattern "anti-HBc alone": characterization of 552 individuals and clinical significance.

AIM: To investigate the prevalence and clinical significance of "anti-HBc alone" in an unselected population of patients and employees of a university hospital in southern Germany. METHODS: All individuals with the pattern "anti-HBc alone" were registered over a time span of 82 mo. HBV-DNA was measured in serum and liver samples, and clinical charts were reviewed. RESULTS: Five hundred and fifty two individuals were "anti-HBc alone" (of 3004 anti-HBc positive individuals; 18.4%), and this pattern affected males (20.5%) more often than females (15.3%; P<0.001). HBV-DNA was detected in serum of 44 of 545 "anti-HBc alone" individuals (8.1%), and in paraffin embedded liver tissue in 16 of 39 patients tested (41.0%). There was no association between the detection of HBV genomes and the presence of biochemical, ultrasonic or histological signs of liver damage. Thirty-eight "anti-HBc alone" patients with cirrhosis or primary liver carcinoma had at least one additional risk factor. HCV-coinfection was present in 20.4% of all individuals with "anti-HBc alone" and was the only factor associated with a worse clinical outcome. CONCLUSION: In an HBV low prevalence area, no evidence is found that HBV alone causes severe liver damage in individuals with "anti-HBc alone". Recommendations for the management of these individuals are given.

Adult↗
PubMed2006

Mitogen-activated protein kinase signaling is activated in prostate tumors but not mediated by B-RAF mutations.

OBJECTIVES: A dysregulated mitogen-activated protein kinase (MAPK) pathway plays an important role in various malignancies and is often mediated by mutations in several oncogenes (eg, RAF, RAS). B-RAF mutations, predominantly the specific V600E mutation and additional alterations in exons 11 and 15, were frequently detected in malignant melanomas, papillary thyroid tumors, and colorectal cancers with microsatellite instability (MSI). The present study investigated B-RAF mutations, MSI status, and activation of MAPK signaling in prostate tumors. METHODS: The V600E mutation of the B-RAF gene was analyzed using allele-specific polymerase chain reaction in 79 archival prostatic adenocarcinomas (pT1aG1 to pT3cG3, median Gleason score 6); exons 11 and 15 were sequenced. MSI status was determined using the National Cancer Institute consensus panel for hereditary nonpolyposis colorectal carcinoma (HNPCC) detection. Active MAPK signaling was investigated using immunohistochemistry for p44/ERK1 and p42/ERK2. RESULTS: No B-RAF mutations could be detected. Six of 79 tumors showed MSI positivity. Active MAPK signaling was detected in 51% of the analyzed tumors. No correlation was found between MAPK activity and histopathologic/clinical characteristics. CONCLUSION: The most frequent B-RAF gene alterations are not involved in prostate carcinogenesis. MSI is infrequent in prostate cancer and is not linked to B-RAF mutations. MAPK signaling is frequently activated in prostate tumors and might be suitable for a therapeutic approach.

Aged↗
PubMed2006

Multifocal urothelial cancers with the mutator phenotype are of monoclonal origin and require panurothelial treatment for tumor clearance.

PURPOSE: UC is a disease of the entire urothelium, characterized by multiplicity and multifocality. The clonal relationship among multiple UCs has implications regarding adjuvant chemotherapy. It has been investigated in studies of chromosomal alteration and single gene mutation. However, these genetic changes can occur in unrelated tumors under similar carcinogenic selection pressures. Tumors with high MSI have numerous DNA mutations, of which many provide no selection benefit. While these tumors represent an ideal model for studying UC clonality, their low frequency has prevented their previous investigation. MATERIALS AND METHODS: We investigated 32 upper and lower urinary tract UCs with high MSI and 4 nonUC primary cancers in 9 patients. We used the high frequency and specificity of individual DNA mutations in these tumors (MSI at 17 loci) and the early timing of epigenetic events (methylation of 7 gene promoters) to investigate tumor clonality. RESULTS: Molecular alterations varied among tumors from different primary organs but they appeared related in the UCs of all 9 patients. While 7 patients had a high degree of concordance among UCs, in 2 the UCs shared only a few similar alterations. Genetic and epigenetic abnormalities were frequently found in normal urothelial samples. CONCLUSIONS: Multiple UCs in each patient appeared to arise from a single clone. The molecular order of tumor development varied from the timing of clinical presentation and suggested that residual malignant cells persist in the urinary tract despite apparent curative surgery. These cells lead to subsequent tumor relapse and new methods are required to detect and eradicate them.

Adult↗