title: The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype.
abstract: OBJECTIVE
  To determine the effect of the breast cancer susceptibility mutation PALB2 1592delT on tumor phenotype and patient survival.
  
  
  METHODS
  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.
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Heikkinen
authors.forename: Hanni
authors.initials: H
authors.lastname: Kärkkäinen
authors.forename: Kirsimari
authors.initials: K
authors.lastname: Aaltonen
authors.forename: Roger L
authors.initials: RL
authors.lastname: Milne
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000556:secondary; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000556:secondary; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D025521:Tumor Suppressor Proteins; C118024:BLID protein, human; C492913:BRCA1 protein, human; C551750:BRCA2 protein, human; C512790:PALB2 protein, human; C508053:ERBB2 protein, human