The Sol Goldman Pancreatic Cancer Research Center

Baltimore, MD, United States

The Sol Goldman Pancreatic Cancer Research Center

Baltimore, MD, United States

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Scrimieri F.,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Calhoun E.S.,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Calhoun E.S.,Alma College | Patel K.,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | And 4 more authors.
Oncotarget | Year: 2011

We found FAM190A transcripts to have internal rearrangements in 40% (19/48) of unselected human cancers. Most of these tumors (84%) had in-frame structures, 94% of which involved deletion of exon 9. The FAM190A gene is located at 4q22.1 in a region of common fragility, FRA4F. Although normally stable in somatic cells, common fragile sites can be hotspots of rearrangement in cancer. The genomic deletion patterns observed at some sites, including FRA4F at 4q22.1, are proposed to be the result of selection for disrupted tumor-suppressor genes. Our evidence, however, indicated additional patterns for FAM190A. We found genomic deletions accounted for some FAM190A in-frame structures, and cases pre-selected for FAM190A genomic deletions had a yet higher prevalence of FAM190A rearrangements. Our evidence of widespread in-frame heterozygous and homozygous rearrangements affecting this gene in tumors of multiple types leads speculation on structural grounds that the mutant forms may retain, provide new, or possibly convey dominant-negative functions. Although a functionally uncharacterized gene, it is evolutionary conserved across vertebrates. In addition to its potential oncogenic role, the in-frame deletions predict the formation of cancer-specific FAM190A peptide sequences (neo-antigens) with potential diagnostic and therapeutic usefulness. © Scrimieri et al.


PubMed | Johns Hopkins University and The Sol Goldman Pancreatic Cancer Research Center
Type: Journal Article | Journal: Cancer biology & therapy | Year: 2016

Despite advances in sequencing, structural variants (SVs) remain difficult to reliably detect due to the short read length (<300bp) of 2nd generation sequencing. Not only do the reads (or paired-end reads) need to straddle a breakpoint, but repetitive elements often lead to ambiguities in the alignment of short reads. We propose to use the long-reads (up to 20kb) possible with 3rd generation sequencing, specifically nanopore sequencing on the MinION. Nanopore sequencing relies on a similar concept to a Coulter counter, reading the DNA sequence from the change in electrical current resulting from a DNA strand being forced through a nanometer-sized pore embedded in a membrane. Though nanopore sequencing currently has a relatively high mismatch rate that precludes base substitution and small frameshift mutation detection, its accuracy is sufficient for SV detection because of its long reads. In fact, long reads in some cases may improve SV detection efficiency. We have tested nanopore sequencing to detect a series of well-characterized SVs, including large deletions, inversions, and translocations that inactivate the CDKN2A/p16 and SMAD4/DPC4 tumor suppressor genes in pancreatic cancer. Using PCR amplicon mixes, we have demonstrated that nanopore sequencing can detect large deletions, translocations and inversions at dilutions as low as 1:100, with as few as 500 reads per sample. Given the speed, small footprint, and low capital cost, nanopore sequencing could become the ideal tool for the low-level detection of cancer-associated SVs needed for molecular relapse, early detection, or therapeutic monitoring.


Norris A.L.,The Sol Goldman Pancreatic Cancer Research Center | Kamiyama H.,The Sol Goldman Pancreatic Cancer Research Center | Makohon-Moore A.,The Sol Goldman Pancreatic Cancer Research Center | Pallavajjala A.,The Sol Goldman Pancreatic Cancer Research Center | And 9 more authors.
Genes Chromosomes and Cancer | Year: 2015

Pancreatic ductal adenocarcinoma (PDAC) is driven by the inactivation of the tumor suppressor genes (TSGs), CDKN2A (P16) and SMAD4 (DPC4), commonly by homozygous deletions (HDs). Using a combination of high density single-nucleotide polymorphism (SNP) microarray and whole genome sequencing (WGS), we fine-mapped novel breakpoints surrounding deletions of CDKN2A and SMAD4 and characterized them by their underlying structural variants (SVs). Only one third of CDKN2A and SMAD4 deletions (6 of 18) were simple interstitial deletions, rather, the majority of deletions were caused by complex rearrangements, specifically, a translocation on one side of the TSG in combination with an inversion on the other side. We designate these as "TransFlip" mutations. Characteristics of TransFlip mutations are: (1) a propensity to target the TSGs CDKN2A and SMAD4 (P<0.005), (2) not present in the germline of the examined samples, (3) non-recurrent breakpoints, (4) relatively small (47 bp to 3.4 kb) inversions, (5) inversions can be either telomeric or centromeric to the TSG, and (6) non-reciprocal, and non-recurrent translocations. TransFlip mutations are novel complex genomic rearrangements with unique breakpoint signatures in pancreatic cancer. We hypothesize that they are a common but poorly understood mechanism of TSG inactivation in human cancer. © 2015 Wiley Periodicals, Inc.


PubMed | The Sol Goldman Pancreatic Cancer Research Center
Type: | Journal: Genes, chromosomes & cancer | Year: 2015

Pancreatic ductal adenocarcinoma (PDAC) is driven by the inactivation of the tumor suppressor genes (TSGs), CDKN2A (P16) and SMAD4 (DPC4), commonly by homozygous deletions (HDs). Using a combination of high density single-nucleotide polymorphism (SNP) microarray and whole genome sequencing (WGS), we fine-mapped novel breakpoints surrounding deletions of CDKN2A and SMAD4 and characterized them by their underlying structural variants (SVs). Only one third of CDKN2A and SMAD4 deletions (6 of 18) were simple interstitial deletions, rather, the majority of deletions were caused by complex rearrangements, specifically, a translocation on one side of the TSG in combination with an inversion on the other side. We designate these as TransFlip mutations. Characteristics of TransFlip mutations are: (1) a propensity to target the TSGs CDKN2A and SMAD4 (P<0.005), (2) not present in the germline of the examined samples, (3) non-recurrent breakpoints, (4) relatively small (47 bp to 3.4 kb) inversions, (5) inversions can be either telomeric or centromeric to the TSG, and (6) non-reciprocal, and non-recurrent translocations. TransFlip mutations are novel complex genomic rearrangements with unique breakpoint signatures in pancreatic cancer. We hypothesize that they are a common but poorly understood mechanism of TSG inactivation in human cancer. 2015 Wiley Periodicals, Inc.


PubMed | The Sol Goldman Pancreatic Cancer Research Center
Type: | Journal: Acta cytologica | Year: 2016

Pancreatic serous cystadenomas (SCAs) are benign tumors. Technological advances in imaging have led to increased recognition of asymptomatic pancreatic cysts, consequently increasing the demand for cytomorphologic evaluations of cyst fluid.A retrospective search through the pathology archives over an 11-year period was performed to identify SCAs from pancreatectomy specimens with a presurgical pancreatic EUS-guided fine-needle aspiration (FNA).Fifty-one FNAs were identified. The average patient age was 59.9 years and 34 (67%) were female. Thirty-five (69%) of the SCAs were located in the body or tail of the pancreas. SCAs ranged in size from 1.3 to 8.0 cm (mean 4.9). On imaging, features suggestive of SCA were seen in 7 (14%) cases. The cytologic diagnoses were as follows: SCA in 5 (10%) cases, suspicious for mucin-producing neoplastic cyst in 4 (8%), pseudocyst in 4 (8%), and benign ductal and/or acinar epithelium, not otherwise specified in 24 (47%). Additionally, 14 (27%) cases were deemed nondiagnostic.A cytopathologic diagnosis of SCA on FNA is extremely difficult. The salient cytomorphologic features for identifying SCAs included scant cellularity, a mostly clear background, absence of extracellular mucin, hemosiderin-laden macrophages, and loose fragments of cuboidal cells with a notable absence of necrosis, atypia, and mitoses.

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