Modern genome sequencing technology has identified thousands of mutations in human tumors, but analysis of the role of genetic mutations in tumor development, utilizing prevalence information from many tumors, has yet to define in patients the functional contribution of genetic mutations, individually and collectively. To understand the genetic basis of human endometrial cancer, the fourth most common cancer in women, transcriptome sequencing was performed on an endometrial tumor paired with normal cervical tissue, and 26 non-synonymous somatic mutations were confirmed in the tumor genome DNA. A phylogenetic tree illustrating the mutational timeline was developed based upon the distribution of 26 mutations in 30 randomly-selected laser-captured single cells from the tumor sections. Five ubiquitous mutations were identified that are presumed to occur in the cancer founder cell of the tumor, which may collectively play critical roles in endometrial oncogenesis. However, further testing in 10 additional endometrial tumors failed to show overlapping mutations, indicating the lack of a single common oncogenic pathway for these endometrial tumors.

Furthermore, we developed a mathematical and phylogenetic calculation of the cell population produced by a mutated ancestor cell, which quantifies the role of tumor-specific individual genetic mutations in cancer cell proliferation in a single resected patient tumor, without relying on prevalence information from other patients. This novel approach will be further tested in a larger sample set to determine whether multiple genetic mutations’ quantitative contributions can be used to predict patient outcomes.

Functional contribution of individual mutations

mutant genesgenetic timeoffspring (million cells)Score
C10orf26, GMPPA CREBL1 PPP2R2D SLCO2A1 30 1000 0.997 
DDEF1 LOC728069 29 833 0.025 
LDLRAP1 PLEC1 29 167 −0.06 
MYST1 28 667 0.025 
GORASP2 ILKAP, LOC729423 28 100 −0.07 
INCENP, ME2 28 67 −0.09 
PDZD8 27 400 0.011 
AP1G2 27 267 −0.01 
POLE4, SDC2 26 300 0.025 
PIF1, XYL2 26 100 −0.04 
TOR3A 25 167 0.01 
LOC642934 25 133 
CCDC50, CIZ1 24 67 −0.01 
LOC645634 24 100 0.014 
mutant genesgenetic timeoffspring (million cells)Score
C10orf26, GMPPA CREBL1 PPP2R2D SLCO2A1 30 1000 0.997 
DDEF1 LOC728069 29 833 0.025 
LDLRAP1 PLEC1 29 167 −0.06 
MYST1 28 667 0.025 
GORASP2 ILKAP, LOC729423 28 100 −0.07 
INCENP, ME2 28 67 −0.09 
PDZD8 27 400 0.011 
AP1G2 27 267 −0.01 
POLE4, SDC2 26 300 0.025 
PIF1, XYL2 26 100 −0.04 
TOR3A 25 167 0.01 
LOC642934 25 133 
CCDC50, CIZ1 24 67 −0.01 
LOC645634 24 100 0.014 

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2191.