Telomerase reverse transcriptase (TERT) promoter mutations are rare in urachal cancer

Thiem, Sebastian; Herold, Thomas; Krafft, Ulrich; Bremmer, Felix; Tolkach, Yuri; Szász, Attila Marcell; Kriegsmann, Joerg; Gaisa, Nadine T.; Niedworok, Christian; Szarvas, Tibor; Reis, Henning

doi:10.1111/pin.12594

Cited by 19 publications

(11 citation statements)

References 30 publications

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“…This notion is further supported by the very low incidence of Telomerase reverse transcriptase (TERT) promoter mutations in urachal adenocarcinomas (4%), which is otherwise a very common event in UC but not in CRC. [29][30][31] Interestingly, our findings regarding MMR-d/MSI-h in UrC are more comparable to figures in UC 32 than in CRC. 23,28 Regarding the rate of PD-L1-expression, UrC (16%) seems to be in the lower range of figures reported for UC (14-28%) 33 and CRC (9-43%).…”

Section: Discussionsupporting

confidence: 79%

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Pathogenic and targetable genetic alterations in 70 urachal adenocarcinomas

Reis

Vos

Niedworok

et al. 2018

Intl Journal of Cancer

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Urachal cancer (UrC) is a rare but aggressive malignancy often diagnosed in advanced stages requiring systemic treatment. Although cytotoxic chemotherapy is of limited effectiveness, prospective clinical studies can hardly be conducted. Targeted therapeutic treatment approaches and potentially immunotherapy based on a biological rationale may provide an alternative strategy. We therefore subjected 70 urachal adenocarcinomas to targeted next-generation sequencing, conducted in situ and immunohistochemical analyses (including PD-L1 and DNA mismatch repair proteins [MMR]) and evaluated the microsatellite instability (MSI) status. The analytical findings were correlated with clinicopathological and outcome data and Kaplan-Meier and univariable/multivariable Cox regression analyses were performed. The patients had a mean age of 50 years, 66% were male and a 5-year overall survival (OS) of 58% and recurrence-free survival (RFS) of 45% was detected. Sequence variations were observed in TP53 (66%), KRAS (21%), BRAF (4%), PIK3CA (4%), FGFR1 (1%), MET (1%), NRAS (1%), and PDGFRA (1%). Gene amplifications were found in EGFR (5%), ERBB2 (2%), and MET (2%). We detected no evidence of MMR-deficiency (MMR-d)/MSI-high (MSI-h), whereas 10 of 63 cases (16%) expressed PD-L1. Therefore, anti-PD-1/PD-L1 immunotherapy approaches might be tested in UrC. Importantly, we found aberrations in intracellular signal transduction pathways (RAS/RAF/PI3K) in 31% of UrCs with potential implications for anti-EGFR therapy. Less frequent potentially actionable genetic alterations were additionally detected in ERBB2 (HER2), MET, FGFR1, and PDGFRA. The molecular profile strengthens the notion that UrC is a distinct entity on the genomic level with closer resemblance to colorectal than to bladder cancer.

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Section: Discussionsupporting

confidence: 79%

“…S4). This notion is further supported by the very low incidence of Telomerase reverse transcriptase ( TERT ) promoter mutations in urachal adenocarcinomas (4%), which is otherwise a very common event in UC but not in CRC . Interestingly, our findings regarding MMR‐d/MSI‐h in UrC are more comparable to figures in UC than in CRC .…”

Section: Discussionsupporting

confidence: 69%

Pathogenic and targetable genetic alterations in 70 urachal adenocarcinomas

Reis

Vos

Niedworok

et al. 2018

Intl Journal of Cancer

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“…TERT, RB1, CDKN1A, ARID1A and KDM6A) as well as TP53 and PIK3CA. A particularly conspicuous aspect is the high level of TERT mutations in UCg which differ from UAC or BAC with only low numbers of TERT mutated cases [40].…”

Section: Discussionmentioning

confidence: 99%

Comparative genomic profiling of glandular bladder tumours

et al. 2020

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Primary glandular bladder tumours (bladder adenocarcinoma [BAC], urachal adenocarcinoma [UAC], urothelial carcinoma with glandular differentiation [UCg]) are rare malignancies with histological resemblance to colorectal adenocarcinoma (CORAD) in the majority of this subgroup. Definite case numbers are very low, molecular data are limited and the pathogenesis remains poorly understood. Therefore, this study was designed to complement current knowledge by in depth analysis of BAC (n = 12), UAC (n = 13), UCg (n = 11) and non-invasive glandular lesions (n = 19). In BAC, in addition to known alterations in TP53, Wnt, MAP kinase and MTOR pathway, mutations in SMAD4, ARID1A and BRAF were identified. Compared to published data on muscle invasive bladder cancer (BLCA) and CORAD, UCg exhibited frequent "urothelial" like alterations while BAC and UAC were characterised by a more "colorectal" like mutational pattern. Immunohistochemically, there was no evidence of DNA mismatch repair deficiency or PD-L1 tumour cell positivity in any sample. Depending on the used antibody 0-45% of BAC, 0-30% of UCg and 0% UAC cases exhibited PD-L1 expressing tumour associated immune cells. A single BAC (9%, 1/11) showed evidence of ARID1A protein loss, and two cases of UCg (20%, 2/10) showed loss of SMARCA1 and PBRM1, respectively. Taken together, our data suggest at least in part involvement of similar pathways driving tumourigenesis of adenocarcinomas like BAC, UAC and CORAD independent of their tissue origin. Alterations of TERT and FBXW7 in single cases of intestinal metaplasia further point towards a possible precancerous character in line with previous reports.

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“…Therapeutic options include (partial) cystectomy with en bloc resection of the median umbilical ligament and umbilicus in local disease and mostly 5-fluorouracil-based chemotherapy regimes in advanced cases [5][6][7]. Recently, molecular studies have allowed more insights in the genetic background of UrC, which seems to be a distinct molecular entity [8][9][10][11][12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Urachal Cancer in Germany and the USA: An RKI/SEER Population-Based Comparison Study

et al. 2020

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Introduction: Urachal cancer (UrC) is a rare but aggressive cancer. Due to its low incidence, structured epidemiological data have only rarely been reported. To date, no valid data on UrC are available for the German population. Methods: Data on incidence and relative 5-year survival of urachal lesions (ICD-10: C67.7) were collected from all populationbased cancer registries in Germany, provided by the Robert Koch-Institut (RKI). Data were anonymized and included age, sex, and general histology (ICD-O-3). For comparison, a similar inquiry of the "Surveillance, Epidemiology, and End Results program" (SEER-18) database for the USA was conducted. Results: From 2011 to 2015, a total of 154 and 152 cases of UrC were reported for Germany (RKI) and the USA (SEER-18 area), respectively. Age-standardized incidence was 0.32/1,000,000 age-standardized cases/year in both cohorts, and elderly persons were more often affected. The major histological type was adenocarcinoma (64.9 and 81.6%). Relative 5-year survival was 54.8% (CI: 45.0-64.6) in Germany (RKI) and 64.4% (54.1-72.1) in the USA (SEER-18 cohort). Discusssion/Conclusion: The collected data demonstrate low incidence rates and similar epidemiological and clinicopathological characteristics of UrC for both registries. This is the first report of structured epidemiological data for UrC for the German population.

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Telomerase reverse transcriptase (TERT) promoter mutations are rare in urachal cancer

Cited by 19 publications

References 30 publications

Pathogenic and targetable genetic alterations in 70 urachal adenocarcinomas

Pathogenic and targetable genetic alterations in 70 urachal adenocarcinomas

Comparative genomic profiling of glandular bladder tumours

Urachal Cancer in Germany and the USA: An RKI/SEER Population-Based Comparison Study

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