Whole-exome sequencing studies of parathyroid carcinomas reveal novel PRUNE2 mutations, distinctive mutational spectra related to APOBEC-catalyzed DNA mutagenesis and mutational enrichment in kinases associated with cell migration and invasion.
BACKGROUND
Cell division cycle 73 (CDC73), encoding the protein parafibromin, is the most prevalent mutated gene in familial and sporadic parathyroid carcinoma (PC).


OBJECTIVE
To identify additional genetic abnormalities in PCs.


METHODS
Whole-exome sequencing was performed using DNA from seven pairs of matched PCs and one triplet containing double primary tumor and normal leukocyte. Somatic variants were confirmed using Sanger sequencing and recurrently mutated genes were assessed in 13 additional PCs as well as 40 parathyroid adenomas (PA).


RESULTS
PC had an average of 51 somatic variants/tumor (range 3-176) with approximately 58% of variants occurring as nonsynonymous single nucleotide variants. The importance of CDC73 in PC is reinforced with a remarkable preferential amplification of the mutant CDC73 allele. Furthermore, recurrent germ line and somatic mutations in prune homolog 2 [Drosophila] (PRUNE2) were found in PC and computationally predicted to be deleterious; in addition, recurrent mutations in kinase genes related to cell migration and invasion were found. PRUNE2 showed recurrent mutations in 18% (4/22) of PCs with additional screening in 40 PAs revealing only one rare missense polymorphism (Asp1677Asn). For the first time, the mutational signature associated with apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-catalyzed cytosine-to-uracil deamination is found in a subset of PC.


CONCLUSIONS
This study outlines the genetic landscape of PC and attempts to characterize the mutational processes shaping the PC genome.
Laboratory of Cancer Epigenome (W.Y., H.L.H., A.G., D.H., S.L.P., C.K.O., B.T.T.), Division of Medical Sciences, National Cancer Centre Singapore, 169610 Singapore; Division of Cancer and Stem Cell Biology (W.Y., J.R.M., H.L.H., D.H., S.L.P., C.K.O., S.G.R., P.T., B.T.T.), Duke-National University of Singapore Graduate Medical School, 169857 Singapore; National University of Singapore Graduate School for Integrative Sciences and Engineering (W.Y.), 117456 Singapore; Academic Endocrine Unit, Nuffield Department of Clinical Medicine (M.S., P.N., R.V.T.), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, OX3 7LJ Oxford, United Kingdom; Department of Pathology (R.v.E., D.R., T.v.W., H.M.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Molecular Endocrinology Group, Molecular Pathobiology Research Centre Unit (U.I.P.M.) (B.C.) of the Portuguese Institute of Oncology from Lisbon Francisco Gentil (IPOLFG) and Chronic Diseases Research Centre (CEDOC), Faculty of Medical Sciences (FCM), New University of Lisbon (UNL), 1099-023 Lisbon, Portugal; Genome Institute of Singapore (P.T.), 138672 Singapore; and Cancer Science Institute of Singapore (P.T., B.T.T.), National University of Singapore, 117599 Singapore.
Willie
W
Yu
John R
JR
McPherson
Mark
M
Stevenson
Ronald
R
van Eijk
Hong Lee
HL
Heng
Paul
P
Newey
Anna
A
Gan
Dina
D
Ruano
Dachuan
D
Huang
Song Ling
SL
Poon
Choon Kiat
CK
Ong
Tom
T
van Wezel
Branca
B
Cavaco
Steven G
SG
Rozen
Patrick
P
Tan
Bin T
BT
Teh
Rajesh V
RV
Thakker
Hans
H
Morreau
D000293:Adolescent; D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
D009363:Neoplasm Proteins; C509845:PRUNE2 protein, human