Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
Cancer Res. 2011 Mar 15;71(6):2222-9. doi: 10.1158/0008-5472.CAN-10-3958. Epub 2011 Feb 1.
Inherited mutations in the BRCA2-interacting protein PALB2 are known to be associated with increased risks of developing breast cancer. To evaluate the contribution of PALB2 to familial breast cancer in the United States, we sequenced the coding sequences and flanking regulatory regions of the gene from constitutional genomic DNA of 1,144 familial breast cancer patients with wild-type sequences at BRCA1 and BRCA2. Overall, 3.4% (33/972) of patients not selected by ancestry and 0% (0/172) of patients specifically of Ashkenazi Jewish ancestry were heterozygous for a nonsense, frameshift, or frameshift-associated splice mutation in PALB2. Mutations were detected in both male and female breast cancer patients. All mutations were individually rare: the 33 heterozygotes harbored 13 different mutations, 5 previously reported and 8 novel mutations. PALB2 heterozygotes were 4-fold more likely to have a male relative with breast cancer (P = 0.0003), 6-fold more likely to have a relative with pancreatic cancer (P = 0.002), and 1.3-fold more likely to have a relative with ovarian cancer (P = 0.18). Compared with their female relatives without mutations, increased risk of developing breast cancer for female PALB2 heterozygotes was 2.3-fold (95% CI: 1.5-4.2) by age 55 and 3.4-fold (95% CI: 2.4-5.9) by age 85. Loss of the wild-type PALB2 allele was observed in laser-dissected tumor specimens from heterozygous patients. Given this mutation prevalence and risk, consideration might be given to clinical testing of PALB2 by complete genomic sequencing for familial breast cancer patients with wild-type sequences at BRCA1 and BRCA2.
已知 BRCA2 相互作用蛋白 PALB2 的遗传突变与乳腺癌风险增加有关。为了评估 PALB2 在美国家族性乳腺癌中的作用，我们对 1144 例 BRCA1 和 BRCA2 野生型家族性乳腺癌患者的外显子组和侧翼调控区进行了测序。总的来说，3.4%（33/972）的无家族史患者和 0%（0/172）的阿什肯纳兹犹太裔患者为 PALB2 错义、移码或移码相关剪接突变的杂合子。在男性和女性乳腺癌患者中均检测到突变。所有突变均为个体罕见突变：33 名杂合子患者携带 13 种不同的突变，其中 5 种为已报道突变，8 种为新突变。PALB2 杂合子发生男性乳腺癌的风险增加 4 倍（P = 0.0003），发生胰腺癌的风险增加 6 倍（P = 0.002），发生卵巢癌的风险增加 1.3 倍（P = 0.18）。与无突变的女性亲属相比，女性 PALB2 杂合子发生乳腺癌的风险增加 2.3 倍（95%CI：1.5-4.2），85 岁时增加 3.4 倍（95%CI：2.4-5.9）。在杂合子患者的激光切割肿瘤标本中观察到野生型 PALB2 等位基因的丢失。鉴于这种突变发生率和风险，对于 BRCA1 和 BRCA2 野生型家族性乳腺癌患者，可能考虑通过全基因组测序进行 PALB2 的临床检测。
