PURPOSE: To determine the effect of the breast cancer susceptibility mutation PALB2 1592delT on tumor phenotype and patient survival. EXPERIMENTAL DESIGN: We defined the PALB2 mutation status in 947 familial and 1,274 sporadic breast cancer patients and 1,079 population controls, and compared tumor characteristics and survival in mutation carriers relative to other familial and sporadic cases and to 79 BRCA1 and 104 BRCA2 mutation carrier cases. RESULTS: The PALB2 1592delT mutation was found in 19 familial [2.0%; odds ratio, 11.03; 95% confidence interval (95% CI), 2.65-97.78; P < 0.0001] and eight sporadic patients (0.6%; odds ratio, 3.40; 95% CI, 0.68-32.95; P = 0.1207) compared with two (0.2%) control individuals. Tumors of the PALB2 mutation carriers presented triple negative (estrogen receptor negative/progesterone receptor negative/HER negative) phenotype more often (54.5%; P < 0.0001) than those of other familial (12.2%) or sporadic (9.4%) breast cancer patients. They were also more often of higher grade (P = 0.0027 and P = 0.0017, respectively) and had higher expression of Ki67 (P = 0.0004 and P = 0.0490, respectively). Carrying a PALB2 mutation was also associated with reduced survival, especially in familial cases (hazard ratio, 2.30; 95% CI, 1.01-5.24; P = 0.0466) and among familial patients with HER2-negative tumors (hazard ratio, 4.57; 95% CI, 1.96-10.64; P = 0.0004). Carrying a BRCA2 mutation was also found to be an independent predictor of poor survival at 10-year follow-up (P = 0.04). CONCLUSIONS: The PALB2 1592delT mutation has a strong effect on familial breast cancer risk. The tumors rising in patients carrying this mutation manifest a phenotype associated with aggressive disease. Our results also suggest a significant impact of carrying a BRCA2 mutation on long-term breast cancer survival.
PURPOSE: To determine the effect of the breast cancer susceptibility mutation PALB21592delT on tumor phenotype and patient survival. EXPERIMENTAL DESIGN: We defined the PALB2 mutation status in 947 familial and 1,274 sporadic breast cancerpatients and 1,079 population controls, and compared tumor characteristics and survival in mutation carriers relative to other familial and sporadic cases and to 79 BRCA1 and 104 BRCA2 mutation carrier cases. RESULTS: The PALB21592delT mutation was found in 19 familial [2.0%; odds ratio, 11.03; 95% confidence interval (95% CI), 2.65-97.78; P < 0.0001] and eight sporadic patients (0.6%; odds ratio, 3.40; 95% CI, 0.68-32.95; P = 0.1207) compared with two (0.2%) control individuals. Tumors of the PALB2 mutation carriers presented triple negative (estrogen receptor negative/progesterone receptor negative/HER negative) phenotype more often (54.5%; P < 0.0001) than those of other familial (12.2%) or sporadic (9.4%) breast cancerpatients. They were also more often of higher grade (P = 0.0027 and P = 0.0017, respectively) and had higher expression of Ki67 (P = 0.0004 and P = 0.0490, respectively). Carrying a PALB2 mutation was also associated with reduced survival, especially in familial cases (hazard ratio, 2.30; 95% CI, 1.01-5.24; P = 0.0466) and among familial patients with HER2-negative tumors (hazard ratio, 4.57; 95% CI, 1.96-10.64; P = 0.0004). Carrying a BRCA2 mutation was also found to be an independent predictor of poor survival at 10-year follow-up (P = 0.04). CONCLUSIONS: The PALB21592delT mutation has a strong effect on familial breast cancer risk. The tumors rising in patients carrying this mutation manifest a phenotype associated with aggressive disease. Our results also suggest a significant impact of carrying a BRCA2 mutation on long-term breast cancer survival.
Authors: Roger L Milne; Justo Lorenzo-Bermejo; Barbara Burwinkel; Núria Malats; Jose Ignacio Arias; M Pilar Zamora; Javier Benítez; Manjeet K Humphreys; Montserrat García-Closas; Stephen J Chanock; Jolanta Lissowska; Mark E Sherman; Arto Mannermaa; Vesa Kataja; Veli-Matti Kosma; Heli Nevanlinna; Tuomas Heikkinen; Kristiina Aittomäki; Carl Blomqvist; Hoda Anton-Culver; Argyrios Ziogas; Peter Devilee; Christie J van Asperen; Rob A E M Tollenaar; Caroline Seynaeve; Per Hall; Kamila Czene; Jianjun Liu; Astrid K Irwanto; Daehee Kang; Keun-Young Yoo; Dong-Young Noh; Fergus J Couch; Janet E Olson; Xianshu Wang; Zachary Fredericksen; Børge G Nordestgaard; Stig E Bojesen; Henrik Flyger; Sara Margolin; Annika Lindblom; Peter A Fasching; Ruediger Schulz-Wendtland; Arif B Ekici; Matthias W Beckmann; Shan Wang-Gohrke; Chen-Yang Shen; Jyh-Cherng Yu; Huan-Ming Hsu; Pei-Ei Wu; Graham G Giles; Gianluca Severi; Laura Baglietto; Dallas R English; Angela Cox; Ian Brock; Graeme Elliott; Malcolm W R Reed; Jonathan Beesley; Xiaoqing Chen; Kconfab Investigators; Olivia Fletcher; Lorna Gibson; Isabel dos Santos Silva; Julian Peto; Bernd Frank; Joerg Heil; Alfons Meindl; Jenny Chang-Claude; Rebecca Hein; Alina Vrieling; Dieter Flesch-Janys; Melissa C Southey; Letitia Smith; Carmel Apicella; John L Hopper; Alison M Dunning; Karen A Pooley; Paul D P Pharoah; Ute Hamann; Beate Pesch; Yon-Dschun Ko; Douglas F Easton; Georgia Chenevix-Trench Journal: J Med Genet Date: 2011-10 Impact factor: 6.318
Authors: Nasim Mavaddat; Paul D Pharoah; Fiona Blows; Kristy E Driver; Elena Provenzano; Deborah Thompson; Robert J Macinnis; Mitul Shah; Douglas F Easton; Antonis C Antoniou Journal: Breast Cancer Res Date: 2010-02-10 Impact factor: 6.466
Authors: Zhi L Teo; Daniel J Park; Elena Provenzano; Catherine A Chatfield; Fabrice A Odefrey; Tu Nguyen-Dumont; James G Dowty; John L Hopper; Ingrid Winship; David E Goldgar; Melissa C Southey Journal: Breast Cancer Res Date: 2013-02-28 Impact factor: 6.466