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. 2023 Nov 9;27(1):9.
doi: 10.3892/ol.2023.14142. eCollection 2024 Jan.

Clinicopathological and molecular pathological characteristics in tamoxifen‑related endometrial cancer

Harumi Saeki  1   2 , Yoshiya Horimoto  1   3 , May Thinzar Hlaing  3 , Yuan Men  2 , Lu Rong  2 , Yumiko Ishizuka  3 , Toshitaka Uomori  3 , Emiko Yoshida  4 , Yasuhisa Terao  4 , Atsushi Arakawa  1 , Tsuyoshi Saito  1   2 , Takashi Yao  1   2
Affiliations

Clinicopathological and molecular pathological characteristics in tamoxifen‑related endometrial cancer

Harumi Saeki et al. Oncol Lett. .

Abstract

Tamoxifen (TAM), a selective estrogen receptor modulator, is often used for long-term adjuvant endocrine therapy in patients with hormone receptor-positive breast cancer. TAM is known to increase the risk of endometrial cancer (EC); however, the mechanism has not yet been fully elucidated. Therefore, molecular genetic analysis of EC following TAM administration (TAM-related EC) was conducted. A total of 10 samples of TAM-related EC and 20 sporadic EC samples (as controls) were analyzed. Copy number variation analysis was conducted, microsatellite instability (MSI) status was assessed, and mismatch repair (MMR) protein expression was examined immunohistochemically. Copy number variation analysis revealed that KDR, NOTCH1, NTRK1, NTRK3 and PDGFRB were more frequently amplified in TAM-related EC (P=0.039, P<0.001, P=0.011, P=0.006 and P=0.035, respectively). In MSI analysis, 4 cases were classified as MSI-high (40%), which is a higher frequency compared with that among patients with sporadic EC (~10% in Japanese women). Loss of MMR proteins was confirmed in all MSI-high cases. In 1 MSI-high case, a benign lesion of hyperplasia prior to EC development was also MSI-high with loss of some MMR protein expression. Several genes were specifically amplified in TAM-related ECs. Furthermore, TAM-related ECs were frequently MSI-high. Further studies are required to be conclusive; however, the present findings may lead to a reduction of unnecessary gynaecological testing in clinical practice and also encourage the testing for MSI status for optimal individualized treatment.

Keywords: breast cancer; copy number variation; endometrial cancer; microsatellite instability; receptor protein-tyrosine kinases; tamoxifen.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1.
Figure 1.
Results of CNV analysis for TAM-related EC (n=10) and sporadic EC (n=20). Each copy number ratio was calculated with the score of nonneoplastic lesion being 2. The heatmap of CNV analysis results is shown. *Indicates genes that showed a significant difference between TAM-related EC and sporadic EC (P<0.05). CNV, copy number variation; EC, endometrial cancer; TAM, tamoxifen.
Figure 2.
Figure 2.
Representative images of immunohistochemistry for MMR proteins in a MSI-high case. Images of MMR proteins of Case #1 (MSI-high) are shown. MSH2 and MSH6 protein expression was lost in this case. Magnification, ×200; inset magnification, ×400. MLH1, mutL homolog 1; MMR, mismatch repair; MSH2, mutS homolog 2; MSH6, mutS homolog 6; MSI, microsatellite instability; PMS2, PMS1 homolog 2, mismatch repair system component.
Figure 3.
Figure 3.
Methylation assay for the MLH1 promoter region in Cases #2 and #4. Methylation assays for the MLH1 promoter region were conducted for Case #2 and Case #4, whose MLH1 and PMS1 homolog 2, mismatch repair system component protein expression was lost. M, reaction for methylated DNA; MLH1, mutL homolog 1; uM, reaction for unmethylated DNA.
See this image and copyright information in PMC

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