Biology subjects

Makohon-Moore, A. P.

Publications and source records attributed to Makohon-Moore, A. P..

5 recordsLinked to original sources

bioRxiv2021

Pancreatic cancer prognosis is predicted by a novel ATAC-array technology for assessing chromatin accessibility

We investigated tumor-cell-intrinsic chromatin accessibility patterns of pancreatic ductal adenocarcinoma (PDAC) by ATAC-seq on EpCAM+ PDAC malignant epithelial cells, sorted from 54 freshly resected human tumors, and discovered a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identified two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further developed a novel chromatin accessibility microarray methodology termed "ATAC-Array", an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this novel methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validated ATAC-array technology in both the original ATAC-Seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a novel, lowcost, clinically feasible technology for assessing chromatin accessibility profiles.

cancer biology↗

bioRxiv2020

Selection for Decreased BRCA2 Functional Activity in Homo sapiens After Divergence from the Chimpanzee-Human Last Common Ancestor

Humans have an increased incidence of epithelial neoplasia compared to non-human primates. We performed a comparative analysis of 21 non-human primate genomes and 54 ancient human genomes to identify variations in known cancer genes that may explain this difference. We identified 299 human-specific fixed non-silent single nucleotide polymorphisms. Bioinformatics analyses for functional consequences identified a number of variants predicted to have altered protein function, one of which was located at the most evolutionarily conserved domain of human BRCA2. This variant, in which a polar threonine residue replaces a hydrophobic methionine residue to codon 2662 within the DSS1 binding domain, decreases the interactions of BRCA2 with other proteins, specifically the binding of BRCA2 and RAD51, as well as the repairing ability of cells for DNA double-strand breaks. We conclude that a 20% reduction in BRCA2 DNA repair ability was positively selected for in the course of human evolution. One Sentence SummaryReduction of BRCA2 functional activity has been selected for during human evolution since the chimpanzee-human last common ancestor.

evolutionary biology↗

bioRxiv2020

Evolutionary Dynamics of Non-Coding Regions in Pancreatic Ductal Adenocarcinoma

While the non-coding genome appears to play a role, the dynamic nature of noncoding alterations with respect to clonal progression of solid tumors remains unexplored. To address this gap in knowledge we performed multiregional whole genome sequencing and clonal analysis to elucidate the evolutionary dynamics of non-coding regions in pancreatic cancer relative to those of the coding genome. We find that the mutational burden of noncoding DNA is higher than coding DNA. However, when noncoding DNA was segregated into enhancer and non-enhancer regions, enhancers were more similar to coding DNA. Mutational signatures of noncoding and coding DNA further revealed the similar mutational spectra of enhancers to coding DNA whereas the mutational spectra of non-enhancer, noncoding DNA had an entirely different pattern. These findings shed light on the role of noncoding DNA in pancreatic cancer.

cancer biology↗

bioRxiv2019

Evolutionary Origins of Recurrent Pancreatic Cancer

Surgery is the only curative option for Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that adjuvant or first-line platinum therapy corresponds to an increased mutational burden of recurrent disease. Recurrent disease is enriched for mutations that activate Mapk/Erk and PI3K/AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In one patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings advocate for combination therapies with immunotherapy and routine post-treatment sampling as a component of management of recurrent pancreatic cancer.

cancer biology↗

bioRxiv2019

The Genetic Basis of Transcriptional and Spatial Heterogeneity of Squamous Features in Pancreatic Ductal Adenocarcinoma

Recent studies indicate that pancreatic cancer expression profiles are variable and largely reflect a classical or basal-type phenotype. We performed genetic sequencing, RNA-seq, and histologic review of multiregion sampled pancreatic cancers and found that squamous and squamoid features, indicators of poor prognosis, correlate with a "basal-like" expressional type. Cancers with squamous features were more likely to have truncal mutations in chromatin modifier genes and intercellular heterogeneity for MYC amplification that was associated with entosis. In most patients the basal phenotype coexisted with a glandular component, and phylogenetic studies indicated that it arose from a subclonal population in the tumor. These data provide a unifying paradigm for understanding the interrelationship of basal-type features, squamous histology, and somatic mutations in chromatin modifier genes in the context of the clonal evolution of pancreatic cancer.

cancer biology↗