Yoon-Sim Yap1,2, Prabhakaran Munusamy3, Cindy Lim4, Claire H T Chan3, Aldo Prawira3, Sau-Yeen Loke3, Swee-Ho Lim5, Kong-Wee Ong6, Wei-Sean Yong6, Sarah B H Ng7, Iain B H Tan8,7, David F Callen9, Jeffrey C T Lim10, Aye-Aye Thike10, Puay-Hoon Tan10, Ann S G Lee11,12,13. 1. Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore. Yap.Y.S@nccs.com.sg. 2. Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide, Australia. Yap.Y.S@nccs.com.sg. 3. Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore. 4. Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore, Singapore. 5. Breast Department, KK Women's and Children's Hospital, Singapore, Singapore. 6. Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore. 7. Genome Institute of Singapore, A*STAR, Singapore, Singapore. 8. Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore. 9. Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide, Australia. 10. Division of Pathology, Singapore General Hospital, Singapore, Singapore. 11. Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore. dmslsg@nccs.com.sg. 12. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. dmslsg@nccs.com.sg. 13. Office of Clinical & Academic Faculty Affairs, Duke-NUS Graduate Medical School, Singapore, Singapore. dmslsg@nccs.com.sg.
Abstract
PURPOSE: The purpose of the study was to improve the understanding of NF1-associated breast cancer, given the increased risk of breast cancer in this tumour predisposition syndrome and the limited data. METHODS: We identified 18 women with NF1 and breast cancer at our institution. Clinical and pathologic characteristics of NF1-associated breast cancers were compared with 7132 breast cancers in patients without NF1 from our institutional database. Next generation sequencing was performed on DNA from blood and breast cancer specimens available. Blood specimens negative for NF1 mutation were subjected to multiplex ligation-dependent probe amplification (MLPA) to identify complete/partial deletions or duplications. Expression of neurofibromin in the NF1-associated breast cancers was evaluated using immunohistochemistry. RESULTS: There was a higher frequency of grade 3 (83.3% vs 45.4%, p = 0.005), oestrogen receptor (ER) negative (66.7% vs 26.3%, p < 0.001) and human epidermal growth factor receptor 2 (HER2)-positive (66.7% vs 23.4%, p < 0.001) tumours among NF1 patients compared to non-NF1 breast cancers. Overall survival was inferior in NF1 patients in multivariable analysis (hazard ratio 2.25, 95% CI 1.11-4.60; p = 0.025). Apart from germline NF1 mutations (11/16; 69%), somatic mutations in TP53 (8/10; 80%), second-hit NF1 (2/10; 20%), KMT2C (4/10; 40%), KMT2D (2/10; 20%), and PIK3CA (2/10; 20%) were observed. Immunohistochemical expression of neurofibromin was seen in the nuclei and/or cytoplasm of all specimens, but without any consistent pattern in the intensity or extent. CONCLUSIONS: This comprehensive series of NF1-associated breast cancers suggests that their aggressive features are related to germline NF1 mutations in cooperation with somatic mutations in TP53, KMT2C and other genes.
PURPOSE: The purpose of the study was to improve the understanding of NF1-associated breast cancer, given the increased risk of breast cancer in this tumour predisposition syndrome and the limited data. METHODS: We identified 18 women with NF1 and breast cancer at our institution. Clinical and pathologic characteristics of NF1-associated breast cancers were compared with 7132 breast cancers in patients without NF1 from our institutional database. Next generation sequencing was performed on DNA from blood and breast cancer specimens available. Blood specimens negative for NF1 mutation were subjected to multiplex ligation-dependent probe amplification (MLPA) to identify complete/partial deletions or duplications. Expression of neurofibromin in the NF1-associated breast cancers was evaluated using immunohistochemistry. RESULTS: There was a higher frequency of grade 3 (83.3% vs 45.4%, p = 0.005), oestrogen receptor (ER) negative (66.7% vs 26.3%, p < 0.001) and humanepidermal growth factor receptor 2 (HER2)-positive (66.7% vs 23.4%, p < 0.001) tumours among NF1patients compared to non-NF1breast cancers. Overall survival was inferior in NF1patients in multivariable analysis (hazard ratio 2.25, 95% CI 1.11-4.60; p = 0.025). Apart from germline NF1 mutations (11/16; 69%), somatic mutations in TP53 (8/10; 80%), second-hit NF1 (2/10; 20%), KMT2C (4/10; 40%), KMT2D (2/10; 20%), and PIK3CA (2/10; 20%) were observed. Immunohistochemical expression of neurofibromin was seen in the nuclei and/or cytoplasm of all specimens, but without any consistent pattern in the intensity or extent. CONCLUSIONS: This comprehensive series of NF1-associated breast cancers suggests that their aggressive features are related to germline NF1 mutations in cooperation with somatic mutations in TP53, KMT2C and other genes.
Entities:
Keywords:
Breast cancer; NF1; Neurofibromatosis type 1; Tumour suppressor
Authors: Robert Galvin; Adrienne L Watson; David A Largaespada; Nancy Ratner; Sara Osum; Christopher L Moertel Journal: Curr Oncol Rep Date: 2021-03-15 Impact factor: 5.075
Authors: Maria Lucia Sur; Ionel Armat; Genel Sur; Diana-Cristina Pop; Gabriel Samasca; Iulia Lupan; Teodora-Larisa Timis; Ioan-Alexandru Florian; Daniel Sur Journal: Children (Basel) Date: 2022-01-02