Breast cancer and rotator cuff injury: a two-sample two-way Mendelian randomization study_West China Medical Journal

Authors：

LI Yuanzhi ¹ , REN Yuehan ² ,  FANG Zhiyuan ¹

1. Department of Orthopedics, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, P. R. China;
2. Department of Gynecology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100000, P. R. China;

Corresponding author：

FANG Zhiyuan, Email: fangzhiyuan168@aliyun.com

Keywords：

Breast cancer; rotator cuff injury; Mendelian randomization

DOI：

10.7507/1002-0179.202405004

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To explore the causal relationship between breast cancer and rotator cuff injury using bidirectional two-sample Mendelian randomization. Methods Instrumental variables for breast cancer and rotator cuff injury were extracted from published genome-wide association study data. The positive study used breast cancer as the exposure and rotator cuff injury as the outcome, with single nucleotide polymorphisms (SNPs) closely associated with both breast cancer and rotator cuff injury as genetic instrumental variables. The reverse study used rotator cuff injury as the exposure and breast cancer as the outcome, with SNPs closely associated with both breast cancer and rotator cuff injury as genetic instrumental variables. Bidirectional MR analysis was conducted using five models: inverse variance weighted (IVW), simple model, weighted median, weighted model, and MR-Egger to assess the causal relationship between breast cancer and rotator cuff injury. Cochran Q test was used to detect heterogeneity, MR-Egger to detect horizontal pleiotropy, and leave-one-out method for sensitivity analysis to ensure the robustness of the results. Results A total of 51 SNPs closely associated with breast cancer were included in the forward study. The results indicated a positive causal association between breast cancer and an increased risk of rotator cuff injury [IVW: odds ratio=1.08, 95% confidence interval (1.02, 1.12), P=0.014], with no evidence of heterogeneity in the causal relationship between breast cancer and rotator cuff injury (P>0.05). Horizontal pleiotropy test results showed no horizontal pleiotropy in the SNPs (P>0.05). Leave-one-out test results did not detect any SNP with a large impact on the results. In the reverse study, a total of 3 SNPs related to rotator cuff injury were included as instrumental variables. There was no strong evidence that rotator cuff injury had a causal effect on breast cancer incidence [IVW: odds ratio=0.95, 95% confidence interval (0.86, 1.05), P=0.334]. Conclusions There is a potential causal association between breast cancer and rotator cuff injury. Therefore, it is suggested to increase the screening for rotator cuff injury in breast cancer patients.

1.	Velasquez Garcia A, Hsu KL, Marinakis K. Advancements in the diagnosis and management of rotator cuff tears. The role of artificial intelligence. J Orthop, 2024, 47: 87-93.
2.	Gagnier J, Bedi A, Carpenter J, et al. A 5-year follow-up of patients treated for full-thickness rotator cuff tears: a prospective cohort study. Orthop J Sports Med, 2021, 9(9): 23259671211021589.
3.	Fu C, Huang AH, Galatz LM, et al. Cellular and molecular modulation of rotator cuff muscle pathophysiology. J Orthop Res, 2021, 39(11): 2310-2322.
4.	Millar NL, Silbernagel KG, Thorborg K, et al. Tendinopathy. Nat Rev Dis Primers, 2021, 7(1): 1.
5.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
6.	Johansen S, Fosså K, Nesvold IL, et al. Arm and shoulder morbidity following surgery and radiotherapy for breast cancer. Acta Oncol, 2014, 53(4): 521-529.
7.	Yang S, Park DH, Ahn SH, et al. Prevalence and risk factors of adhesive capsulitis of the shoulder after breast cancer treatment. Supportive Care in Cancer, 2017, 25(4): 1317-1322.
8.	Leonardis JM, Lulic-Kuryllo T, Lipps DB. The impact of local therapies for breast cancer on shoulder muscle health and function. Crit Rev Oncol Hematol, 2022, 177: 103759.
9.	Kim SY, Jung MW, Kim JM. The shoulder pain due to metastatic breast cancer - a case report. Korean J Pain, 2011, 24(2): 119-122.
10.	Lang AE, Milosavljevic S, Dickerson CR, et al. Evidence of rotator cuff disease after breast cancer treatment: scapular kinematics of post-mastectomy and post-reconstruction breast cancer survivors. Ann Med, 2022, 54(1): 1058-1066.
11.	Seidenstuecker K, Fertsch S, Ghazaleh AA, et al. Improving quality of life after breast cancer: a comparison of two microsurgical treatment options for breast cancer-related lymphedema (BCRL). Clin Exp Med, 2024, 24(1): 82.
12.	Huo M, Zhang X, Fan J, et al. Short-term effects of a new resistance exercise approach on physical function during chemotherapy after radical breast cancer surgery: a randomized controlled trial. BMC Womens Health, 2024, 24(1): 160.
13.	Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
14.	Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet, 2014, 23(R1): R89-R98.
15.	Barrera-Gómez J, Basagaña X. Models with transformed variables: interpretation and software. Epidemiology, 2015, 26(2): e16-e17.
16.	Sun T, Wang J, Zheng M, et al. Assessment of the relationship between genetic determinants of obesity, unhealthy eating habits and chronic obstructive pulmonary disease: a Mendelian randomisation study. COPD, 2024, 21(1): 2309236.
17.	Michailidou K, Lindström S, Dennis J, et al. Association analysis identifies 65 new breast cancer risk loci. Nature, 2017, 551(7678): 92-94.
18.	Tashjian RZ, Kim SK, Roche MD, et al. Genetic variants associated with rotator cuff tearing utilizing multiple population-based genetic resources. J Shoulder Elbow Surg, 2021, 30(3): 520-531.
19.	Wang M, He X. Mendelian randomization analysis reveals causal associations of inflammatory bowel disease with spondylarthritis. Gene, 2024, 902: 148170.
20.	Kamat MA, Blackshaw JA, Young R, et al. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics, 2019, 35(22): 4851-4853.
21.	Liang J, Cai Y, Zhang J, et al. Metformin treatment reduces the incidence of rheumatoid arthritis: a two-sample Mendelian randomized study. J Clin Med, 2023, 12(7): 2461.
22.	Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol, 2011, 40(3): 740-752.
23.	Zhong H, Liu S, Zhu J, et al. Associations between genetically predicted levels of blood metabolites and pancreatic cancer risk. Int J Cancer, 2023, 153(1): 103-110.
24.	Su Y, Xu S, Ma Y, et al. A modified debiased inverse-variance weighted estimator in two-sample summary-data Mendelian randomization. Stat Med, 2024: 1-13.
25.	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
26.	Cai X, Liang C, Zhang M, et al. Mitochondrial DNA copy number and cancer risks: a comprehensive Mendelian randomization analysis. Int J Cancer, 2024, 154(8): 1504-1513.
27.	Greco M FD, Minelli C, Sheehan NA, et al. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med, 2015, 34(21): 2926-2940.
28.	Cheng Q, Zhang X, Chen LS, et al. Mendelian randomization accounting for complex correlated horizontal pleiotropy while elucidating shared genetic etiology. Nat Commun, 2022, 13(1): 6490.
29.	Ni Y, Wang W, Liu Y, et al. Causal associations between liver traits and colorectal cancer: a Mendelian randomization study. BMC Med Genomics, 2023, 16(1): 316.
30.	Wang Y, Liu S, Wu C, et al. Association between circulating unsaturated fatty acid and preeclampsia: a two-sample Mendelian randomization study. J Matern Fetal Neonatal Med, 2024, 37(1): 2294691.
31.	Mohite PP, Kanase SB. Effectiveness of scapular strengthening exercises on shoulder dysfunction for pain and functional disability after modified radical mastectomy: a controlled clinical trial. Asian Pac J Cancer Prev, 2023, 24(6): 2099-2104.
32.	Samanta SK, Choudhury P, Kandimalla R, et al. Mahanine mediated therapeutic inhibition of estrogen receptor-α and CDK4/6 expression, decipher the chemoprevention-signaling cascade in preclinical model of breast cancer. J Ethnopharmacol, 2024, 319(Pt 2): 117235.
33.	Lee CA, Lee-Barthel A, Marquino L, et al. Estrogen inhibits lysyl oxidase and decreases mechanical function in engineered ligaments. J Appl Physiol (1985), 2015, 118(10): 1250-1257.
34.	Longo UG, Mazzola A, Carotti S, et al. The role of estrogen and progesterone receptors in the rotator cuff disease: a retrospective cohort study. BMC Musculoskelet Disord, 2021, 22(1): 891.
35.	Stamiris D, Valasidis A, Cheva A, et al. Interventions used to mitigate muscle fatty degeneration following the repair of massive rotator cuff tears. A systematic review of animal studies. Orthop Traumatol Surg Res, 2024, 110(1): 103723.
36.	Giri A, Freeman TH, Kim P, et al. Obesity and sex influence fatty infiltration of the rotator cuff: the Rotator Cuff Outcomes Workgroup (ROW) and Multicenter Orthopaedic Outcomes Network (MOON) cohorts. J Shoulder Elbow Surg, 2022, 31(4): 726-735.
37.	Karastergiou K, Smith SR, Greenberg AS, et al. Sex differences in human adipose tissues – the biology of pear shape. Biol Sex Differ, 2012, 3(1): 13.
38.	Holmes GB, Lin J. Etiologic factors associated with symptomatic achilles tendinopathy. Foot Ankle Int, 2006, 27(11): 952-959.
39.	Tashjian RZ, Zitnay J, Kazmers NH, et al. Estrogen and testosterone supplementation improves tendon healing and functional recovery after rotator cuff repair. J Orthop Res, 2024, 42(2): 259-266.
40.	Marigi EM, Johnson QJ, Dancy ME, et al. Shoulder arthroplasty after prior external beam radiation therapy: a matched cohort analysis. J Shoulder Elbow Surg, 2023, 32(3): e85-e93.
41.	Harrington SE, Hoffman J, Katsavelis D. Measurement of pectoralis minor muscle length in women diagnosed with breast cancer: reliability, validity, and clinical application. Phys Ther, 2020, 100(3): 429-437.
42.	Yeung WM, McPhail SM, Kuys SS. A systematic review of axillary web syndrome (AWS). J Cancer Surviv, 2015, 9(4): 576-598.
43.	Takayesu JSK, Jiang SJ, Marsh R, et al. Pectoralis muscle dosimetry and posttreatment rehabilitation utilization for patients with early-stage breast cancer. Pract Radiat Oncol, 2024, 14(1): e20-e28.

1. Velasquez Garcia A, Hsu KL, Marinakis K. Advancements in the diagnosis and management of rotator cuff tears. The role of artificial intelligence. J Orthop, 2024, 47: 87-93.
2. Gagnier J, Bedi A, Carpenter J, et al. A 5-year follow-up of patients treated for full-thickness rotator cuff tears: a prospective cohort study. Orthop J Sports Med, 2021, 9(9): 23259671211021589.
3. Fu C, Huang AH, Galatz LM, et al. Cellular and molecular modulation of rotator cuff muscle pathophysiology. J Orthop Res, 2021, 39(11): 2310-2322.
4. Millar NL, Silbernagel KG, Thorborg K, et al. Tendinopathy. Nat Rev Dis Primers, 2021, 7(1): 1.
5. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
6. Johansen S, Fosså K, Nesvold IL, et al. Arm and shoulder morbidity following surgery and radiotherapy for breast cancer. Acta Oncol, 2014, 53(4): 521-529.
7. Yang S, Park DH, Ahn SH, et al. Prevalence and risk factors of adhesive capsulitis of the shoulder after breast cancer treatment. Supportive Care in Cancer, 2017, 25(4): 1317-1322.
8. Leonardis JM, Lulic-Kuryllo T, Lipps DB. The impact of local therapies for breast cancer on shoulder muscle health and function. Crit Rev Oncol Hematol, 2022, 177: 103759.
9. Kim SY, Jung MW, Kim JM. The shoulder pain due to metastatic breast cancer - a case report. Korean J Pain, 2011, 24(2): 119-122.
10. Lang AE, Milosavljevic S, Dickerson CR, et al. Evidence of rotator cuff disease after breast cancer treatment: scapular kinematics of post-mastectomy and post-reconstruction breast cancer survivors. Ann Med, 2022, 54(1): 1058-1066.
11. Seidenstuecker K, Fertsch S, Ghazaleh AA, et al. Improving quality of life after breast cancer: a comparison of two microsurgical treatment options for breast cancer-related lymphedema (BCRL). Clin Exp Med, 2024, 24(1): 82.
12. Huo M, Zhang X, Fan J, et al. Short-term effects of a new resistance exercise approach on physical function during chemotherapy after radical breast cancer surgery: a randomized controlled trial. BMC Womens Health, 2024, 24(1): 160.
13. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
14. Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet, 2014, 23(R1): R89-R98.
15. Barrera-Gómez J, Basagaña X. Models with transformed variables: interpretation and software. Epidemiology, 2015, 26(2): e16-e17.
16. Sun T, Wang J, Zheng M, et al. Assessment of the relationship between genetic determinants of obesity, unhealthy eating habits and chronic obstructive pulmonary disease: a Mendelian randomisation study. COPD, 2024, 21(1): 2309236.
17. Michailidou K, Lindström S, Dennis J, et al. Association analysis identifies 65 new breast cancer risk loci. Nature, 2017, 551(7678): 92-94.
18. Tashjian RZ, Kim SK, Roche MD, et al. Genetic variants associated with rotator cuff tearing utilizing multiple population-based genetic resources. J Shoulder Elbow Surg, 2021, 30(3): 520-531.
19. Wang M, He X. Mendelian randomization analysis reveals causal associations of inflammatory bowel disease with spondylarthritis. Gene, 2024, 902: 148170.
20. Kamat MA, Blackshaw JA, Young R, et al. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics, 2019, 35(22): 4851-4853.
21. Liang J, Cai Y, Zhang J, et al. Metformin treatment reduces the incidence of rheumatoid arthritis: a two-sample Mendelian randomized study. J Clin Med, 2023, 12(7): 2461.
22. Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol, 2011, 40(3): 740-752.
23. Zhong H, Liu S, Zhu J, et al. Associations between genetically predicted levels of blood metabolites and pancreatic cancer risk. Int J Cancer, 2023, 153(1): 103-110.
24. Su Y, Xu S, Ma Y, et al. A modified debiased inverse-variance weighted estimator in two-sample summary-data Mendelian randomization. Stat Med, 2024: 1-13.
25. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
26. Cai X, Liang C, Zhang M, et al. Mitochondrial DNA copy number and cancer risks: a comprehensive Mendelian randomization analysis. Int J Cancer, 2024, 154(8): 1504-1513.
27. Greco M FD, Minelli C, Sheehan NA, et al. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med, 2015, 34(21): 2926-2940.
28. Cheng Q, Zhang X, Chen LS, et al. Mendelian randomization accounting for complex correlated horizontal pleiotropy while elucidating shared genetic etiology. Nat Commun, 2022, 13(1): 6490.
29. Ni Y, Wang W, Liu Y, et al. Causal associations between liver traits and colorectal cancer: a Mendelian randomization study. BMC Med Genomics, 2023, 16(1): 316.
30. Wang Y, Liu S, Wu C, et al. Association between circulating unsaturated fatty acid and preeclampsia: a two-sample Mendelian randomization study. J Matern Fetal Neonatal Med, 2024, 37(1): 2294691.
31. Mohite PP, Kanase SB. Effectiveness of scapular strengthening exercises on shoulder dysfunction for pain and functional disability after modified radical mastectomy: a controlled clinical trial. Asian Pac J Cancer Prev, 2023, 24(6): 2099-2104.
32. Samanta SK, Choudhury P, Kandimalla R, et al. Mahanine mediated therapeutic inhibition of estrogen receptor-α and CDK4/6 expression, decipher the chemoprevention-signaling cascade in preclinical model of breast cancer. J Ethnopharmacol, 2024, 319(Pt 2): 117235.
33. Lee CA, Lee-Barthel A, Marquino L, et al. Estrogen inhibits lysyl oxidase and decreases mechanical function in engineered ligaments. J Appl Physiol (1985), 2015, 118(10): 1250-1257.
34. Longo UG, Mazzola A, Carotti S, et al. The role of estrogen and progesterone receptors in the rotator cuff disease: a retrospective cohort study. BMC Musculoskelet Disord, 2021, 22(1): 891.
35. Stamiris D, Valasidis A, Cheva A, et al. Interventions used to mitigate muscle fatty degeneration following the repair of massive rotator cuff tears. A systematic review of animal studies. Orthop Traumatol Surg Res, 2024, 110(1): 103723.
36. Giri A, Freeman TH, Kim P, et al. Obesity and sex influence fatty infiltration of the rotator cuff: the Rotator Cuff Outcomes Workgroup (ROW) and Multicenter Orthopaedic Outcomes Network (MOON) cohorts. J Shoulder Elbow Surg, 2022, 31(4): 726-735.
37. Karastergiou K, Smith SR, Greenberg AS, et al. Sex differences in human adipose tissues – the biology of pear shape. Biol Sex Differ, 2012, 3(1): 13.
38. Holmes GB, Lin J. Etiologic factors associated with symptomatic achilles tendinopathy. Foot Ankle Int, 2006, 27(11): 952-959.
39. Tashjian RZ, Zitnay J, Kazmers NH, et al. Estrogen and testosterone supplementation improves tendon healing and functional recovery after rotator cuff repair. J Orthop Res, 2024, 42(2): 259-266.
40. Marigi EM, Johnson QJ, Dancy ME, et al. Shoulder arthroplasty after prior external beam radiation therapy: a matched cohort analysis. J Shoulder Elbow Surg, 2023, 32(3): e85-e93.
41. Harrington SE, Hoffman J, Katsavelis D. Measurement of pectoralis minor muscle length in women diagnosed with breast cancer: reliability, validity, and clinical application. Phys Ther, 2020, 100(3): 429-437.
42. Yeung WM, McPhail SM, Kuys SS. A systematic review of axillary web syndrome (AWS). J Cancer Surviv, 2015, 9(4): 576-598.
43. Takayesu JSK, Jiang SJ, Marsh R, et al. Pectoralis muscle dosimetry and posttreatment rehabilitation utilization for patients with early-stage breast cancer. Pract Radiat Oncol, 2024, 14(1): e20-e28.

West China Medical Journal

Latest ArticlesBreast cancer and rotator cuff injury: a two-sample two-way Mendelian randomization study

Abstract Full text Figures/Tables Video References Cited by

Format

Content