Crona Joakim, Gustavsson Tobias, Norlén Olov, Edfeldt Katarina, Åkerström Tobias, Westin Gunnar, Hellman Per, Björklund Peyman, Stålberg Peter
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Ann Surg Oncol. 2015 Dec;22 Suppl 3:S1428-35. doi: 10.1245/s10434-014-4351-9. Epub 2015 Jan 14.
Until recently, the genetic landscape of small intestinal neuroendocrine tumors (SI-NETs) was limited to recurrent copy number alterations, most commonly a loss on chromosome 18. Intertumor heterogeneity with nonconcordant genotype in paired primary and metastatic lesions also is described, further contributing to the difficulty of unraveling the genetic enigma of SI-NETs. A recent study analyzing 55 SI-NET exomes nominated CDKN1B (p27) as a haploinsufficient tumor suppressor gene.
This study aimed to determine the frequency of CDKN1B inactivation and to investigate genotype-phenotype correlations. It investigated 362 tumors from 200 patients. All samples were resequenced for mutations in CDKN1B using automated Sanger sequencing. The expression of p27 was investigated in 12 CDKN1B mutant and nine wild type tumors.
Some 8.5 % (17/200) of patients had tumors with pathogenic mutations in CDKN1B including 13 insertion deletions, four nonsense variants, and one stop-loss variant. All variants with available nontumoral DNA were classified as somatic. Inter- and intratumor heterogeneity at the CDKN1B locus was detected respectively in six of ten and two of ten patients. Patients with CDKN1B mutated tumors had both heterogeneous disease presentation and diverse prognosis. Expression of the p27 protein did not correlate with CDKN1B mutation status, and no differences in the clinical characteristics between CDKN1B mutated and CDKN1B wild type tumor carriers were found.
This study corroborates the finding of CDKN1B as a potential haplo-insufficient tumor suppressor gene characterized by inter- and intratumor heterogeneity in SI-NETs.
直到最近，小肠神经内分泌肿瘤（SI-NETs）的遗传图谱还局限于反复出现的拷贝数改变，最常见的是18号染色体缺失。也有关于配对的原发性和转移性病变中肿瘤间异质性以及基因型不一致的描述，这进一步增加了揭开SI-NETs遗传谜团的难度。最近一项分析55个SI-NET外显子组的研究将CDKN1B（p27）确定为单倍体不足的肿瘤抑制基因。
本研究旨在确定CDKN1B失活的频率，并研究基因型与表型的相关性。该研究调查了来自200名患者的362个肿瘤。使用自动桑格测序对所有样本重新测序以检测CDKN1B中的突变。在12个CDKN1B突变肿瘤和9个野生型肿瘤中研究了p27的表达。
约8.5%（17/200）的患者肿瘤中存在CDKN1B致病突变，包括13个插入缺失、4个无义变体和1个失活变体。所有具有可用非肿瘤DNA的变体均被分类为体细胞突变。分别在十分之六和十分之二的患者中检测到CDKN1B位点的肿瘤间和肿瘤内异质性。患有CDKN1B突变肿瘤的患者具有异质性疾病表现和不同的预后。p27蛋白的表达与CDKN1B突变状态无关，并且在CDKN1B突变和CDKN1B野生型肿瘤携带者之间未发现临床特征上的差异。
本研究证实了CDKN1B作为潜在的单倍体不足肿瘤抑制基因的发现，其特征是SI-NETs中存在肿瘤间和肿瘤内异质性。
