HRAS mutations are frequent in inverted urothelial neoplasms

McDaniel, Andrew S.; Zhai, Yali; Cho, Kathleen R.; Dhanasekaran, Saravana M.; Montgomery, Jeffrey S.; Palapattu, Ganesh S.; Siddiqui, Javed; Morgan, Todd M.; Alva, Ajjai; Weizer, Alon Z.; Lee, Cheryl T.; Chinnaiyan, Arul M.; Quist, Michael J.; Grasso, Catherine S.; Tomlins, Scott A.; Mehra, Rohit

doi:10.1016/j.humpath.2014.06.003

Cited by 40 publications

(51 citation statements)

References 34 publications

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“…Variants passing filtering in APCCs that were called as variants (regardless of filtering status) in any normal tissue were considered germ line/artifacts and excluded from additional analysis unless occurring at a previously reported residue associated with APA. These filtering criteria are more stringent than our previously validated criteria for calling single-nucleotide/indel variants from AmpliSeq data (41,43). All somatic APCC variants were visually confirmed in Integrative Genomics Viewer (Broad Institute), and paired normal samples were inspected in Integrative Genomics Viewer to confirm lack of substantial read support for the called variant.…”

Section: Methodsmentioning

confidence: 99%

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

Nishimoto

Tomlins

Kuick

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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270

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Primary aldosteronism (PA) represents the most common cause of secondary hypertension, but little is known regarding its adrenal cellular origins. Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. PA-causing aldosteroneproducing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression. Herein, we hypothesized that APCCs have APArelated aldosterone-stimulating somatic gene mutations. APCCs were studied in 42 normal adrenals from kidney donors. To clarify APCC molecular characteristics, we used microarrays to compare the APCC transcriptome with conventional adrenocortical zones [zona glomerulosa (ZG), zona fasciculata, and zona reticularis]. The APCC transcriptome was most similar to ZG but with an enhanced capacity to produce aldosterone. To determine if APCCs harbored APA-related mutations, we performed targeted next generation sequencing of DNA from 23 APCCs and adjacent normal adrenal tissue isolated from both formalin-fixed, paraffin-embedded, and frozen tissues. Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations in calcium channel, voltage-dependent, L-type, α1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, Na + /K + transporting, α1-polypeptide (ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent normal adrenal tissue. Overall, we show three major findings: (i) APCCs are common in normal adrenals, (ii) APCCs harbor somatic mutations known to cause excess aldosterone production, and (iii) the mutation spectrum of aldosteronedriving mutations is different in APCCs from that seen in APA. These results provide molecular support for APCC as a precursor of PA.primary aldosteronism | aldosterone | adrenal | somatic mutations | aldosterone-producing cell cluster P rimary aldosteronism (PA) accounts for 8% of hypertension and is the most common adrenal disease (1-4). PA patients can be classified into those with aldosterone-producing adenomas (APAs), idiopathic hyperaldosteronism, or familial hyperaldosteronism (FH), which is further divided into FH types 1-3 (FHI-FHIII) (5). In 1992, FHI was shown to result from a gene fusion of cytochrome P450, family 11, subfamily B, polypeptide 2 (CYP11B2: aldosterone synthase) and cytochrome P450, family 11, subfamily B, polypeptide 1 (CYP11B1; cortisol synthase) that resulted in zona fasciculata (ZF) expression of CYP11B2 and excess aldosterone production (6). For almost two decades after the original report, no other genetic abnormalities were identified in the other forms of PA.First reported in 2011, exome sequencing identified a series of germ-line and somatic mutations in genes that altered adrenal cell intracellular Ca 2+ in PA. The most common mutations are somatic mutations of the gene encoding the potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5)...

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Section: Methodsmentioning

confidence: 99%

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

Nishimoto

Tomlins

Kuick

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

270

273

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“…Data analysis was performed essentially as described(12) in Torrent Suite 4.0.2, with alignment by TMAP using default parameters, and variant calling using the Torrent Variant Caller plugin (version 4.0-r76860) using default low-stringency somatic variant settings. Variants were annotated using Annovar(13).…”

Section: Methodsmentioning

confidence: 99%

Next-Gen Sequencing Exposes Frequent MED12 Mutations and Actionable Therapeutic Targets in Phyllodes Tumors

Cani

Hovelson

McDaniel

et al. 2015

Molecular Cancer Research

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129

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Phyllodes tumors are rare fibroepithelial tumors with variable clinical behavior accounting for a small subset of all breast neoplasms, yet little is known about the genetic alterations that drive tumor initiation and/or progression. Here targeted next generation sequencing (NGS) was used to identify somatic alterations in formalin fixed paraffin embedded (FFPE) patient specimens from malignant, borderline and benign cases. NGS revealed mutations in mediator complex subunit 12 (MED12) affecting the G44 hotspot residue in the majority (67%) of cases spanning all three histological grades. In addition, loss-of-function mutations in p53 (TP53) as well as deleterious mutations in the tumor suppressors retinoblastoma (RB1) and neurofibromin 1 (NF1) were identified exclusively in malignant tumors. High-level copy number alterations (CNAs) were nearly exclusively confined to malignant tumors, including potentially clinically actionable gene amplifications in IGF1R and EGFR. Taken together, this study defines the genomic landscape underlying phyllodes tumor development, suggests potential molecular correlates to histologic grade, expands the spectrum of human tumors with frequent recurrent MED12 mutations, and identifies IGF1R and EGFR as potential therapeutic targets in malignant cases.

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“…However, HPV has not been detected through immunohistochemistry or in situ hybridization (ISH), which is more specific for HPV infection in tissues. 1,15 …”

Section: Etiologymentioning

confidence: 99%

“…This mutation is rarely seen in UC. 15 Telomere shortening is another useful biomarker in distinguishing IUP from UC. Williamson et al found a statistically significant reduction in the relative telomere length (RTL) in UC with inverted growth compared to those found in IUP.…”

Section: Distinguishing Iup From Ucmentioning

confidence: 99%

Inverted urothelial papilloma: A review of diagnostic pitfalls and clinical management

Sweeney

Rais‐Bahrami

Gordetsky

2017

CUAJ

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Inverted urothelial papilloma (IUP) is a rare, non-invasive endophytic lesion that accounts for 1-2% of urothelial tumours. On cystoscopy, IUP appears as a pedunculated/papillary mass with a smooth surface. On microscopy, IUP has an endophytic growth pattern with the bulk of the tumour covered by a superficial layer of urothelium, which can be hyperplastic or attenuated. The cytology should be bland, with uniform, spindled cells arranged in anastomosing trabeculae and cords with peripheral palisading of basaloid cells. Exophytic papillae and mitotic activity should be absent or focal. Pseudoglandular spaces and squamous metaplasia may also be present. There are distinct molecular differences between IUP and urothelial carcinoma (UC). IUP rarely has mutations of FGFR3, homozygous loss of 9p21, or gain of chromosomes 3, 7, and 17, whereas these mutations are frequently seen in UC. In addition, IUP is much less likely to have TERT mutations compared to UC. Immunohistochemistry can also be helpful in distinguishing the two entities as IUP is typically negative for CK20 and has a low Ki-67 proliferation index. Positivity for p53 may be seen in a minority of IUP. IUP can recur and be seen in association with UC.Distinguishing IUP from UC can be difficult due to the similarity between the two entities both on cystoscopy and histology, as up to 25% of UCs will also have inverted growth. Given the morphologic variants of IUP and UC, it is possible for a diagnostic error to occur, which can significantly impact patient management.

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HRAS mutations are frequent in inverted urothelial neoplasms

Cited by 40 publications

References 34 publications

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

Next-Gen Sequencing Exposes Frequent MED12 Mutations and Actionable Therapeutic Targets in Phyllodes Tumors

Inverted urothelial papilloma: A review of diagnostic pitfalls and clinical management

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