Part1.Genome-wide Mutation Analysis In Precancerous Lesions Of Endometrial Carcinoma Part2.Personalized Analysis Of Minimal Residual Cancer Cells In Peritoneal Lavage Fluid Predicts Peritoneal Dissemination Of Gastric Cancer

Endometrioid carcinoma(EC)is the most common gynecologic malignancy and its morbidity and mortality rate are increasing year by year.Clinicopathological evidence supports endometrial atypical hyperplasia(AH)or endometrial intraepithelial neoplasia as the precursor of EC.However,the pathogenic progression from AH to EC remains unclear.Here,we employed whole-exome sequencing to identify somatic mutations and copy number changes in micro-dissected lesions from 30 pairs of newly diagnosed AH and EC.At the same time,we performed capillary electrophoresis and immunohistochemistry to detect the state of microsatellites and evaluate gene expression in mismatch repair genes.We found that all but one pair of AHs shared the same DNA mismatch repair status as their corresponding ECs.The percentage of common mutations between AH lesions and corresponding ECs varied significantly,ranging from 0.1%to 82%.Microsatellite stable AHs had fewer cancer driver mutations than ECs(5 versus 7,P=0.017),but among microsatellite unstable AHs and ECs there was no difference in mutational numbers(36 versus 38,P=0.65).As compared to AH specimens,19(79%)of 24 microsatellite stable EC tumors gained new cancer driver mutations,most of which involved PTEN,ARID1A,PIK3CA,CTNNB1,or CHD4.Our results suggest that some AH lesions are the immediate precursor of ECs,and progression depends on acquisition of additional cancer driver mutations.However,a complex clonal relationship between AH and EC can also be appreciated,as in some cases both lesions diverge very early or arise independently,thus co-developing with distinct genetic trajectories.Our genome-wide profile of mutations in AH and EC shines new light on the molecular landscape of tumor progression.Peritoneal dissemination(PD)is the major type of gastric cancer(GC)recurrence and leads to rapid death.Current approach cannot precisely determine which patients are at high risk of PD.Mutation-based detection of minimal residual cancer cells in peritoneal lavage fluid(PLF)provides accurate prediction of PD.In this study,we developed a technology to detect minimal residual cancer cells in PLF samples by parallel profiling tumor-specific mutations.We applied the technology to a cohort of 110 GC patients at the National Cancer Center,Cancer Hospital,Chinese Academy of Medical Sciences in China from 2017 to 2019.Tumor tissues,matched white blood cells and PLF samples were collected.Twenty somatic mutations were selected from exome sequencing of the tumor tissues from individual patients.The technology showed ultra-high sensitivity by successfully detecting all the 27 cases that developed PD.The minimal residual cancer cells in PLF was associated with an increased risk of PD and significantly shorter overall survival.PLF cancer cell fraction remained the strongest independent predictor of PD and recurrence-free survival over pathologic diagnosis and cytological diagnosis in GC patients.This approach may help in the postsurgical management of GC patients by detecting PD far before the metastatic lesions grow to significant size detectable by conventional methods such as MRI and CT scanning.Early intervention can be provided for these patients with predicted metastasis,reducing the metastasis rate and prolonging the survival time.