TY - JOUR
T1 - Genome-wide mutation analysis in precancerous lesions of endometrial carcinoma
AU - Li, Lihong
AU - Yue, Pinli
AU - Song, Qianqian
AU - Yen, Ting Tai
AU - Asaka, Shiho
AU - Wang, Tian Li
AU - Beavis, Anna L.
AU - Fader, Amanda N.
AU - Jiao, Yuchen
AU - Yuan, Guangwen
AU - Shih, Ie Ming
AU - Song, Yan
N1 - Publisher Copyright:
© 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - atypical hyperplasia
KW - endometrioid carcinoma
KW - microsatellite instability-high
KW - mutation
KW - PapSEEK
KW - whole-exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85096793685&partnerID=8YFLogxK
U2 - 10.1002/path.5566
DO - 10.1002/path.5566
M3 - 文章
C2 - 33016334
AN - SCOPUS:85096793685
SN - 0022-3417
VL - 253
SP - 119
EP - 128
JO - Journal of Pathology
JF - Journal of Pathology
IS - 1
ER -