FGFR3 and TP53 mutation analysis in inverted urothelial papilloma: incidence and etiological considerations

Lott, Sarah; Wang, Mingsheng; Zhang, Shaobo; MacLennan, Gregory T.; López-Beltrán, Antonio; Montironi, Rodolfo; Sung, Ming Tse; Tan, Puay Hoon; Liu, Cheng

doi:10.1038/modpathol.2009.28

Cited by 46 publications

(38 citation statements)

References 20 publications

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“…During a mean follow-up of 78 months, none of these patients had recurrence or developed urothelial carcinoma. These findings support the concept that low-grade and low-stage urothelial neoplasms arise in a background of molecular changes that are distinctly different from the molecular changes of high-grade and high-stage urothelial cancers [55].…”

Section: Fgfr3 and Tp53 Mutations Define Two Urothelial Carcinogenesis supporting

confidence: 85%

Molecular Determinants of Tumor Recurrence in The Urinary Bladder

et al. 2009

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Tumor recurrence is a major clinical concern for patients with urothelial carcinoma of the urinary bladder. Traditional morphological analysis is of limited utility for identifying cases in which recurrence will occur. However, molecular and genetic analyses offer new perspectives on the prediction of bladder tumor recurrence. Recent studies have suggested that urothelial carcinogenesis occurs as a 'field effect' that can involve any number of sites in the bladder mucosa. Accumulating evidence supports the notion that resident urothelial stem cells in the affected field are transformed into cancer stem cells by acquiring genetic alterations that lead to tumor formation through clonal expansion. Both initial and recurrent tumors are derived from cancer stem cells in the affected field via two distinct molecular pathways. These provide a genetic framework for understanding urothelial carcinogenesis, tumor recurrence and progression: the FGFR3-associated pathway and the TP53-associated pathway. These two pathways are characterized by different genomic, epigenetic and gene-expression alterations. Their outcomes correlate with the markedly different clinical and pathologic features of both relatively indolent low-grade cancers and the aggressive high-grade cancers. As such, these molecular findings are potentially useful for counseling patients and for assessing risk of recurrence or biological aggressiveness of the patient's tumor. The molecular changes may additionally prove useful for developing preventive and therapeutic strategies for urothelial bladder cancer. A unifying model of urothelial carcinogenesis, tumor recurrence and progression is proposed in this review.

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Section: Fgfr3 and Tp53 Mutations Define Two Urothelial Carcinogenesis supporting

confidence: 85%

Molecular Determinants of Tumor Recurrence in The Urinary Bladder

et al. 2009

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“…Comparison of Urothelial Inverted Papillomas With Those From Other Sites12,14,53,56,57 Reports exist to the contrary of this evidence, but the consensus in the literature supports the assertions made in the table.…”

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confidence: 62%

“…[3][4][5][6][7][8][9] More recent studies, using strict diagnostic criteria, have established that inverted papilloma is a benign neoplasm with minimal propensity for recurrence. [10][11][12][13][14][15][16] Recently, a number of investigators have examined the possibility that human papillomavirus (HPV) plays a role in the development of urothelial carcinoma. The reported findings have been conflicting and inconclusive.…”

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confidence: 99%

Human Papillomavirus is Not an Etiologic Agent of Urothelial Inverted Papillomas

Alexander

Davidson

López-Beltrán

et al. 2013

American Journal of Surgical Pathology

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Inverted papilloma of the urinary bladder is rare, accounting for <1% of all bladder neoplasms. Although there is general consensus that inverted papilloma is benign in nature, little is known about its pathogenesis. Some have suggested that human papillomavirus (HPV) plays an etiologic role in the development of this neoplasm. These claims have not been adequately substantiated, and there is controversy as to the role of HPV in other urinary bladder neoplasms as well. To further investigate a possible etiologic role of HPV in urothelial neoplasia, we evaluated 27 inverted papillomas of the urinary bladder for the presence of HPV. Both immunohistochemical and in situ hybridization (ISH) studies for HPV and immunohistochemical analysis for p16, a surrogate marker for HPV infection, were used to assess HPV infection status. In the urinary bladder inverted papillomas of these 27 patients (age range, 35 to 78 y; M:F ratio, 11:1), no HPV was detected by HPV immunohistochemistry or by ISH. Immunoreactivity to p16 was detected in 11/27 (41%) of the cases. Expression of p16 is seen inconsistently within these neoplasms and does not correlate with the presence of HPV antigens or genes by immunohistochemistry or ISH, respectively. Therefore, p16 is not a reliable surrogate marker for HPV infection in urothelial inverted papilloma. Our findings indicate the absence of HPV in urothelial inverted papillomas. HPV testing should not be used as a diagnostic adjunct for inverted papilloma cases.

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“…Three of the five IUP demonstrated identical HRAS T to C transitions leading to a Q61R amino acid substitution. One IUP contained a point mutation in FGFR3 at a location (S249C) described previously in IUP [4, 5] and in papillary UCA [15]. …”

Section: Resultsmentioning

confidence: 99%

“…A limited number of IUP studies using single gene based assays have identified mutations in FGFR3 , in 9.8% to 45% of cases [4, 5]. However, IUP rarely show other features associated with UCA such as p53 overexpression, high Ki-67 expression, and chromosomal abnormalities highlighted by UroVysion FISH [3, 6].…”

Section: Introductionmentioning

confidence: 99%

HRAS mutations are frequent in inverted urothelial neoplasms

McDaniel¹,

Zhai²,

Cho³

et al. 2014

Human Pathology

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Inverted urothelial papilloma (IUP) is an uncommon neoplasm of the urinary bladder with distinct morphological features. Studies regarding the role of human papillomavirus (HPV) in the etiology of IUP have provided conflicting evidence of HPV infection. Additionally, little is known regarding the molecular alterations present in IUP or other urothelial neoplasms which might demonstrate inverted growth pattern like low-grade or high-grade urothelial carcinoma. Here, we evaluated for the presence of common driving somatic mutations and HPV within a cohort of inverted urothelial papillomas, (n=7) non-invasive low-grade papillary urothelial carcinomas with inverted growth pattern (n=5,) and non-invasive high-grade papillary urothelial carcinomas with inverted growth pattern (n=8). HPV was not detected in any case of inverted urothelial papilloma or inverted urothelial carcinoma by either ISH or by PCR. Next generation sequencing identified recurrent mutations in HRAS (Q61R) in 3 of 5 inverted urothelial papillomas, described for the first time in this neoplasm. Additional mutations of Ras pathway members were detected including HRAS, KRAS, and BRAF. The presence of Ras pathway member mutations at a relatively high rate suggests this pathway may contribute to pathogenesis of inverted urothelial neoplasms. Additionally, we did not find any evidence supporting a role for HPV in the etiology of inverted urothelial papilloma.

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FGFR3 and TP53 mutation analysis in inverted urothelial papilloma: incidence and etiological considerations

Cited by 46 publications

References 20 publications

Molecular Determinants of Tumor Recurrence in The Urinary Bladder

Molecular Determinants of Tumor Recurrence in The Urinary Bladder

Human Papillomavirus is Not an Etiologic Agent of Urothelial Inverted Papillomas

HRAS mutations are frequent in inverted urothelial neoplasms

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