High relative levels of satellite alpha transcripts predict increased risk of bilateral breast cancer and multiple primary cancer in patients with breast cancer and lacking BRCA‑related clinical features

  • Authors:
    • Nao Kakizawa
    • Koichi Suzuki
    • Iku Abe
    • Yuhei Endo
    • Sawako Tamaki
    • Hideki Ishikawa
    • Fumiaki Watanabe
    • Kosuke Ichida
    • Masaaki Saito
    • Kazusige Futsuhara
    • Fumio Konishi
    • Toshiki Rikiyama
  • View Affiliations

  • Published online on: June 3, 2019     https://doi.org/10.3892/or.2019.7182
  • Pages: 857-865
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Abstract

Patients with breast cancer who undergo surgery have a risk of developing multiple cancers in the contralateral breast and other organs. We previously reported that overexpression of satellite alpha transcripts (SAT) facilitates chromosomal instability, which is involved in the development of multiple tumors in patients with colorectal and gastric cancer. In this study, we elucidated the significance of SAT in the development of multiple tumors in patients with breast cancer. Relative expression of SAT (rSAT) was calculated in normal and tumor tissues from 167 patients. In total, 27 patients developed bilateral breast cancer (BBC) and 27 patients showed multiple primary cancer (MPC), with patients with BBC and MPC showing higher rSAT levels in tumor tissues than those in patients with single breast cancer (SBC) (P=0.0312 and P=0.0420, respectively). Additionally, higher rSAT levels in tumor tissues from patients with BBC were a significant factor according to univariate analysis, and multivariate analysis showed that rSAT >1.5 was a significant predictor of MPC [hazard ratio (HR): 2.96; P=0.0243); however, we did not clarify the involvement of SAT in normal tissues. Excluding 71 patients with BRCA‑related clinical features, rSAT levels were higher in patients with BBC and MPC than in patients with SBC in tumor tissues and normal tissues (P<0.05). Significant predictors according to univariate analysis included rSAT >1.5 in tumor tissues, rSAT >2.4 in normal tissues, and T <2, whereas those for multivariate analysis included rSAT >2.4 in normal tissues for BBC (HR: 22.7; P=0.00120) and MPC (HR: 13.0; P=0.00601). Our data indicated that patients with breast cancer and high rSAT levels in their breast tissues exhibit a 10‑ to 20‑fold increased risk for the development of multiple cancers when harboring no BRCA‑related clinical features.

References

1 

Beinart G, Gonzalez-Angulo AM, Broglio K, Mejia J, Ruggeri A, Mininberg E, Hortobagyi GN and Valero V: Clinical course of 771 patients with bilateral breast cancer: Characteristics associated with overall and recurrence-free survival. Clin Breast Cancer. 7:867–874. 2007. View Article : Google Scholar : PubMed/NCBI

2 

Chen Y, Thompson W, Semenciw R and Mao Y: Epidemiology of contralateral breast cancer. Cancer Epidemiol Biomarkers Prev. 8:855–861. 1999.PubMed/NCBI

3 

Kheirelseid EA, Jumustafa H, Miller N, Curran C, Sweeney K, Malone C, McLaughlin R, Newell J and Kerin MJ: Bilateral breast cancer: Analysis of incidence, outcome, survival and disease characteristics. Breast Cancer Res Treat. 126:131–140. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, Petty PM, Sellers TA, Johnson JL, McDonnell SK, et al: Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med. 340:77–84. 1999. View Article : Google Scholar : PubMed/NCBI

5 

Li CI, Malone KE, Porter PL and Daling JR: Epidemiologic and molecular risk factors for contralateral breast cancer among young women. Br J Cancer. 89:513–518. 2003. View Article : Google Scholar : PubMed/NCBI

6 

Shibahara Y, Sugawara Y, Miki Y, Hata S, Takahashi H, Nakamura Y, Suzuki T, Ohuchi N, Tsuji I and Sasano H: Analysis of multiple primary cancer autopsy cases associated with breast cancer: 2002-2010. Pathol Int. 66:695–700. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Momoh AO, Cohen WA, Kidwell KM, Hamill JB, Qi J, Pusic AL, Wilkins EG and Matros E: Tradeoffs associated with contralateral prophylactic mastectomy in women choosing breast reconstruction: Results of a prospective multicenter cohort. Ann Surg. 266:158–164. 2017. View Article : Google Scholar : PubMed/NCBI

8 

Tuttle TM, Habermann EB, Grund EH, Morris TJ and Virnig BA: Increasing use of contralateral prophylactic mastectomy for breast cancer patients: A trend toward more aggressive surgical treatment. J Clin Oncol. 25:5203–5209. 2007. View Article : Google Scholar : PubMed/NCBI

9 

Albornoz CR, Matros E, Lee CN, Hudis CA, Pusic AL, Elkin E, Bach PB, Cordeiro PG and Morrow M: Bilateral mastectomy versus breast-conserving surgery for early-stage breast cancer: The role of breast reconstruction. Plast Reconstr Surg. 135:1518–1526. 2015. View Article : Google Scholar : PubMed/NCBI

10 

Kamiyama H, Suzuki K, Maeda T, Koizumi K, Miyaki Y, Okada S, Kawamura YJ, Samuelsson JK, Alonso S, Konishi F and Perucho M: DNA demethylation in normal colon tissue predicts predisposition to multiple cancers. Oncogene. 31:5029–5037. 2012. View Article : Google Scholar : PubMed/NCBI

11 

Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR and Brakenhoff RH: A genetic explanation of Slaughter's concept of field cancerization: Evidence and clinical implications. Cancer Res. 63:1727–1730. 2003.PubMed/NCBI

12 

Suzuki K, Suzuki I, Leodolter A, Alonso S, Horiuchi S, Yamashita K and Perucho M: Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage. Cancer Cell. 9:199–207. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Deng G, Lu Y, Zlotnikov G, Thor AD and Smith HS: Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science. 274:2057–2059. 1996. View Article : Google Scholar : PubMed/NCBI

14 

Ahlquist T, Lind GE, Costa VL, Meling GI, Vatn M, Hoff GS, Rognum TO, Skotheim RI, Thiis-Evensen E and Lothe RA: Gene methylation profiles of normal mucosa, and benign and malignant colorectal tumors identify early onset markers. Mol Cancer. 7:942008. View Article : Google Scholar : PubMed/NCBI

15 

Belshaw NJ, Pal N, Tapp HS, Dainty JR, Lewis MP, Williams MR, Lund EK and Johnson IT: Patterns of DNA methylation in individual colonic crypts reveal aging and cancer-related field defects in the morphologically normal mucosa. Carcinogenesis. 31:1158–1163. 2010. View Article : Google Scholar : PubMed/NCBI

16 

Konishi K, Shen L, Jelinek J, Watanabe Y, Ahmed S, Kaneko K, Kogo M, Takano T, Imawari M, Hamilton SR and Issa JP: Concordant DNA methylation in synchronous colorectal carcinomas. Cancer Prev Res (Phila). 2:814–822. 2009. View Article : Google Scholar : PubMed/NCBI

17 

Menigatti M, Truninger K, Gebbers JO, Marbet U, Marra G and Schär P: Normal colorectal mucosa exhibits sex- and segment-specific susceptibility to DNA methylation at the hMLH1 and MGMT promoters. Oncogene. 28:899–909. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Paun BC, Kukuruga D, Jin Z, Mori Y, Cheng Y, Duncan M, Stass SA, Montgomery E, Hutcheon D and Meltzer SJ: Relation between normal rectal methylation, smoking status, and the presence or absence of colorectal adenomas. Cancer. 116:4495–4501. 2010. View Article : Google Scholar : PubMed/NCBI

19 

Ushijima T: Epigenetic field for cancerization. J Biochem Mol Biol. 40:142–150. 2007.PubMed/NCBI

20 

Worthley DL, Whitehall VL, Buttenshaw RL, Irahara N, Greco SA, Ramsnes I, Mallitt KA, Le Leu RK, Winter J, Hu Y, et al: DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer. Oncogene. 29:1653–1662. 2010. View Article : Google Scholar : PubMed/NCBI

21 

Saito M, Suzuki K, Maeda T, Kato T, Kamiyama H, Koizumi K, Miyaki Y, Okada S, Kiyozaki H and Konishi F: The accumulation of DNA demethylation in Sat α in normal gastric tissues with Helicobacter pylori infection renders susceptibility to gastric cancer in some individuals. Oncol Rep. 27:1717–1725. 2012.PubMed/NCBI

22 

Herrera LA, Prada D, Andonegui MA and Dueñas-González A: The epigenetic origin of aneuploidy. Curr Genomics. 9:43–50. 2008. View Article : Google Scholar : PubMed/NCBI

23 

Kawano H, Saeki H, Kitao H, Tsuda Y, Otsu H, Ando K, Ito S, Egashira A, Oki E, Morita M, et al: Chromosomal instability associated with global DNA hypomethylation is associated with the initiation and progression of esophageal squamous cell carcinoma. Ann Surg Oncol. 21 (Suppl 4):S696–S702. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Rodriguez J, Frigola J, Vendrell E, Risques RA, Fraga MF, Morales C, Moreno V, Esteller M, Capellà G, Ribas M and Peinado MA: Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Res. 66:8462–9468. 2006. View Article : Google Scholar : PubMed/NCBI

25 

Ichida K, Suzuki K, Fukui T, Takayama Y, Kakizawa N, Watanabe F, Ishikawa H, Muto Y, Kato T, Saito M, et al: Overexpression of satellite alpha transcripts leads to chromosomal instability via segregation errors at specific chromosomes. Int J Oncol. Mar 16–2018.(Epub ahead of print). doi: 10.3892/ijo.2018.4321 2018. View Article : Google Scholar : PubMed/NCBI

26 

Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, et al: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 31:3997–4013. 2013. View Article : Google Scholar : PubMed/NCBI

27 

Reiner AS, John EM, Brooks JD, Lynch CF, Bernstein L, Mellemkjaer L, Malone KE, Knight JA, Capanu M, Teraoka SN, et al: Risk of asynchronous contralateral breast cancer in noncarriers of BRCA1 and BRCA2 mutations with a family history of breast cancer: A report from the Women's Environmental Cancer and Radiation Epidemiology Study. J Clin Oncol. 31:433–439. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Kanda Y: Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 48:452–458. 2013. View Article : Google Scholar : PubMed/NCBI

29 

Kang E, Seong MW, Park SK, Lee JW, Lee J, Kim LS, Lee JE, Kim SY, Jeong J, Han SA, et al: The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: Recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. Breast Cancer Res Treat. 151:157–168. 2015. View Article : Google Scholar : PubMed/NCBI

30 

Feinberg AP and Vogelstein B: Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 301:89–92. 1983. View Article : Google Scholar : PubMed/NCBI

31 

Rebbeck TR, Friebel T, Lynch HT, Neuhausen SL, vant Veer L, Garber JE, Evans GR, Narod SA, Isaacs C, Matloff E, et al: Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: The PROSE Study Group. J Clin Oncol. 22:1055–1062. 2004. View Article : Google Scholar : PubMed/NCBI

32 

Bevers TB, Armstrong DK, Arun B, Carlson RW, Cowan KH, Daly MB, Fleming I, Garber JE, Gemignani M, Gradishar WJ, et al: Breast cancer risk reduction. J Natl Compr Canc Netw. 5:676–701. 2007.PubMed/NCBI

33 

Fu Y, Zhuang Z, Dewing M, Apple S and Chang H: Predictors for contralateral prophylactic mastectomy in breast cancer patients. Int J Clin Exp Pathol. 8:3748–3764. 2015.PubMed/NCBI

34 

Kato T, Suzuki K, Muto Y, Sasaki J, Tsujinaka S, Kawamura YJ, Noda H, Horie H, Konishi F and Rikiyama T: Multiple primary malignancies involving primary sporadic colorectal cancer in Japan: Incidence of gastric cancer with colorectal cancer patients may be higher than previously recognized. World J Surg Oncol. 13:232015. View Article : Google Scholar : PubMed/NCBI

35 

Kondratova VN, Botezatu IV, Shelepov VP and Likhtenshtein AV: Transcripts of satellite DNA in blood plasma: Probable markers of tumor growth. Mol Biol (Mosk). 48:999–1007. 2014.(In Russian). View Article : Google Scholar : PubMed/NCBI

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August 2019
Volume 42 Issue 2

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Copy and paste a formatted citation
APA
Kakizawa, N., Suzuki, K., Abe, I., Endo, Y., Tamaki, S., Ishikawa, H. ... Rikiyama, T. (2019). High relative levels of satellite alpha transcripts predict increased risk of bilateral breast cancer and multiple primary cancer in patients with breast cancer and lacking BRCA‑related clinical features. Oncology Reports, 42, 857-865. https://doi.org/10.3892/or.2019.7182
MLA
Kakizawa, N., Suzuki, K., Abe, I., Endo, Y., Tamaki, S., Ishikawa, H., Watanabe, F., Ichida, K., Saito, M., Futsuhara, K., Konishi, F., Rikiyama, T."High relative levels of satellite alpha transcripts predict increased risk of bilateral breast cancer and multiple primary cancer in patients with breast cancer and lacking BRCA‑related clinical features". Oncology Reports 42.2 (2019): 857-865.
Chicago
Kakizawa, N., Suzuki, K., Abe, I., Endo, Y., Tamaki, S., Ishikawa, H., Watanabe, F., Ichida, K., Saito, M., Futsuhara, K., Konishi, F., Rikiyama, T."High relative levels of satellite alpha transcripts predict increased risk of bilateral breast cancer and multiple primary cancer in patients with breast cancer and lacking BRCA‑related clinical features". Oncology Reports 42, no. 2 (2019): 857-865. https://doi.org/10.3892/or.2019.7182