Publications by authors named "Dean C Pavlick"

22 Publications

  • Page 1 of 1

FoundationOne CDx testing accurately determines whole arm 1p19q codeletion status in gliomas.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab017. Epub 2021 Feb 4.

Foundation Medicine, Inc., Cambridge, Massachusetts and Morrisville, North Carolina.

Background: Molecular profiling of gliomas is vital to ensure diagnostic accuracy, inform prognosis, and identify clinical trial options for primary and recurrent tumors. This study aimed to determine the accuracy of reporting the whole arm 1p19q codeletion status from the FoundationOne platform.

Methods: Testing was performed on glioma samples as part of clinical care and analyzed up to 395 cancer-associated genes (including ). The whole arm 1p19q codeletion status was predicted from the same assay using a custom research-use only algorithm, which was validated using 463 glioma samples with available fluorescence in-situ hybridization (FISH) data. For 519 patients with available outcomes data, progression-free and overall survival were assessed based on whole arm 1p19q codeletion status derived from sequencing data.

Results: Concordance between 1p19q status based on FISH and our algorithm was 96.7% (449/463) with a positive predictive value (PPV) of 100% and a positive percent agreement (PPA) of 91.0%. All discordant samples were positive for codeletion by FISH and harbored genomic alterations inconsistent with oligodendrogliomas. Median overall survival was 168 months for the mutant, codeleted group, and 122 months for mutant-only (hazard ratio (HR): 0.42; < .05).

Conclusions: 1p19q codeletion status derived from FoundationOne testing is highly concordant with FISH results. Genomic profiling may be a reliable substitute for traditional FISH testing while also providing status.
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http://dx.doi.org/10.1093/noajnl/vdab017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986056PMC
February 2021

Revealing the BRD4-NOTCH3 fusion: A novel hill in the cancer landscape.

Lung Cancer 2021 Apr 17;154:146-150. Epub 2021 Feb 17.

Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Hospital Sírio-Libanês, São Paulo, Brazil.

Objectives: Gene fusions are becoming more evident in cancer scenario for either being the driver alterations, or for the great therapeutic target potential in many cases. Our aim was to characterize the BRD4-NOTCH3 fusion correlating with clinical features, and to determine the frequency of this fusion in the oncological population.

Material And Methods: One patient diagnosed with lung adenocarcinoma at Hospital Sírio-Libanês (Brazil) was included. Foundation Medicine database was searched for all BRD4-NOTCH3 fusions among 233,804 specimens.

Results: A 76-year-old male patient was diagnosed with lung adenocarcinoma. Molecular assessments demonstrated negative ALK and EGFR, with PD-L1 expression positive by 60 %. He was treated with first line chemotherapy and second line immunotherapy. Subsequent treatments resume re-exposures to chemotherapy with poor responses. A next-generation sequencing (NGS) based assay was performed in the tumor biopsy, revealing mainly mutation in STK11, microsatellite stability, TMB-intermediate, MYC amplification and a BRD4-NOTCH3 fusion. The breakpoint analysis of this fusion indicates that BRD4 active domains are preserved, suggesting that it maintained DNA binding activity, as well as its capacity to be halt by BET inhibitors. Foundation Medicine database was searched for all BRD4-NOTCH3 fusions among more than 230-thousand specimens and it was found in 87 new cases in a rate of 0.04 % occurrence in solid tumors, predominately in gynecological cancers. The same rate was found when we analyzed a different dataset.

Conclusion: In conclusion, this is the first report of the BRD4-NOTCH3 gene fusion associated with clinical characterization and, although rare, the occurrence of this fusion is constant in different population. Our data suggest that this fusion has great potential to targeted-therapy.
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http://dx.doi.org/10.1016/j.lungcan.2021.02.016DOI Listing
April 2021

Structure-function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting.

Nat Commun 2021 03 2;12(1):1382. Epub 2021 Mar 2.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Mechanistic understanding of oncogenic variants facilitates the development and optimization of treatment strategies. We recently identified in-frame, tandem duplication of EGFR exons 18 - 25, which causes EGFR Kinase Domain Duplication (EGFR-KDD). Here, we characterize the prevalence of ERBB family KDDs across multiple human cancers and evaluate the functional biochemistry of EGFR-KDD as it relates to pathogenesis and potential therapeutic intervention. We provide computational and experimental evidence that EGFR-KDD functions by forming asymmetric EGF-independent intra-molecular and EGF-dependent inter-molecular dimers. Time-resolved fluorescence microscopy and co-immunoprecipitation reveals EGFR-KDD can form ligand-dependent inter-molecular homo- and hetero-dimers/multimers. Furthermore, we show that inhibition of EGFR-KDD activity is maximally achieved by blocking both intra- and inter-molecular dimerization. Collectively, our findings define a previously unrecognized model of EGFR dimerization, providing important insights for the understanding of EGFR activation mechanisms and informing personalized treatment of patients with tumors harboring EGFR-KDD. Finally, we establish ERBB KDDs as recurrent oncogenic events in multiple cancers.
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http://dx.doi.org/10.1038/s41467-021-21613-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925532PMC
March 2021

Somatic HLA Class I Loss Is a Widespread Mechanism of Immune Evasion Which Refines the Use of Tumor Mutational Burden as a Biomarker of Checkpoint Inhibitor Response.

Cancer Discov 2021 Feb 30;11(2):282-292. Epub 2020 Oct 30.

Foundation Medicine, Inc., Cambridge, Massachusetts.

Neoantigen presentation arises as a result of tumor-specific mutations and is a critical component of immune surveillance that can be abrogated by somatic LOH of the human leukocyte antigen class I (HLA-I) locus. To understand the role of HLA-I LOH in oncogenesis and treatment, we utilized a pan-cancer genomic dataset of 83,644 patient samples, a small subset of which had treatment outcomes with immune checkpoint inhibitors (ICI). HLA-I LOH was common (17%) and unexpectedly had a nonlinear relationship with tumor mutational burden (TMB). HLA-I LOH was frequent at intermediate TMB, yet prevalence decreased above 30 mutations/megabase, suggesting highly mutated tumors require alternate immune evasion mechanisms. In ICI-treated patients with nonsquamous non-small cell lung cancer, HLA-I LOH was a significant negative predictor of overall survival. Survival prediction improved when combined with TMB, suggesting TMB with HLA-I LOH may better identify patients likely to benefit from ICIs. SIGNIFICANCE: This work shows the pan-cancer landscape of HLA-I LOH, revealing an unexpected "Goldilocks" relationship between HLA-I LOH and TMB, and demonstrates HLA-I LOH as a significant negative predictor of outcomes after ICI treatment. These data informed a combined predictor of outcomes after ICI and have implications for tumor vaccine development..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0672DOI Listing
February 2021

-Null Leiomyosarcoma: A Novel, Genomically Distinct Class of /-Wild-Type Tumor With Frequent Genomic Alterations and 1p/19q-Codeletion.

JCO Precis Oncol 2020 1;4. Epub 2020 Sep 1.

Foundation Medicine, Cambridge, MA.

Purpose: Leiomyosarcoma (LMS) harbors frequent mutations in and but few actionable genomic alterations. Here, we searched for recurrent actionable genomic alterations in LMS that occur in the absence of common untreatable oncogenic drivers.

Methods: Tissues from 276,645 unique advanced cancers, including 2,570 uterine and soft tissue LMS, were sequenced by hybrid-capture-based next-generation DNA and RNA sequencing/comprehensive genomic profiling of up to 406 genes. We characterized clinicopathologic features of relevant patient cases.

Results: Overall, 77 LMS exhibited homozygous copy loss of at chromosome 1p32.3 (3.0% of LMS). Genomic alterations (GAs) in , , and were rare compared with the remainder of the LMS cohort (11.7% 73.4%, 0% 54.5%, 2.6% 24.5%, respectively; all < .0001). -null LMS patient cases were significantly enriched for GAs in (40.3% 1.4%) at 19q13.2, (46.8% 7.0%), and (16.9% 1.7%; all < .0001). Chromosome arm-level aneuploidy analysis of available LMS patient cases (n = 1,284) found that 81% (58 of 72) of -null LMS exhibited 1p/19q-codeletion, a significant enrichment compared with 5.1% in the remainder of the LMS cohort ( < .0001). In total, 99% of -null LMS were in women; the median age was 61 years at surgery (range, 36-81 years). Fifty-five patient cases were uterine primary, four were nonuterine, and the remaining 18 were of uncertain primary site. Sixty percent of cases showed at least focal epithelioid variant histology. Most patients had advanced-stage disease, with 62% of confirmed uterine primary LMS at International Federation of Gynecology and Obstetrics stage IVB. We further validated our findings in two publicly available datasets: The Cancer Genome Atlas and the Project GENIE initiative.

Conclusion: -null LMS defines a genomically distinct tumor that may have prognostic and/or therapeutic clinical implications, including possible use of specific cyclin-dependent kinase inhibitors.
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http://dx.doi.org/10.1200/PO.20.00040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529542PMC
September 2020

PIK3CA C-terminal frameshift mutations are novel oncogenic events that sensitize tumors to PI3K-α inhibition.

Proc Natl Acad Sci U S A 2020 09 14;117(39):24427-24433. Epub 2020 Sep 14.

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;

hotspot mutation is well established as an oncogenic driver event in cancer and its durable and efficacious inhibition is a focus in the development and testing of clinical cancer therapeutics. However, hundreds of cancer-associated mutations remain uncharacterized, their sensitivity to PI3K inhibitors unknown. Here, we describe a series of C-terminal mutations, primarily nucleotide insertions, that produce a frame-shifted protein product with an extended C terminus. We report that these mutations occur at a low frequency across multiple cancer subtypes, including breast, and are sufficient to drive oncogenic transformation in vitro and in vivo. We demonstrate that the oncogenicity of these mutant p110α proteins is dependent on p85 but not Ras association. P110α-selective pharmacologic inhibition blocks transformation in cells and mammary tumors characterized by C-terminal mutation. Taken together, these results suggest patients with breast and other tumors characterized by C-terminal frameshift mutations may derive benefit from p110α-selective inhibitors, including the recently FDA-approved alpelisib.
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http://dx.doi.org/10.1073/pnas.2000060117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533832PMC
September 2020

Vulvar Squamous Cell Carcinoma: Comprehensive Genomic Profiling of HPV+ Versus HPV- Forms Reveals Distinct Sets of Potentially Actionable Molecular Targets.

JCO Precis Oncol 2020 16;4. Epub 2020 Jun 16.

Foundation Medicine, Cambridge, MA.

Purpose: Vulvar squamous cell carcinoma (vSCC) encompasses two predominant variants: one associated with detectable high-risk strains of human papillomavirus (hrHPV) and a second form often occurring in the context of chronic dermatitis in postmenopausal women. Genomic assessment of a large-scale cohort of patients with aggressive vSCC may identify distinct mutational signatures.

Materials And Methods: Tumor samples from a total of 280 patients with vSCC underwent hybridization capture with analysis of up to 406 cancer-related genes. Human papillomavirus (HPV) sequences were detected by de novo assembly of nonhuman sequencing reads and aligned to the RefSeq database. Immunohistochemistry for programmed death-ligand 1 (PD-L1) was assessed.

Results: One hundred two of 280 vSCCs (36%) contained hrHPV sequences, predominantly HPV 16 (88%). The HPV-positive (HPV+) group was significantly younger (median age, 59 64 years; = .001). Compared with HPV-negative (HPV-) vSCCs, HPV+ tumors showed more frequent pathogenic alterations in (31% 16%; = .004), (14% 2%; < .0001), (14% 1%; < .0001), (14% 1%; < .0001), (5% 0%; = .006), and (10% 3%; = .03). In contrast, HPV- vSCCs showed more alterations in (83% 6%; < .0001), (71% 9%; < .0001), (55% 2%; < .0001), amplification (22% 2%; < .0001), (25% 4%; < .0001), (19% 6%; = .002), and amplification (11% 0%; < .0001), as well as a higher rate of 9p24.1 ( amplification (5% 1%) and PD-L1 immunohistochemistry high-positive tumor staining (33% 9%; = .04).

Conclusion: Comprehensive molecular profiles of vSCC vary considerably with hrHPV status and may inform patient selection into clinical trials. Sixty-one percent of HPV+ vSCCs had a pathogenic alteration in the PI3K/mTOR pathway, whereas HPV- vSCCs showed alterations in , , , , and , and biomarkers associated with responsiveness to immunotherapy.
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http://dx.doi.org/10.1200/PO.19.00406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446361PMC
June 2020

An ErbB2 splice variant lacking exon 16 drives lung carcinoma.

Proc Natl Acad Sci U S A 2020 08 29;117(33):20139-20148. Epub 2020 Jul 29.

Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada;

Lung cancer causes more deaths annually than any other malignancy. A subset of non-small cell lung cancer (NSCLC) is driven by amplification and overexpression or activating mutation of the receptor tyrosine kinase (RTK) In some contexts, notably breast cancer, alternative splicing of causes skipping of exon 16, leading to the expression of an oncogenic ERBB2 isoform (ERBB2ΔEx16) that forms constitutively active homodimers. However, the broader implications of alternative splicing in human cancers have not been explored. Here, we have used genomic and transcriptomic analysis to identify elevated expression in a subset of NSCLC cases, as well as splicing site mutations facilitating exon 16 skipping and deletions of exon 16 in a subset of these lung tumors and in a number of other carcinomas. Supporting the potential of ERBB2ΔEx16 as a lung cancer driver, its expression transformed immortalized lung epithelial cells while a transgenic model featuring inducible ERBB2ΔEx16 specifically in the lung epithelium rapidly developed lung adenocarcinomas following transgene induction. Collectively, these observations indicate that is a lung cancer oncogene with potential clinical importance for a proportion of patients.
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http://dx.doi.org/10.1073/pnas.2007474117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443881PMC
August 2020

Clinical, histopathologic, and molecular profiles of PRKAR1A-inactivated melanocytic neoplasms.

J Am Acad Dermatol 2021 Apr 16;84(4):1069-1071. Epub 2020 Jul 16.

Foundation Medicine, Inc, Cambridge, Massachusetts; Department of Pathology and Laboratory Medicine, Tufts University School of Medicine, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.jaad.2020.07.050DOI Listing
April 2021

Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer: Preplanned Secondary Analysis of the BRE12-158 Randomized Clinical Trial.

JAMA Oncol 2020 09;6(9):1410-1415

Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis.

Importance: A significant proportion of patients with early-stage triple-negative breast cancer (TNBC) are treated with neoadjuvant chemotherapy. Sequencing of circulating tumor DNA (ctDNA) after surgery, along with enumeration of circulating tumor cells (CTCs), may be used to detect minimal residual disease and assess which patients may experience disease recurrence.

Objective: To determine whether the presence of ctDNA and CTCs after neoadjuvant chemotherapy in patients with early-stage TNBC is independently associated with recurrence and clinical outcomes.

Design, Setting, And Participants: A preplanned secondary analysis was conducted from March 26, 2014, to December 18, 2018, using data from 196 female patients in BRE12-158, a phase 2 multicenter randomized clinical trial that randomized patients with early-stage TNBC who had residual disease after neoadjuvant chemotherapy to receive postneoadjuvant genomically directed therapy vs treatment of physician choice. Patients had blood samples collected for ctDNA and CTCs at time of treatment assignment; ctDNA analysis with survival was performed for 142 patients, and CTC analysis with survival was performed for 123 patients. Median clinical follow-up was 17.2 months (range, 0.3-58.3 months).

Interventions: Circulating tumor DNA was sequenced using the FoundationACT or FoundationOneLiquid Assay, and CTCs were enumerated using an epithelial cell adhesion molecule-based, positive-selection microfluidic device.

Main Outcomes And Measures: Primary outcomes were distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS).

Results: Among 196 female patients (mean [SD] age, 49.6 [11.1] years), detection of ctDNA was significantly associated with inferior DDFS (median DDFS, 32.5 months vs not reached; hazard ratio [HR], 2.99; 95% CI, 1.38-6.48; P = .006). At 24 months, DDFS probability was 56% for ctDNA-positive patients compared with 81% for ctDNA-negative patients. Detection of ctDNA was similarly associated with inferior DFS (HR, 2.67; 95% CI, 1.28-5.57; P = .009) and inferior OS (HR, 4.16; 95% CI,1.66-10.42; P = .002). The combination of ctDNA and CTCs provided additional information for increased sensitivity and discriminatory capacity. Patients who were ctDNA positive and CTC positive had significantly inferior DDFS compared with those who were ctDNA negative and CTC negative (median DDFS, 32.5 months vs not reached; HR, 5.29; 95% CI, 1.50-18.62; P = .009). At 24 months, DDFS probability was 52% for patients who were ctDNA positive and CTC positive compared with 89% for those who were ctDNA negative and CTC negative. Similar trends were observed for DFS (HR, 3.15; 95% CI, 1.07-9.27; P = .04) and OS (HR, 8.60; 95% CI, 1.78-41.47; P = .007).

Conclusions And Relevance: In this preplanned secondary analysis of a randomized clinical trial, detection of ctDNA and CTCs in patients with early-stage TNBC after neoadjuvant chemotherapy was independently associated with disease recurrence, which represents an important stratification factor for future postneoadjuvant trials.

Trial Registration: ClinicalTrials.gov Identifier: NCT02101385.
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http://dx.doi.org/10.1001/jamaoncol.2020.2295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349081PMC
September 2020

Melanoma with in-frame deletion of MAP2K1: a distinct molecular subtype of cutaneous melanoma mutually exclusive from BRAF, NRAS, and NF1 mutations.

Mod Pathol 2020 12 1;33(12):2397-2406. Epub 2020 Jun 1.

Departments of Pathology and Dermatology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.

While the genomics of BRAF, NRAS, and other key genes influencing MAP kinase (MAPK) activity have been thoroughly characterized in melanoma, mutations in MAP2K1 (MEK1) have received significantly less attention and have consisted almost entirely of missense mutations considered secondary oncogenic drivers of melanoma. Here, we investigated melanomas with in-frame deletions of MAP2K1, alterations characterized as MAPK-activating in recent experimental models. Our case archive of clinical melanoma samples with comprehensive genomic profiling by a hybrid capture-based DNA sequencing platform was searched for MAP2K1 genetic alterations. Clinical data, pathology reports, and histopathology were reviewed for each case. From a cohort of 7119 advanced melanomas, 37 unique cases (0.5%) featured small in-frame deletions in MAP2K1. These included E102_I103del (n = 11 cases), P105_A106del (n = 8), Q58_E62del (n = 6), I103_K104del (n = 5), I99_K104del (n = 3), L98_I103del (n = 3), and E41_F53del (n = 1). All 37 were wild type for BRAF, NRAS, and NF1 genomic alterations ("triple wild-type"), representing 2.0% of triple wild-type melanomas overall (37/1882). Median age was 66 years and 49% were male. The majority arose from primary cutaneous sites (35/37; 95%) and demonstrated a UV signature when available (21/25; 84%). Tumor mutational burden was typical for cutaneous melanoma (median = 9.6 mut/Mb, range 0-35.7), and frequently mutated genes included TERTp (63%), CDKN2A (46%), TP53 (11%), PTEN (8%), APC (8%), and CTNNB1 (5%). Histopathology revealed a spectrum of appearances typical of melanoma. For comparison, we evaluated 221 cases with pathogenic missense single nucleotide variants in MAP2K1. The vast majority of melanomas with missense SNVs in MAP2K1 showed co-mutations in BRAF (58%), NF1 (23%), or NRAS (18%). In-frame deletions in MAP2K1, previously shown in experimental models to be strongly MAPK-activating, characterized a significant subset of triple wild-type melanoma (2.0%), suggesting a primary oncogenic role for these mutations. Comprehensive genomic profiling of melanomas enables detection of this alteration, which may have implications for potential therapeutic options.
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http://dx.doi.org/10.1038/s41379-020-0581-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685971PMC
December 2020

CYLD-mutant cylindroma-like basaloid carcinoma of the anus: a genetically and morphologically distinct class of HPV-related anal carcinoma.

Mod Pathol 2020 12 27;33(12):2614-2625. Epub 2020 May 27.

Departments of Pathology and Dermatology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA.

Rare reports of anal carcinoma (AC) describe histologic resemblance to cutaneous cylindroma, but mutations in the tumor suppressor CYLD, the gene responsible for familial and sporadic cylindromas, have not been systematically investigated in AC. Here, we investigate CYLD-mutant AC, focusing on molecular correlates of distinct histopathology. Comprehensive genomic profiling (hybrid-capture-based DNA sequencing) was performed on 574 ACs, of which 75 unique cases (13%) harbored a CYLD mutation. Clinical data, pathology reports, and histopathology were reviewed for each CYLD-mutant case. The spectrum of CYLD mutations included truncating (n = 50; 67%), homozygous deletion (n = 10; 13%), missense (n = 16; 21%), and splice-site (n = 3; 4%) events. Compared with CYLD-wildtype AC (n = 499), CYLD-mutant ACs were significantly enriched for females (88% vs. 67%, p = 0.0001), slightly younger (median age 59 vs. 61 years, p = 0.047), and included near-universal detection of high-risk HPV sequences (97% vs. 88%, p = 0.014), predominantly HPV16 (96%). The CYLD-mutant cohort also showed significantly lower tumor mutational burden (TMB; median 2.6 vs. 5.2 mut/Mb, p < 0.00001) and less frequent alterations in PIK3CA (13% vs. 31%, p = 0.0015). On histopathologic examination, 73% of CYLD-mutant AC (55/75 cases) showed a striking cylindroma-like histomorphology, composed of aggregates of basaloid cells surrounded by thickened basement membranes and containing characteristic hyaline globules, while only 8% of CYLD-wildtype tumors (n = 34/409) contained cylindroma-like hyaline globules (p < 0.0001). CYLD-mutant carcinomas with cylindroma-like histomorphology (n = 55) showed significantly lower TMB compared with CYLD-mutant cases showing basaloid histology without the distinctive hyaline globules (n = 14) (median 1.7 vs. 4.4 mut/Mb, p = 0.0058). Only five CYLD-mutant cases (7%) showed nonbasaloid conventional squamous cell carcinoma histology (median TMB = 5.2 mut/Mb), and a single CYLD-mutant case showed transitional cell carcinoma-like histology. Within our cohort of ACs, CYLD mutations characterize a surprisingly large subset (13%), with distinct clinical and genomic features and, predominantly, a striking cylindroma-like histopathology, representing a genotype-phenotype correlation which may assist in classification of AC.
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http://dx.doi.org/10.1038/s41379-020-0584-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685972PMC
December 2020

Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1-KMT2A-YAP1 and VIM-KMT2A fusions.

Mod Pathol 2020 11 27;33(11):2307-2317. Epub 2020 May 27.

Foundation Medicine, Inc., 150 Second Street, Cambridge, MA, 02141, USA.

Sarcomas are driven by diverse pathogenic mechanisms, including gene rearrangements in a subset of cases. Rare soft tissue sarcomas containing KMT2A fusions have recently been reported, characterized by a predilection for young adults, sclerosing epithelioid fibrosarcoma-like morphology, and an often aggressive course. Nonetheless, clinicopathologic and molecular descriptions of KMT2A-rearranged sarcomas remain limited. In this study, we identified by targeted next-generation RNA sequencing an index patient with KMT2A fusion-positive soft tissue sarcoma. In addition, we systematically searched for KMT2A structural variants in a comprehensive genomic profiling database of 14,680 sarcomas interrogated by targeted next-generation DNA and/or RNA sequencing. We characterized the clinicopathologic and molecular features of KMT2A fusion-positive sarcomas, including KMT2A breakpoints, rearrangement partners, and concurrent genetic alterations. Collectively, we identified a cohort of 34 sarcomas with KMT2A fusions (0.2%), and YAP1 was the predominant partner (n = 16 [47%]). Notably, a complex rearrangement with YAP1 consistent with YAP1-KMT2A-YAP1 fusion was detected in most cases, with preservation of KMT2A CxxC-binding domain in the YAP1-KMT2A-YAP1 fusion and concurrent deletions of corresponding exons in KMT2A. The tumors often affected younger adults (age 20-66 [median 40] years) and histologically showed variably monomorphic epithelioid-to-spindle shaped cells embedded in a dense collagenous stroma. Ultrastructural evidence of fibroblastic differentiation was noted in one tumor examined. Our cohort also included two sarcomas with VIM-KMT2A fusions, each harboring concurrent mutations in CTNNB1, SMARCB1, and ARID1A and characterized histologically by sheets of spindle-to-round blue cells. The remaining 16 KMT2A-rearranged sarcomas in our cohort exhibited diverse histologic subtypes, each with unique novel fusion partners. In summary, KMT2A-fusion-positive sarcomas most commonly exhibit sclerosing epithelioid fibrosarcoma-like morphology and complex YAP1-KMT2A-YAP1 fusions. Cases also include rare spindle-to-round cell sarcomas with VIM-KMT2A fusions and tumors of diverse histologic subtypes with unique KMT2A fusions to non-YAP1 non-VIM partners.
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http://dx.doi.org/10.1038/s41379-020-0582-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581494PMC
November 2020

Frequent inactivating mutations of the PBAF complex gene PBRM1 in meningioma with papillary features.

Acta Neuropathol 2020 07 13;140(1):89-93. Epub 2020 May 13.

Translational Neuro‑Oncology Laboratory, Department of Neurosurgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1007/s00401-020-02161-7DOI Listing
July 2020

Melanomas with activating RAF1 fusions: clinical, histopathologic, and molecular profiles.

Mod Pathol 2020 08 2;33(8):1466-1474. Epub 2020 Mar 2.

Departments of Pathology and Dermatology, Virginia Commonwealth University School of Medicine, 1200 East Marshall Street, Richmond, VA, 23298, USA.

A subset of melanomas is characterized by fusions involving genes that encode kinases. Melanomas with RAF1 fusions have been rarely reported, mostly in clinical literature. To investigate this distinctive group of melanomas, we searched for melanomas with activating structural variants in RAF1, utilizing our case archive of clinical samples with comprehensive genomic profiling (CGP) by a hybrid capture-based DNA sequencing platform. Clinical data, pathology reports, and histopathology were reviewed for each case. RAF1 breakpoints, fusion partners, and co-occurring genetic alterations were characterized. From a cohort of 7119 melanomas, 40 cases (0.6%) featured fusions that created activating structural variants in RAF1. Cases with activating RAF1 fusions had median age of 62 years, were 58% male, and consisted of 9 primary tumors and 31 metastases. Thirty-nine cases were cutaneous primary, while one case was mucosal (anal) primary. Primary cutaneous melanomas showed variable architectures, including wedge-shaped and nodular growth patterns. Cytomorphology was predominantly epithelioid, with only one case, a desmoplastic melanoma, consisting predominantly of spindle cells. RAF1 5' rearrangement partners were predominantly intrachromosomal (n = 18), and recurrent partners included MAP4 (n = 3), CTNNA1 (n = 2), LRCH3 (n = 2), GOLGA4 (n = 2), CTDSPL (n = 2), and PRKAR2A (n = 2), all 5' of the region encoding the kinase domain. RAF1 breakpoints occurred in intron 7 (n = 32), intron 9 (n = 4), intron 5 (n = 2), and intron 6 (n = 2). Ninety-eight percent (n = 39) were wild type for BRAF, NRAS, and NF1 genomic alterations (triple wild type). Activating RAF1 fusions were present in 2.1% of triple wild-type melanomas overall (39/1882). In melanomas with activating RAF1 fusions, frequently mutated genes included TERTp (62%), CDKN2A (60%), TP53 (13%), ARID2 (10%), and PTEN (10%). Activating RAF1 fusions characterize a significant subset of triple wild-type melanoma (2.1%) with frequent accompanying mutations in TERTp and CDKN2A. CGP of melanomas may improve tumor classification and inform potential therapeutic options, such as consideration of specific kinase inhibitors.
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http://dx.doi.org/10.1038/s41379-020-0510-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384985PMC
August 2020

PARP-1 activity (PAR) determines the sensitivity of cervical cancer to olaparib.

Gynecol Oncol 2019 10 18;155(1):144-150. Epub 2019 Aug 18.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:

Objectives: Cervical cancer (CC) remains a major health problem worldwide. Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi) have emerged as a promising class of chemotherapeutics in ovarian cancer. We explored the preclinical in vitro and in vivo activity of olaparib against multiple primary whole exome sequenced (WES) CC cells lines and xenografts.

Methods: Olaparib cell-cycle, apoptosis, homologous-recombination-deficiency (HRD), PARP trapping and cytotoxicity activity was evaluated against 9 primary CC cell lines in vitro. PARP and PAR expression were analyzed by Western blot assays. Finally, olaparib in vivo antitumor activity was tested against CC xenografts.

Results: While none of the cell lines demonstrated HRD, three out of 9 (33.3%) primary CC cell lines showed strong PARylation activity and demonstrated high sensitivity to olaparib in vitro treatment (cutoff IC values < 2 μM, p = 0.0012). Olaparib suppressed CC cell growth through cell cycle arrest in the G2/M phase and caused apoptosis (p < 0.0001). Olaparib activity in CC involved both PARP enzyme inhibition and trapping. In vivo, olaparib significantly impaired CC xenografts tumor growth (p = 0.0017) and increased overall animal survival (p = 0.008).

Conclusions: A subset of CC primary cell lines is highly responsive to olaparib treatment in vitro and in vivo. High level of PARylation correlated with olaparib preclinical activity and may represent a useful biomarker for the identification of CC patients benefitting the most from PARPi.
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http://dx.doi.org/10.1016/j.ygyno.2019.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788971PMC
October 2019

Comprehensive genomic profiling identifies novel NTRK fusions in neuroendocrine tumors.

Oncotarget 2018 Nov 9;9(88):35809-35812. Epub 2018 Nov 9.

Foundation Medicine, Inc. Cambridge, MA, USA.

CGP results from >60,000 cases were screened to identify NTRK fusion events from cases of neuroendocrine tumors. 2417 NET patients from diverse anatomic sites were identified. From this dataset, six cases harbored NTRK fusions which included intra- and inter-chromosomal translocations. A NTRK fusion frequency of approximately 0.3% was found across all subtypes of NETs. Three cases involved translocations of NTRK1 with unique fusion partners (GPATCH4, PIP5K1A, CCDC19). Co-occurring alterations occurred in five cases. NTRK alterations were identified in nearly the full spectrum of NETs, including from the small intestine, pancreas, lung, and others. With the late stage clinical development of NTRK TKIs (including entrectinib and larotrectinib), these findings may further inform targeted approaches to therapy in NET.
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http://dx.doi.org/10.18632/oncotarget.26260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254675PMC
November 2018

Durable Clinical Response to Larotrectinib in an Adolescent Patient With an Undifferentiated Sarcoma Harboring an - Fusion.

JCO Precis Oncol 2018 2;2. Epub 2018 Aug 2.

, , , , and , The University of Texas Southwestern Medical Center; , , , , , , , and , Children's Health, Dallas, TX; , , , , and , Foundation Medicine, Cambridge, MA; and and , Loxo Oncology, South San Francisco, CA.

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http://dx.doi.org/10.1200/PO.18.00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446438PMC
August 2018

Identifying a Clinically Applicable Mutational Burden Threshold as a Potential Biomarker of Response to Immune Checkpoint Therapy in Solid Tumors.

JCO Precis Oncol 2017 7;2017. Epub 2017 Dec 7.

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.

Purpose: An association between mutational burden and response to immune checkpoint therapy has been documented in several cancer types. The potential for such a mutational burden threshold to predict response to immune checkpoint therapy was evaluated in several clinical datasets, where mutational burden was measured either by whole-exome sequencing (WXS) or using commercially available sequencing panels.

Methods: WXS and RNA-seq data of 33 solid cancer types from TCGA were analyzed to determine whether a robust immune checkpoint activating mutation (iCAM) burden threshold associated with evidence of immune checkpoint activation exists in these cancers that may serve as a biomarker for response to immune checkpoint blockade therapy.

Results: We find that a robust iCAM threshold, associated with signatures of immune checkpoint activation, exists in 8 of 33 solid cancers: melanoma, lung adenocarcinoma, colon adenocarcinoma, endometrial cancer, stomach adenocarcinoma, cervical cancer, ER+HER2- breast cancer, and bladder-urothelial cancer. Tumors with mutational burden higher than the threshold (iCAM+) also had clear histologic evidence of lymphocytic infiltration. In published datasets of melanoma, lung adenocarcinoma and colon cancer, patients with iCAM+ tumors had significantly better response to immune checkpoint therapy compared to those with iCAM- tumors. ROC analysis using TCGA predictions as gold standard showed that iCAM+ tumors are accurately identifiable using clinical sequencing assays, such as FoundationOne or StrandAdvantage. Using the FoundationOne derived threshold, analysis of 113 melanoma tumors, showed that iCAM+ patients have significantly better response to immune checkpoint therapy. iCAM+ and iCAM- tumors have distinct mutation patterns and different immune microenvironments.

Conclusion: In 8 solid cancers, a mutational burden threshold exists that may predict response to immune checkpoint blockade. This threshold is identifiable using available clinical sequencing assays.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016848PMC
http://dx.doi.org/10.1200/PO.17.00146DOI Listing
December 2017

Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer.

J Clin Invest 2016 06 9;126(6):2334-40. Epub 2016 May 9.

Antibodies that target the immune checkpoint receptor programmed cell death protein 1 (PD-1) have resulted in prolonged and beneficial responses toward a variety of human cancers. However, anti-PD-1 therapy in some patients provides no benefit and/or results in adverse side effects. The factors that determine whether patients will be drug sensitive or resistant are not fully understood; therefore, genomic assessment of exceptional responders can provide important insight into patient response. Here, we identified a patient with endometrial cancer who had an exceptional response to the anti-PD-1 antibody pembrolizumab. Clinical grade targeted genomic profiling of a pretreatment tumor sample from this individual identified a mutation in DNA polymerase epsilon (POLE) that associated with an ultramutator phenotype. Analysis of The Cancer Genome Atlas (TCGA) revealed that the presence of POLE mutation associates with high mutational burden and elevated expression of several immune checkpoint genes. Together, these data suggest that cancers harboring POLE mutations are good candidates for immune checkpoint inhibitor therapy.
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http://dx.doi.org/10.1172/JCI84940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887167PMC
June 2016