The Breast Cancer Susceptibility Mutation PALB2 1592delT Is Associated with an Aggressive Tumor Phenotype

Abstract

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 and1,274 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.Breast cancer, the most common cancer among women in the world, has been estimated to have an inherited component of up to 27% (1). Mutations in the two high-penetrance predisposing genes, BRCA1 and BRCA2, are estimated to cause f15% of familial predisposition to breast cancer (2). Based on a meta-analysis, individuals with an inactivating germline mutation in BRCA1 have f57% risk for developing breast cancer and 40% risk for ovarian cancer by the age of 70 years, and individuals with a BRCA2 mutation have 49% risk for breast cancer and 18% risk for ovarian cancer (3). However, the risks may vary depending on family history or other modifying risk alleles (4, 5). The proteins encoded by these genes have an essential role in the maintenance of genomic integrity by homologous recombination repair of DNA double-strand breaks. They carry out these functions through interactions with a diverse network of other proteins (6). One of the most important interaction partners for BRCA2 is PALB2.PALB2 (partner and localizer for BRCA2) has an important function in the regulation and localization of BRCA2 (7). PALB2 protein colocalizes with BRCA2 in nuclear foci, strongly increasing the stability of BRCA2. PALB2 p...

PALB2 sequencing in Italian familial breast cancer cases reveals a high-risk mutation recurrent in the province of Bergamo

“…An OR of ~11 was estimated in Finnish familial cases and controls in two separate studies for the c.1592delT mutation. 29,30 The French-Canadian c.2323C>T mutation was tested in earlyonset cases and controls, yielding an OR of 103. This OR value was most likely overestimated, given that no mutation carriers were found among controls.…”

“…27,28 To date, PALB2 recurrent mutations have been reported in four populations. The Finnish c.1592delT (p.Leu531fs) mutation was investigated in two studies 29,30 and identified in 3/113 (2.7%) and 19/947 (2.0%) familial cases and in 6/2,501 (0.2%) and 2/1,079 (0.2%) controls, respectively. The c.2323C>T (p.Gln775X) mutation was detected in 4/564 (0.7%) FrenchCanadian early-onset cases and in 0/6,443 newborn infant controls.…”

PALB2 analysis in BRCA2-like families

“…In total, 77 PALB2 mutation-positive cases have been identified mainly in familial or early onset breast cancer cohorts from different populations [13,15,[18][19][20][21][22][23][24][25]. Of the 77 described PALB2 mutation cases, 52 are carrier of the 1592delT Finnish founder mutation, which could influence the currently known phenotype [19,24,26].…”

“…Of the 77 described PALB2 mutation cases, 52 are carrier of the 1592delT Finnish founder mutation, which could influence the currently known phenotype [19,24,26]. The selection criteria of these previous breast cancer studies varied, but most studies included BRCA1/2 mutation negative early onset breast cancer patients with diagnosis under 50 years or breast cancer patients from families with first or second degree relatives affected with breast-or ovarian cancer in unknown numbers.…”

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

“…Recurrent founder mutations in several cancer susceptibility genes, including the BRCA2, PALB2, and RAD51C FA genes, have been identified in the Finnish population (14)(15)(16). The PALB2 and RAD51C founder mutations have been detected at 2% frequency in Finnish breast or ovarian cancer families (15)(16)(17), whereas, in other populations, mutations in these genes are rare and often unique for each family. Founder effects in the isolated populations such as Finland or Iceland may enrich certain mutations and thus explain a significant proportion of all mutations in certain genes (18,19).…”