Genome‐wide mutation analysis in precancerous lesions of endometrial carcinoma

Abstract

Clinicopathological evidence supports endometrial atypical hyperplasia (AH) or endometrial intraepithelial neoplasia as the precursor of uterine endometrioid carcinoma (EC), the most common gynecologic malignancy. 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. 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.

Endometrial carcinoma: molecular subtypes, precursors and the role of pathology in early diagnosis

“…EAH/EIN is the precursor lesion of almost all endometrioid carcinomas and a subset of serous carcinomas [58]. The mutational profile of EAH/EIN and the concurrent EC is highly concordant [18,59–62] in the majority of cases; however, Li et al showed that, in 5 out of 30 EAH/EIC cases with concurrent EEC, the EAH/EIC and EC shared less than 5% of the mutations identified, indicating clonality but with a high degree of divergence [62]. Serous intraepithelial carcinoma (SEIC) is characterized by pre‐existing endometrial glands lined by markedly atypical glandular epithelial cells in the absence of invasive disease.…”

“…In recent work comparing resolving and progressing EAH/EIN and comparing EAH/EIN and subsequent carcinoma, Russo et al identified NSMP, MMRd, and p53abn EAH/EIN lesions [61,71]. Evidence of clonal evolution has been demonstrated in whole‐exome sequencing studies of paired EAH/EIN and concurrent EC (mostly of NSMP and MMRd molecular subtypes [62]. p53abn : This is the prototypical type II EC and accounts for a large majority of serous ECs.…”

“…progestins [73]. Progression from AEH/EIN to EC is associated with the acquisition of driver mutations [62]. POLE mut : The histogenesis of this molecular subtype is the least understood.…”

Multi-compartment tumor organoids

“…4a). ARID1A and PTEN are two key tumor suppressors in endometrioid carcinoma, the most common type of human uterine carcinoma and ARID1A mutation and loss of its expression correlate with tumor invasion in human endometrial carcinoma [44][45][46][47][48] . Deletion of Arid1a significantly accelerates tumor progression of Pten-deleted endometrial and ovarian carcinomas as evidenced by marked invasion and metastasis in genetically engineered mouse models 49,50 .…”

Serial genomic analysis of endometrium supports the existence of histologically indistinct endometrial cancer precursors

“…In the uterine cervix or vulva, precancers driven by HPV often resolve spontaneously [17,18], a phenomenon undocumented in the endometrium. These factors could make the endometrium a useful model system for the systematic study of the formation and progression of early precancers [19].…”