Centromeric cohesion failure invokes a conserved choreography of chromosomal mis-segregations in pancreatic neuroendocrine tumor

Abstract

Background: Pancreatic neuroendocrine tumors (PANETs) are rare, slow growing cancers that often present with local and distant metastasis upon detection. PANETS contain distinct karyotypes, epigenetic dysregulation, and recurrent mutations in MEN1, ATRX, and DAXX (MAD+); however, the molecular basis of disease progression remains uncharacterized. Methods: We evaluated associations between aneuploidy and the MAD+ mutational state of 532 PANETs from 11 published genomic studies and 19 new cases using a combination of exome, targeted panel, shallow WGS, or RNA-seq. We mapped the molecular timing of MAD+ PANET progression using cellular fractions corrected for inferred tumor content. Results: In 287 PANETs with mutational data, MAD+ tumors always exhibited a highly recurrent signature of loss of heterozygosity (LOH) and copy-number alterations affecting 11 chromosomes, typically followed by genome doubling upon metastasis. These LOH chromosomes substantially overlap with those that undergo non-random mis-segregation due to ectopic CENP-A localization to flanking centromeric regions in DAXX-depleted cell lines. Using expression data from 122 PANETs, we found decreased gene expression in the regions immediately adjacent to the centromere in MAD+ PANETs. Using 43 PANETs from AACR GENIE, we inferred this signature to be preceded by mutations in MEN1, ATRX, and DAXX. We conducted a meta-analysis on 226 PANETs from 8 CGH studies to show an association of this signature with metastatic incidence. Our study shows that MAD+ tumors are a genetically diverse and aggressive subtype of PANETs that display extensive chromosomal loss after MAD+ mutation, which is followed by genome doubling.

CENP-A is a potential prognostic biomarker and correlated with immune infiltration levels in glioma patients

“…Accordingly, mislocalization of CENP-A resulting from its overexpression contributes to chromosomal instability and aneuploidy ( Shrestha et al, 2021 ), which have long been recognized as hallmarks of tumor growth, malignant progression, and treatment resistance ( Zhang et al, 2016 ; Sansregret et al, 2018 ). Recent studies have indicated that CENP-A overexpression induces chromosomal instability in cancer cells ( Amato et al, 2009 ; Quevedo et al, 2020 ). Additionally, increased CENP-A expression is implicated in malignant progression ( Sun et al, 2016 ) and correlates with poor prognosis in cancers ( Zhang et al, 2020a ; Saha et al, 2020 ; Xu et al, 2020 ), including breast ( Rajput et al, 2011 ), lung ( Wu et al, 2012 ; Liu et al, 2018 ), and hepatic carcinoma ( Zhang et al, 2020b ).…”

Recurrent Loss of Heterozygosity in Pancreatic Neuroendocrine Tumors

“…The index paper we reference (Lawrence and colleagues) used the terms “recurrent 10 chromosome monosomy” and “10 chromosome loss of heterozygosity (LOH)” which are more accurate; however, other authors have referenced the loss of a slightly different number of chromosomes. For example, Quevedo et al13 referenced a “signature of loss of heterozygosity and copy-number alterations affecting 11 chromosomes.” Importantly, mentioning only the lost chromosomes excludes which chromosomes must be preserved, thus a case with global loss of heterozygosity could inappropriately fall into this category. In addition, many authors referenced the signature predominantly as a relative gain or absolute gain of the nonlost chromosomes.…”

“…12 This simple biologic mechanism to explain recurrent chromosomal losses has come into question recently. 13 Quevedo and colleagues found the 11-chromosome loss of heterozygosity signature (losses of chromosomes 1, 2, 3, 6, 8, 10, 11, 15, 16, 21, and 22), associated with mutations of MEN1, DAXX and/or ATRX, is likely the result of centromeric cohesion failure and mis-segregation, not necessarily ALT as previously described. Although they found indications that an ALT phenotype existed in these DAXX/ATRX/MEN1 mutant tumors, they postulate that the disruption of H3.3 deposition at genomic repeats, found both at telomeres and centromeres, could be the potential mechanism of genomic instability.…”

“…When DAXX or ATRX are mutated ALT is reportedly increased 12. This simple biologic mechanism to explain recurrent chromosomal losses has come into question recently 13…”

RSF1 in cancer: interactions and functions

“…Centromere, which contains a special nucleosome CENP-A histone, provides not only the basis for centromere chromatin and kinetochore assembly but also a locus for kinetochore-microtubule attachment and spindle assembly checkpoints. Recent studies have emphatically pointed out that ectopic localization of CENP-A induces kinetochore defects and the chromosomal instability phenotype in many cancers [ 46 , 47 ]. Previously, Obuse C et al identified that RSF1 and SNF2H co-exist in CENP-A affinity eluates using chromatin immunoprecipitation (ChIP) and mass spectrometric analysis in HeLa cells [ 48 ].…”