Next-generation sequencing of salivary high-grade neuroendocrine carcinomas identifies alterations in RB1 and the mTOR pathway

Goyal, Bella; Duncavage, Eric J.; Martínez, David; Lewis, James S.; Chernock, Rebecca D.

doi:10.1016/j.yexmp.2014.10.011

Cited by 12 publications

(8 citation statements)

References 39 publications

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“…They were chosen primarily because they have been validated for use in hybridization capture analysis. 21 However, a set of genes with essential roles in the maintenance of lens transparency has been identified through studies of inherited forms of cataract. 51 Many of these genes encode proteins that are strongly or specifically expressed in lens tissue, such as α-, β-, or γ-crystallin, and gap junction proteins, such as connexin46 and connexin50.…”

Section: Discussionmentioning

confidence: 99%

“…Adapter ligated DNA was subjected to limited (7–10 cycles) PCR amplification. Sequencing libraries were hybridized at 65°C for 24 hours to the Washington University Cancer Mutation Profiling version 2 (WUCaMP2) gene set 21 using custom SureSelect biotinylated cRNA capture baits (Agilent Technologies, Santa Clara, CA, USA), according to the manufacturer's instructions. The WUCaMP2 panel includes coding exons from 151 cancer-related genes (see Table 2 ) totaling 0.83 Mb of captured sequence.…”

Section: Methodsmentioning

confidence: 99%

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Somatic Variants in the Human Lens Epithelium: A Preliminary Assessment

Mesa

Tyagi

Harocopos

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeWe hypothesize that somatic mutations accumulate in cells of the human lens and may contribute to the development of cortical or posterior sub-capsular cataracts. Here, we used a Next-generation sequencing (NGS) strategy to screen for low-allelic frequency variants in DNA extracted from human lens epithelial samples.MethodsNext-Generation sequencing of 151 cancer-related genes (WUCaMP2 panel) was performed on DNA extracted from post-mortem or surgical specimens obtained from 24 individuals. Usually, pairwise comparisons were made between two or more ocular samples from the same individual, allowing putative somatic variants detected in lens samples to be differentiated from germline variants.ResultsUse of a targeted hybridization approach enabled high sequence coverage (>1000-fold) of the WUCaMP2 genes. In addition to high-frequency variants (corresponding to homozygous or heterozygous SNPs and Indels), somatic variants with allelic frequencies of 1-4% were detected in the lens epithelial samples. The presence of one such variant, a T > C point substitution at position 32907082 in BRCA2, was verified subsequently using droplet digital PCR.ConclusionsLow-allelic fraction variants are present in the human lens epithelium, at frequencies consistent with the presence of millimeter-sized clones.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Somatic Variants in the Human Lens Epithelium: A Preliminary Assessment

Mesa

Tyagi

Harocopos

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Recent data have shown that small cell NEC is associated with a highly distinctive molecular signature, characterised by the bi-allelic inactivation of both TP53 and RB1, as a result of various mechanisms, from mutations to large chromosomal rearrangements. First documented in the lung (George et al 2015(George et al , 2018, this molecular signature has subsequently been confirmed in all body sites, including the digestive tract (Jesinghaus et al 2017), the pancreas (Yachida et al 2012, Hijioka et al 2017, the head and neck region (Goyal et al 2014, Wasserman et al 2019, the genitourinary tract (Chang et al 2018) and the uterine cervix (Frumovitz et al 2016, Xing et al 2018. This does not mean that other molecular alterations could not be found in small cell NEC.…”

Section: Molecular Profiling In Ep-necmentioning

confidence: 91%

Extrapulmonary poorly differentiated NECs, including molecular and immune aspects

McNamara

Scoazec

Walter

2020

Endocrine-Related Cancer

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Patients with extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PD-NECs) have a poor prognosis. Surgery is offered for those with localised disease, but the majority of patients present with advanced disease. Treatment strategies adopted are analogous to that of high grade NECs of the lung, with platinum/etoposide-based regimens advocated in the first-line setting for advanced disease. There is no standard second-line therapy. Research into their molecular and immune pathways may pave the way for novel drug discovery. The molecular drivers of NEC are best identified in small cell lung carcinoma, which present with near universal genomic alterations in TP53 and RB1. The genetics of EP-PD-NEC remain poorly understood; TP53, KRAS, PIK3CA/PTEN and BRAF mutations have been identified, with alterations in the BRCA pathway reported additionally in small cell NEC of the cervix and absence of argininosuccinate synthetase 1 expression in NEC of the urinary bladder. The use of cell lines and patient-derived xenografts (PDX) to predict response to treatment in NEC and the emergence of alternative biomarkers, such as circulating tumour cells and cell-free DNA, will also be explored. Despite limited published data on the immune microenvironment of EP-NEC, there are a number of clinical trials investigating the use of immune-targeted agents in this disease category, with conflicting emerging data from studies thus far. This review will summarise the treatment and available molecular and immune data in this under researched diagnosis and may stimulate the direction of future exploratory studies.

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“…Limited genetic studies have been performed on a small number of salivary high-grade NECs. We previously performed next-generation sequencing of 151 cancer-related genes in 4 high-grade salivary NECs (3 small cell and 1 large cell type) [29]. Retinoblastoma (RB1) deletions were found in 2 of 3 small cell carcinomas and the 1 large cell NEC with loss of retinoblastoma protein (pRB) expression in all 4 cases ( Fig.…”

Section: Molecular Geneticsmentioning

confidence: 99%

“…Retinoblastoma (RB1) deletions were found in 2 of 3 small cell carcinomas and the 1 large cell NEC with loss of retinoblastoma protein (pRB) expression in all 4 cases ( Fig. 3) [29]. Other common genetic Review of the literature yields only two additional molecular studies.…”

Section: Molecular Geneticsmentioning

confidence: 99%

Proceedings of the NASHNP Companion Meeting, March 18th, 2018, Vancouver, BC, Canada: Salivary Neuroendocrine Carcinoma—An Overview of a Rare Disease with an Emphasis on Determining Tumor Origin

Chernock

Duncavage

2018

Head and Neck Pathol

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Salivary neuroendocrine carcinomas are rare and the overwhelming majority is high-grade. The parotid gland is the most commonly involved site followed by the submandibular gland. Most arise de novo but rare examples occurring as a high-grade transformation of another type of salivary gland neoplasm exist. There is significant morphologic and immunophenotypic overlap with neuroendocrine carcinomas of other sites, especially the skin. Like cutaneous neuroendocrine (or Merkel cell) carcinomas, approximately three-fourths are cytokeratin 20 positive. Cytokeratin 20 positive salivary neuroendocrine carcinomas are often referred to as being of the 'Merkel cell type' since most other non-cutaneous neuroendocrine carcinomas are cytokeratin 20 negative. Salivary neuroendocrine carcinomas may be challenging to separate from Merkel cell carcinomas of the head and neck on pathologic grounds because the latter often metastasize to the parotid gland. Clinical history is often relied upon to separate primary salivary tumors from cutaneous metastases but may not be helpful in all cases. Here we review the clinical, pathologic and molecular features of salivary neuroendocrine carcinomas focusing on high-grade major salivary gland tumors. The difficulty in separating salivary tumors from metastatic Merkel cell carcinoma will be highlighted.

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Next-generation sequencing of salivary high-grade neuroendocrine carcinomas identifies alterations in RB1 and the mTOR pathway

Cited by 12 publications

References 39 publications

Somatic Variants in the Human Lens Epithelium: A Preliminary Assessment

Somatic Variants in the Human Lens Epithelium: A Preliminary Assessment

Extrapulmonary poorly differentiated NECs, including molecular and immune aspects

Proceedings of the NASHNP Companion Meeting, March 18th, 2018, Vancouver, BC, Canada: Salivary Neuroendocrine Carcinoma—An Overview of a Rare Disease with an Emphasis on Determining Tumor Origin

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