Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

Rettig, Eleni M.; Talbot, C. Conover; Sausen, Mark; Jones, Siân; Bishop, Justin A.; Wood, Laura D.; Tokheim, Collin; Niknafs, Noushin; Karchin, Rachel; Fertig, Elana J.; Wheelan, Sarah J.; Marchionni, Luigi; Considine, Michael; Fakhry, Carole; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Ha, Patrick K.; Agrawal, Nishant

doi:10.1158/1940-6207.capr-15-0316

Cited by 88 publications

(82 citation statements)

References 48 publications

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“…In addition to the PRKD2 rearrangement, the recurrent PAC RS3T also harboured a clonal NOTCH2 Q2409* truncating mutation and a MEF2B P315Qfs* frameshift mutation (Figure A; Table ). Mutations affecting genes of the Notch signalling pathway have been described in salivary gland cancers, particularly in adenoid cystic carcinoma . Consistent with the previously described paucity of gene CNAs in PACs, the gene copy number analysis performed here did not reveal complex patterns of CNAs or any recurrent CNA, despite the fact that all PACs analysed here were of high grade histologically (Figure ).…”

Section: Resultssupporting

confidence: 90%

Genomic analysis of recurrences and high‐grade forms of polymorphous adenocarcinoma

et al. 2019

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Aims Polymorphous adenocarcinoma (PAC) usually follows an indolent course, but some cases may show recurrences and high‐grade features. The genetic events associated with recurrences and high‐grade versions are yet to be defined. Our aim was to determine the genetic underpinning of recurrent PACs of the salivary gland and the repertoire of somatic genetic alterations in cases with high‐grade histology. Methods and results Four PACs from three patients, including one case with matching primary and recurrent tumours, one de‐novo high‐grade PAC, and a PAC that transformed to a high‐grade tumour following multiple recurrences, were subjected to targeted sequencing (Memorial Sloan Kettering Mutation Profiling of Actionable Cancer Targets assay) or whole‐exome sequencing. Both matching primary and recurrent tumours, and the de‐novo high‐grade PAC, harboured clonal PRKD1 E710D hotspot mutations, whereas the PAC that underwent high‐grade transformation upon recurrence, which was wild‐type for PRKD1, harboured a PRKD2 rearrangement. The PACs analysed here also harboured mutations targeting cancer genes such as PIK3CA, SETD2, ARID1A, and NOTCH2. A clonal decomposition analysis of the matching primary and recurrent PACs revealed that a minor subclone from the primary tumour became dominant in the recurrent tumour following a clonal selection evolutionary pattern. Conclusions Our findings demonstrate that recurrent and high‐grade PACs are underpinned by PRKD1 E710D hotspot mutations or PRKD2 rearrangements, and that recurrences of PACs may stem from the selection of pre‐existing subclones in the primary tumour.

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Section: Resultssupporting

confidence: 90%

Genomic analysis of recurrences and high‐grade forms of polymorphous adenocarcinoma

et al. 2019

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“…Of the 14 tumors with diffuse NICD1 positivity, we found that 11 harbored sequence variants within NOTCH1 mutational hotspots (exons 25-28, exon 34) that are predicted to produce NOTCH1 gain-of-function. The observed frequency of NOTCH1 mutations in ACCs from different patients that are diffusely positive for NICD1 (8 of 11 tumors, or 73%) is substantially higher than the frequency of NOTCH1 mutations that has been observed in NGS studies on unselected ACCs (7–11). By contrast, none of the 15 tumors with subset positivity for NICD1 had NOTCH1 mutations, a frequency significantly lower than that observed in ACCs with diffuse NICD1 positivity (p < 0.001, Fisher exact test).…”

Section: Resultsmentioning

confidence: 61%

“…The sets the stage for a second cleavage carried out by gamma-secretase, which allows the intracellular portion of Notch to translocate to the nucleus and turn on Notch target genes. Genes encoding Notch receptor and other components of the Notch pathway are recurrently mutated in many cancers, including ACC (7–11). We recently noted in a small series of primary ACCs and patient-derived xenograft (PDX) models that epithelial differentiation in ACC is associated with activation of NOTCH1 (12–14), as assessed by immunohistochemical staining with a rabbit monoclonal antibody specific for a neoepitope located at the N-terminus of the NOTCH1 intracellular domain (NICD1) that is created when NOTCH1 is activated by gamma-secretase cleavage (15).…”

Section: Introductionmentioning

confidence: 99%

Diffuse Staining for Activated NOTCH1 Correlates With NOTCH1 Mutation Status and Is Associated With Worse Outcome in Adenoid Cystic Carcinoma

Sajed

Faquin

Carey

et al. 2017

American Journal of Surgical Pathology

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NOTCH1 is frequently mutated in adenoid cystic carcinoma (ACC). To test the idea that immunohistochemical staining (IHC) can identify ACCs with NOTCH1 mutations, we performed IHC for activated NOTCH1 (NICD1) in 197 cases diagnosed as ACC from 173 patients. NICD1 staining was positive in 194 cases (98%) in two major patterns: subset positivity, which correlated with tubular/cribriform histology; and diffuse positivity, which correlated with a solid histology. To determine the relationship between NICD1 staining and NOTCH1 mutational status, targeted exome sequencing data was obtained on 14 diffusely NICD1-positive ACC specimens from 11 patients and 15 subset NICD1-positive ACC specimens from 15 patients. This revealed NOTCH1 gain-of-function mutations in 11 of 14 diffusely NICD1-positive ACC specimens, whereas all subset-positive tumors had wild type NOTCH1 alleles. Notably, tumors with diffuse NICD1 positivity were associated with significantly worse outcomes (p=0.003). To determine if NOTCH1 activation is unique among tumors included in the differential diagnosis with ACC, we performed NICD1 IHC on a cohort of diverse salivary gland and head and neck tumors. High fractions of each of these tumor types were positive for NICD1 in a subset of cells, particularly in basaloid squamous cell carcinomas; however, sequencing of basaloid squamous cell carcinomas failed to identify NOTCH1 mutations. These findings indicate that diffuse NICD1 positivity in ACC correlates with solid growth pattern, the presence of NOTCH1 gain of function mutations, and unfavorable outcome, and suggest that staining for NICD1 can be helpful in distinguishing ACC with solid growth patterns from other salivary gland and head and neck tumors.

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“…Chromosomal translocations resulting in gene fusions and mutations in known cancer pathways appear to be of particular importance in several tumors of salivary origin. In adenoid cystic carcinoma, for example, the t(6;9) translocation resulting in the MYB-NFIB fusion product is well-described, and two recent next-generation sequencing studies found alterations in chromatin regulation and Notch signaling pathways(43, 44). The significance of the MECT1-MAML2 translocation and of TP53 mutation demonstrated here in MEC is therefore consistent with findings in other salivary tumors.…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing of Salivary Gland Mucoepidermoid Carcinoma

Kang

Tan

Bishop

et al. 2017

Clinical Cancer Research

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Purpose-Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. To explore the genetic origins of MEC, we performed systematic genomic analyses of these tumors.Experimental Design-Whole-exome sequencing and gene copy number analyses were performed for 18 primary cancers with matched normal tissue. Fluorescence in situ hybridization (FISH) was used to determine the presence or absence of the MECT1-MAML2 translocation in 17 tumors.Results-TP53 was the most commonly mutated gene in MEC (28%), and mutations were found only in intermediate-and high-grade tumors. Tumors with TP53 mutations had more mutations overall than tumors without TP53 mutations (p=0.006). POU6F2 was the second most frequently mutated gene, found in three low-grade MECs with the same in-frame deletion. Somatic alterations in IRAK1, MAP3K9, ITGAL, ERBB4, OTOGL, KMT2C, and OBSCN were identified in at least two of the 18 tumors sequenced. FISH analysis confirmed the presence of the MECT1-MAML2 translocation in 15 of 17 tumors (88%).Conclusions-Through these integrated genomic analyses, MECT1-MAML2 translocation and somatic TP53 and POU6F2 mutations appear to be the main drivers of mucoepidermoid carcinoma.

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Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

Cited by 88 publications

References 48 publications

Genomic analysis of recurrences and high‐grade forms of polymorphous adenocarcinoma

Genomic analysis of recurrences and high‐grade forms of polymorphous adenocarcinoma

Diffuse Staining for Activated NOTCH1 Correlates With NOTCH1 Mutation Status and Is Associated With Worse Outcome in Adenoid Cystic Carcinoma

Whole-Exome Sequencing of Salivary Gland Mucoepidermoid Carcinoma

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