KRAS mutations in uterine endometrium are associated with gravidity and parity.

is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visithttp://creativecommons.org/licenses/by/4.0/. Correspondence: Satoshi Inoue ( [email protected]) 1Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo 104-0045, Japan 2Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan Full list of author information is available at the end of the article These authors contributed equally: Satoshi Inoue, Emiko Yoshida, Yamato Fukui Official journal of the Cell Death Differentiation Association 1234567890():,;1234567890():,; 1234567890():,; 1234567890():,; and parity may drive adenomyosis pathogenesis, poten- tially explaining the increased frequency of KRAS-muta- ted clones in NE of these individuals. Our work may have signi ficant clinical implications. Identification of KRAS-mutated clones in NE of parous women may allow clinicians to choose an alternative protocol that might prevent or mitigate adenomyosis development, perhaps maintaining a better quality-of life for these women. In addition, our genomic analyses of NE have yielded novel biological insights that could lead to the identi fication of new therapeutic strategies to elim- inate KRAS-mutated clones in NE and prevent gravidity/ parity-associated adenomyosis. Author details 1Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo 104-0045, Japan. 2Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan. 3Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-0033, Japan. 4Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan Conflict of interest The authors declare that they have no con flict of interest. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional af filiations. Supplementary Information accompanies this paper at ( https://doi.org/ 10.1038/s41419-020-2559-0). Received: 1 April 2020 Revised: 24 April 2020 Accepted: 24 April 2020

1. Yokoyama, A. et al. Age-related rem odelling of oesophageal epithelia by mutated cancer drivers.Nature 565,3 1 2–317 (2019). 2. Kakiuchi, N. et al. Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis.Nature 577,2 6 0–265 (2020). 3. Inoue, S. et al. Uterine adenomyosis is a n oligoclonal disorder associated with KRAS mutations. Nat. Commun. 10, 5785 (2019). 4. Lac, V. et al. Oncogenic mutations in h istologically normal endometrium: the new normal? J. Pathol. 249,1 7 3–181 (2019). 5. Moore, L. et al. The mutational landscape of normal human endometrial epi- thelium. Nature 580, 640–646 (2020). 6. Suda, K. et al. Clonal expansion and diversi fication of cancer-associated muta- tions in endometriosis and normal endometrium. Cell Rep. 24,1 7 7 7–1789 (2018). 7. Parazzini, F. et al. Risk factors for adenomyosis. Hum. Reprod. 12,1 2 7 5–1279 (1997). 8. Templeman, C. et al. Adenomyosis and endometriosis in the California Teachers Study. Fertil. Steril.90,4 1 5–424 (2008). Table 1 Relationship between individual characteristics and KRAS mutation status. Value (%) KRAS wild type KRAS mutated Characteristics ( N = 40) ( N = 58) Statistics Median age at operation (range), years 46 (35 –87) 45 (33 –65) Gravidity, n (%) ≥1 12/40 (30.00) 38/58 (65.52) 0.001 0 28/40 (70.00) 20/58 (34.48) 1 5/40 (12.50) 16/58 (27.59) 2 5/40 (12.50) 11/58 (18.97) ≥3 2/40 (5.00) 11/58 (18.97) Parity, n (%) ≥1 11/40 (27.50) 33/58 (56.90) 0.007 0 29/40 (72.50) 25/58 (43.10) 1 5/40 (12.50) 15/58 (25.86) 2 5/40 (12.50) 10/58 (17.24) ≥3 1/40 (2.50) 8/58 (13.79) Abortion or stillborn, n (%) ≥1 3/40 (7.50) 11/58 (18.97) n.s. 0 37/40 (92.50) 47/58 (81.03) 1 2/40 (5.00) 7/58 (12.07) 2 1/40 (2.50) 3/58 (5.17) ≥3 0/40 (0.00) 1/58 (1.72) Caesarean section, n (%) ≥1 6/40 (15.00) 5/58 (8.62) n.s. 0 34/40 (85.00) 53/58 (91.38) 1 4/40 (10.00) 2/58 (3.45) 2 2/40 (5.00) 1/58 (1.72) ≥3 0/40 (0.00) 2/58 (3.45) Vaginal delivery, n (%) ≥1 7/40 (17.50) 28/58 (48.28) 0.003 0 33/40 (82.50) 30/58 (51.72) 1 4/40 (10.00) 13/58 (22.41) 2 3/40 (7.50) 10/58 (17.24) ≥3 0/40 (0.00) 5/58 (8.62) Smoking history, n (%) 8/40 (20.00) 5/58 (8.62) n.s. n.s. not signi ficant assessed by Fisher ’s exact test. Inoue et al. Cell Death and Disease (2020) 11:347 Page 2 of 2 Official journal of the Cell Death Differentiation Association