Alterations of the PPP2R1B gene located at 11q23 in human colorectal cancers
Alterations of the PPP2R1B gene located at 11q23 in human colorectal cancers
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作者：
Takagi, Y;Futamura, M;Saji, S
背景/目的：1998年，编码丝氨酸/苏氨酸蛋白磷酸酶A亚基的PPPZR1B基因在染色体11q22-24区被鉴定为肺癌和结肠癌的推定肿瘤抑制基因。本研究的目的是确定原发性直肠癌和结肠癌的改变类型以及这些改变与临床病理数据之间的关系。方法：采用聚合酶链反应和随后的直接DNA测序相结合的方法，对30例原发性结直肠癌标本和相应的正常组织的cDNA样本进行了编码催化C亚基（亨廷顿延伸A亚基TOR （HEAT）重复11-15）结合位点和调控B亚基部分结合位点的PPP2R1B基因序列的突变分析。结果：在4例结肠癌中（13.3%，30例结直肠癌中有4例）检测到5个产生氨基酸替换的错义突变：（15）甘氨酸（GGT）变为丙氨酸（GCT），（499）亮氨酸（TTA）变为异亮氨酸（ATA），（498）缬氨酸（GTG）变为谷氨酸（GAG），（500）缬氨酸（GTA）变为甘氨酸（GGA），（365）丝氨酸（TCT）变为脯氨酸（CCT）。在这5个突变中，3个（60%）位于HEAT repeat 13, 4个（80%）向其他核苷酸取代显示T。此外，还发现了正常多态性（478）亮氨酸。这些突变与临床病理数据没有相关性。结论：我们的研究结果表明PPP2R1B基因是11q23的真正靶点之一，其失活参与了所有类型结直肠癌的发展。
Background/aims-In 1998 the PPPZR1B gene encoding the A subunit of the serine/ threonine protein phosphatase was identified as a putative tumour suppressor gene in lung and colon cancer in the chromosome region 11q22-24. The aim of the present study was to determine the type of alterations in primary rectal cancers as well as colon cancers and the correlation between these alterations and clinicopathological data.Methods-Mutation analyses of the PPP2R1B gene sequence encoding the binding sites of the catalytic C subunit (Huntington elongation A subunit TOR (HEAT) repeats 11-15) and partial binding sites of the regulatory B subunit were carried out on cDNA samples from 30 primary colorectal cancer specimens and corresponding normal tissues using a combination of the polymerase chain reaction and subsequent direct DNA sequencing.Results-Five missense mutations producing amino acid substitutions were detected in the four colon cancer cases (13.3%; four of 30 colorectal cancers): (15)glycine (GGT) to alanine (GCT) and (499)leucine (TTA) to isoleucine (ATA) in the same case, and (498)valine (GTG) to glutamic acid (GAG), (500)valine (GTA) to glycine (GGA), and (365)serine (TCT) to proline (CCT). Of these five mutations, three (60%) were located in HEAT repeat 13 and four (80%) showed T to other nucleotide substitutions. In addition, a normal polymorphism, (478)leucine, was found. No correlation was found between these mutations and clinicopathological data.Conclusion-Our results suggest that the PPP2R1B gene is one of the true targets at 11q23, and its inactivation is involved in the development of all types of colorectal cancers.