Study on the correlation between PIK3CA/TP53 gene mutations and molecular typing andhistological grading of breast cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YANG Bo ¹ , ZHANG Xiaoyan ² , ZENG Hong ³ , LIU Hailiang ⁴ ,  LIU Yanhui ² , HAN Shuzhen ⁵

1. Department of Breast Surgery, Dongguan Maternal and Child Health Hospital, Dongguan, Guangdong 523000, P. R. China;
2. Center of Prenatal Diagnosis, Dongguan Institute of Reproductive and Genetic Research, Dongguan Maternal and Child Health Hospital, Dongguan, Guangdong 523000, P. R. China;
3. Department of Pathology, Dongguan Maternal and Child Health Hospital, Dongguan, Guangdong 523000, P. R. China;
4. Capital Bio Technology Inc, Dongguan, Guangdong 523808, P. R. China;
5. Department of Pathology, Dongguan Houjie Hospital, Dongguan, Guangdong 523000, P. R. China;

Corresponding author：

LIU Yanhui, Email: liuliang71215@163.com

Keywords：

breast cancer; mutate spectrum; genetic screening; high-throughput sequencing

DOI：

10.7507/1007-9424.201812093

Video：

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Objective To provide reference for further treatment by analyzing the relationship between mutant genes of breast cancer and histological classification and molecular typing of breast cancer.Methods Retrospectively collectted the pathological specimens of 46 breast cancer patients who treated by the Dongguan Maternal and Child Health Hospital and the Dongguan Houjie Hospital between February 2016 and August 2017 without chemotherapy. Among the selected 46 breast cancer patients, we detected tumor tissue estrogen receptor (ER)/ pregnancy hormone receptor (PR)/human epidermal growth factor receptor-2 (HER-2) status by immunohistochemistry and classified the pathological tissue section. By using multiple PCR techniques, we detected 207 hot mutation regions of the 50 extended tumor-related genes on the semiconductor sequencing platform.Results There were 8 cases of grade Ⅰ, 18 cases of grade Ⅱ, 20 cases of grade Ⅲ in 46 breast cancer patients according to histological grade. Of the 46 cases, there were 23 cases of Luminal B, 9 cases of Luminal A, 9 cases of HER-2 (+), 5 cases of type besal-like according to ER/PR/HER-2 expression status. Moreover, we found that there were 33 gene locus mutations of 8 genes, including AKT1, APC, BRAF, CDKN2A, KRAS, PTEN, PIK3CA, and TP53. Among of them, the mutation of PIK3CA gene took the most of 24 cases, followed by TP53 (18 cases), 2 cases of CDKN2A gene mutation, and 1 case in the remaining four types of genes respectively. we found that the gene mutations of breast cancer were not related to the histological classification and molecular type (P>0.05), the PIK3CA gene mutation was related to the histological classification of breast cancer, the lower the histological classification level, the higher PIK3CA gene mutation rate (P<0.05). TP53 gene mutation was not related to histological grading and molecular type (P>0.05).Conclusions The PIK3CA gene mutation rate in patients with histological grading Ⅰ level increased significantly. The combination of PIK3CA gene mutation and histological grading of breast cancer may become a molecular biological indicator to judge the degree of malignancy and prognosis of breast cancer.

Citation： YANG Bo, ZHANG Xiaoyan, ZENG Hong, LIU Hailiang, LIU Yanhui, HAN Shuzhen. Study on the correlation between PIK3CA/TP53 gene mutations and molecular typing andhistological grading of breast cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2019, 26(5): 573-578. doi: 10.7507/1007-9424.201812093 Copy

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6.	Lips EH, Michaut M, Hoogstraat M, et al. Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response. Breast Cancer Res, 2015, 17(1): 134.
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11.	Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med, 2004, 351(27): 2817-2826.
12.	Kataoka Y, Mukohara T, Shimada H, et al. Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol, 2010, 21(2): 255-262.
13.	袁鹏飞, 汪建光, 张丽柯, 等. PIK3CA 基因在乳腺癌不同分子亚型中突变的研究. 河南科技大学学报: 医学版, 2014, 32(4): 245-246, 250.
14.	Bhat-Nakshatri P, Goswami CP, Badve S, et al. Molecular insights of pathways resulting from two common PIK3CA mutations in breast cancer. Cancer Res, 2016, 76(13): 3989-4001.
15.	von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol, 2014, 15(7): 747-756.
16.	Kalinsky K, Jacks LM, Heguy A, et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res, 2009, 15(16): 5049-5059.
17.	李少英, 王维, 李建梅, 等. PIK3CA 基因突变与乳腺癌恶性程度和预后的关系. 中华肿瘤杂志, 2011, 33(8): 605-608.
18.	Park BH, Davidson NE. PI3 kinase activation and response to trastuzumab therapy: what’s neu with herceptin resistance? Cancer Cell, 2007, 12(4): 297-299.
19.	Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell, 2007, 12(4): 395-402.
20.	邓粤敏, 徐韫健. PIK3CA 基因突变状态在乳腺癌不同临床病理特征中的研究. 国际检验医学杂志, 2016, 37(15): 2110-2111, 2114.
21.	Lalloo F, Varley J, Moran A, et al. BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer, 2006, 42(8): 1143-1150.
22.	樊菁, 吕勇刚, 王廷, 等. 易感基因突变与遗传性乳腺癌的关系. 中华乳腺病杂志: 电子版, 2014, 8(6): 34-42.
23.	Lee DS, Yoon SY, Looi LM, et al. Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients. Breast Cancer Res, 2012, 14(2): R66.
24.	Mouchawar J, Korch C, Byers T, et al. Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Res, 2010, 70(12): 4795-4800.
25.	杨晓晨, 胡震, 吴炅, 等. 中国乳腺癌高风险人群中 TP53 基因胚系突变的研究. 中华医学遗传学杂志, 2015, 32(6): 761-765.

1. Fan L, Strasser-Weippl K, Li JJ, et al. Breast cancer in China. Lancet Oncol, 2014, 15(7): e279-e289.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin, 2017, 67(1): 7-30.
3. Banin Hirata BK, Oda JM, Losi Guembarovski R, et al. Molecular markers for breast cancer: prediction on tumor behavior. Dis Markers, 2014, 2014: 513158.
4. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature, 2002, 415(6871): 530-536.
5. Ivshina AV, George J, Senko O, et al. Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer. Cancer Res, 2006, 66(21): 10292-10301.
6. Lips EH, Michaut M, Hoogstraat M, et al. Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response. Breast Cancer Res, 2015, 17(1): 134.
7. Lakhani SR, Ellis IO, Schnitt SJ, et al. WHO classification of tumours of the breast. Lyon: IABC Press, 2012: 13-15.
8. Almendro V, Fuster G. Heterogeneity of breast cancer: etiology and clinical relevance. Clin Transl Oncol, 2011, 13(11): 767-773.
9. Ariga R, Zarif A, Korasick J, et al. Correlation of her-2/neu gene amplification with other prognostic and predictive factors in female breast carcinoma. Breast J, 2005, 11(4): 278-280.
10. 徐倩倩, 王常珺, 孙强. 三阴性乳腺癌分子分型与个体化靶向治疗现状. 中华肿瘤防治杂志, 2017, 24(11): 788-794.
11. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med, 2004, 351(27): 2817-2826.
12. Kataoka Y, Mukohara T, Shimada H, et al. Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol, 2010, 21(2): 255-262.
13. 袁鹏飞, 汪建光, 张丽柯, 等. PIK3CA 基因在乳腺癌不同分子亚型中突变的研究. 河南科技大学学报: 医学版, 2014, 32(4): 245-246, 250.
14. Bhat-Nakshatri P, Goswami CP, Badve S, et al. Molecular insights of pathways resulting from two common PIK3CA mutations in breast cancer. Cancer Res, 2016, 76(13): 3989-4001.
15. von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol, 2014, 15(7): 747-756.
16. Kalinsky K, Jacks LM, Heguy A, et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res, 2009, 15(16): 5049-5059.
17. 李少英, 王维, 李建梅, 等. PIK3CA 基因突变与乳腺癌恶性程度和预后的关系. 中华肿瘤杂志, 2011, 33(8): 605-608.
18. Park BH, Davidson NE. PI3 kinase activation and response to trastuzumab therapy: what’s neu with herceptin resistance? Cancer Cell, 2007, 12(4): 297-299.
19. Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell, 2007, 12(4): 395-402.
20. 邓粤敏, 徐韫健. PIK3CA 基因突变状态在乳腺癌不同临床病理特征中的研究. 国际检验医学杂志, 2016, 37(15): 2110-2111, 2114.
21. Lalloo F, Varley J, Moran A, et al. BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer, 2006, 42(8): 1143-1150.
22. 樊菁, 吕勇刚, 王廷, 等. 易感基因突变与遗传性乳腺癌的关系. 中华乳腺病杂志: 电子版, 2014, 8(6): 34-42.
23. Lee DS, Yoon SY, Looi LM, et al. Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients. Breast Cancer Res, 2012, 14(2): R66.
24. Mouchawar J, Korch C, Byers T, et al. Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Res, 2010, 70(12): 4795-4800.
25. 杨晓晨, 胡震, 吴炅, 等. 中国乳腺癌高风险人群中 TP53 基因胚系突变的研究. 中华医学遗传学杂志, 2015, 32(6): 761-765.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Study on the correlation between PIK3CA/TP53 gene mutations and molecular typing andhistological grading of breast cancer

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