TY - JOUR
T1 - Frequent mutations in the RPL22 gene and its clinical and functional implications
AU - Novetsky, Akiva P.
AU - Zighelboim, Israel
AU - Thompson, Dominic M.
AU - Powell, Matthew A.
AU - Mutch, David G.
AU - Goodfellow, Paul J.
PY - 2013/3
Y1 - 2013/3
N2 - Objective: To determine the frequency and spectrum of mutations in RPL22 a gene identified by The Cancer Genome Atlas (TCGA) as mutated in endometrioid endometrial cancer, and determine the relationship between RPL22 defects and clinicopathologic features. Methods: Direct sequencing of the entire coding region of the RPL22 cDNA and exons 2/4 was performed in tumors with/without microsatellite instability (MSI). RPL22 expression was assessed by immunofluorescence microscopy in the KLE, RL952 and AN3CA cell lines, wildtype, heterozygous and homozygous mutants, respectively. Relationships between RPL22 mutation and clinicopathological features were assessed using Chi-squared analysis and Student's t test. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of recurrence. Results: A single nucleotide deletion in an A8 coding repeat was identified in exon 2 of the RPL22 gene in 116/226 (52%) of MSI-high tumors. No mutations were identified in MSI-stable tumors. Only 2% of the tumors expressed a homozygous A deletion. RPL22 mutation was not associated with stage, grade, race and lymphovascular space invasion. Women whose tumors harbored RPL22 mutations were significantly older (67 vs. 63 years, p = 0.005). There was no difference in PFS between patients with the wildtype and mutant genotypes. Conclusions: RPL22 is frequently mutated in MSI-high endometrioid endometrial cancers. The A8 mutation identified was not reported in the whole exome sequences analyzed by the TCGA. The demonstration of frequent mutation in RPL22 may point to a limitation of the exome capture and next generation sequencing analysis methods for some mononucleotide string mutations. Functional assessment of the RPL22 knockdown may be warranted.
AB - Objective: To determine the frequency and spectrum of mutations in RPL22 a gene identified by The Cancer Genome Atlas (TCGA) as mutated in endometrioid endometrial cancer, and determine the relationship between RPL22 defects and clinicopathologic features. Methods: Direct sequencing of the entire coding region of the RPL22 cDNA and exons 2/4 was performed in tumors with/without microsatellite instability (MSI). RPL22 expression was assessed by immunofluorescence microscopy in the KLE, RL952 and AN3CA cell lines, wildtype, heterozygous and homozygous mutants, respectively. Relationships between RPL22 mutation and clinicopathological features were assessed using Chi-squared analysis and Student's t test. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of recurrence. Results: A single nucleotide deletion in an A8 coding repeat was identified in exon 2 of the RPL22 gene in 116/226 (52%) of MSI-high tumors. No mutations were identified in MSI-stable tumors. Only 2% of the tumors expressed a homozygous A deletion. RPL22 mutation was not associated with stage, grade, race and lymphovascular space invasion. Women whose tumors harbored RPL22 mutations were significantly older (67 vs. 63 years, p = 0.005). There was no difference in PFS between patients with the wildtype and mutant genotypes. Conclusions: RPL22 is frequently mutated in MSI-high endometrioid endometrial cancers. The A8 mutation identified was not reported in the whole exome sequences analyzed by the TCGA. The demonstration of frequent mutation in RPL22 may point to a limitation of the exome capture and next generation sequencing analysis methods for some mononucleotide string mutations. Functional assessment of the RPL22 knockdown may be warranted.
KW - Endometrial cancer
KW - Microsatellite instability
KW - RPL22
UR - http://www.scopus.com/inward/record.url?scp=84873741277&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2012.10.026
DO - 10.1016/j.ygyno.2012.10.026
M3 - Article
C2 - 23127973
AN - SCOPUS:84873741277
SN - 0090-8258
VL - 128
SP - 470
EP - 474
JO - Gynecologic oncology
JF - Gynecologic oncology
IS - 3
ER -