Nakagomi Hiroshi, Sakamoto Ikuko, Hirotsu Yosuke, Amemiya Kenji, Mochiduki Hitoshi, Omata Masao
Department of Breast Surgery, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu, 400-0027, Japan.
Department of Surgery, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu, 400-0027, Japan.
Int J Clin Oncol. 2016 Apr;21(2):270-275. doi: 10.1007/s10147-015-0906-4. Epub 2015 Sep 28.
PALB2 (Partner and Localizer of BRCA2) was identified as a moderate-risk gene in breast and pancreatic cancers. Recently, it was reported that PALB2 carriers have a high risk of developing breast cancer, with the cumulative risk of 34 % by the age of 70.
Peripheral blood samples from 155 patients at risk for hereditary breast and/or ovarian cancer were tested for BRCA1/2 and PALB2 by targeted sequencing using a next-generation sequencer. Of these 155, 146 met NCCN criteria and the remaining 9 did not.
BRCA1/2 analysis was performed on 155 patients, for whom the results were reported previously (Hirotsu Y et al. Mol Genet Genomic Med, doi:10.1002/mgg3.157, 2015). Eleven patients were identified to have deleterious BRCA mutations (Hirotsu Y et al. Mol Genet Genomic Med, doi:10.1002/mgg3.157, 2015). However, none of the 155 patients were found to have deleterious PALB2 germline mutations. Missense mutations [variants of uncertain significance (VUS)] of PALB2 were found in 12 cases. In silico analyses by SIFT (Sorting Intolerant Form Tolerant) and PolyPhen2 (Polymorphism Phenotyping version 2) indicated that 2 of 12 VUS were deleterious and probably damaging.
This is the first report on PALB2 mutations in Japan, revealing two missense mutations as "deleterious and probably damaging" by in silico analyses, but no PALB2 premature truncation mutations were identified. The sample size is relatively small and a larger cohort study is needed in Japan.
PALB2（BRCA2的伙伴和定位蛋白）被确定为乳腺癌和胰腺癌的中度风险基因。最近，有报道称PALB2携带者患乳腺癌的风险很高，到70岁时累积风险为34%。
使用下一代测序仪通过靶向测序对155例有遗传性乳腺癌和/或卵巢癌风险的患者的外周血样本进行BRCA1/2和PALB2检测。在这155例患者中，146例符合NCCN标准，其余9例不符合。
对155例患者进行了BRCA1/2分析，其结果先前已报道（Hirotsu Y等人，《分子遗传学与基因组医学》，doi:10.1002/mgg3.157，2015年）。确定有11例患者存在有害的BRCA突变（Hirotsu Y等人，《分子遗传学与基因组医学》，doi:10.1002/mgg3.157，2015年）。然而，在这155例患者中未发现有有害的PALB2种系突变。在12例患者中发现了PALB2的错义突变[意义未明的变异（VUS）]。通过SIFT（筛选耐受型与不耐受型）和PolyPhen2（多态性表型分析版本2）进行的计算机分析表明，12个VUS中有2个是有害的且可能具有破坏性。
这是日本关于PALB2突变的首次报告，通过计算机分析揭示了两个错义突变是“有害的且可能具有破坏性”，但未发现PALB2的截短突变。样本量相对较小，日本需要开展更大规模的队列研究。
