Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer
Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer
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DOI：
10.1073/pnas.1407909111
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发表时间：
2014-10-21
影响因子：
11.1
通讯作者：
Nevanlinna, Heli
中科院分区：
文献类型：
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作者：
Kiiski, Johanna I.;Pelttari, Liisa M.;Nevanlinna, Heli
众所周知，遗传性乳腺癌的易感性是由BRCA1、BRCA2、PALB2、CHEK2和其他参与DNA修复的基因的功能丧失突变引起的。然而，大多数严重受乳腺癌影响的家庭都没有这些基因的突变。在芬兰，在这些基因中的每一个都观察到了创始人突变，这表明芬兰人口可能是鉴定其他此类基因的极好资源。为此，我们对来自11个芬兰乳腺癌家系的24名乳腺癌患者的构成基因组DNA进行了外显子组测序。从所有罕见的破坏性变异中，对3166名乳腺癌患者、569名卵巢癌患者和2090名对照组的21个DNA修复基因的22个变异进行了基因分型，这些患者都来自芬兰的赫尔辛基或坦佩雷地区。Fanconi贫血互补基因M无义突变c.5101C>；T(p.Q1701X)在乳腺癌患者中显著高于对照组[优势比(OR)=1.86，95%CI=1.26~2.75；P=0.0018]，在三阴性乳腺癌患者中尤为明显(P=0.0002)。在赫尔辛基和坦佩雷地区，FANCM p.Q1701X的携带率在乳腺癌患者中分别为2.9%和4.0%，在TNBC患者中分别为5.6%和6.6%，在卵巢癌患者中为2.2%(来自赫尔辛基)，在对照组中分别为1.4%和2.5%。这些发现确定FANCM是乳腺癌的易感基因，突变使TNBC具有特别强的易感性。
Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26-2.75; P = 0.0018], with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81-6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.