Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer.
Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer.
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DOI：
10.1158/0008-5472.can-10-3958
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发表时间：
2011-03-15
期刊：
影响因子：
11.2
通讯作者：
King MC
中科院分区：
文献类型：
--
作者：
Casadei S;Norquist BM;Walsh T;Stray S;Mandell JB;Lee MK;Stamatoyannopoulos JA;King MC
已知BRCA 2相互作用蛋白PALB 2的遗传突变与乳腺癌风险增加有关。为了评估PALB 2在美国家族性乳腺癌中的作用，我们对1144例BRCA 1和BRCA 2野生型家族性乳腺癌患者的基因组DNA中的编码序列和侧翼调控区进行了测序。总体而言，3.4%（33/972）的未按血统选择的患者和0%（0/172）的德系犹太血统患者为PALB 2无义、移码或移码相关剪接突变杂合子。在男性和女性乳腺癌患者中都检测到突变。所有突变都是罕见的：33个杂合子携带13个不同的突变，5个以前报道过，8个新的。PALB 2杂合子的男性亲属患乳腺癌的可能性高4倍（P=0.0003），患胰腺癌的可能性高6倍（P=0.002），患卵巢癌的可能性高1.3倍（P=0.18）。与没有突变的女性亲属相比，女性PALB 2杂合子的乳腺癌风险在55岁时增加2.3倍（95%CI [1.5-4.2]），在85岁时增加3.4倍（95%CI [2.4-5.9]）。在来自杂合子患者的激光切割肿瘤标本中观察到野生型PALB 2等位基因的缺失。考虑到这种突变的发生率和风险，可以考虑通过对BRCA 1和BRCA 2野生型序列的家族性乳腺癌患者进行全基因组测序来进行PALB 2的临床检测。
Inherited mutations in the BRCA2-interacting protein PALB2 are known to be associated with increased risks of breast cancer. In order 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 1144 familial breast cancer patients with wildtype 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. PALB2 heterozygotes were 4-fold more likely to have a male relative with breast cancer (P=0.0003) and 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 to their female relatives without mutations, increased risk of 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 wildtype 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 wildtype sequences at BRCA1 and BRCA2.