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Alterations of the PPP2R1B Gene Located at 11Q23 in Human Colorectal Cancers Gut: First Published As 10.1136/Gut.47.2.268 on 1 August 2000

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Alterations of the PPP2R1B Gene Located at 11Q23 in Human Colorectal Cancers Gut: First Published As 10.1136/Gut.47.2.268 on 1 August 2000 268 Gut 2000;47:268–271 Alterations of the PPP2R1B gene located at 11q23 in human colorectal cancers Gut: first published as 10.1136/gut.47.2.268 on 1 August 2000. Downloaded from Y Takagi, M Futamura, K Yamaguchi, S Aoki, T Takahashi, S Saji Abstract recently identified as a candidate tumour Background/aims—In 1998 the PPP2R1B suppressor gene in lung and colon cancer in gene encoding the A subunit of the serine/ this chromosome region.5 The PPP2R1B gene threonine protein phosphatase was identi- encodes the â isoform of the A subunit of the fied as a putative tumour suppressor gene serine/threonine protein phosphatase 2A in lung and colon cancer in the chromo- (PP2A). The PP2A holoenzyme consists of some region 11q22–24. The aim of the three subunits: a 65 kD structural/regulatory A present study was to determine the type of (PR65/A) subunit, a 36 kD catalytic C alterations in primary rectal cancers as (PP2Ac) subunit, and a variable regulatory B well as colon cancers and the correlation subunit.6 The holoenzyme, in forming a trimer, between these alterations and clinico- regulates diverse activities such as diVerentia- pathological data. tion, proliferation, or apoptosis, by reversible Methods—Mutation analyses of the phosphorylation.7 The PR65/A subunit dis- PPP2R1B gene sequence encoding the plays a series of 15 tandem internal repeats, binding sites of the catalytic C subunit termed a HEAT (Huntington elongation A (Huntington elongation A subunit TOR subunit TOR) motif.89 The HEAT repeat (HEAT) repeats 11–15) and partial bind- motif is characterised by a pair of antiparallel á ing sites of the regulatory B subunit were helices (termed A and B) that are stacked in a carried out on cDNA samples from 30 pri- consecutive array to generate a regular repeti- mary colorectal cancer specimens and tive protein architecture, reflecting the internal corresponding normal tissues using a repeats of the protein sequence. The A and B combination of the polymerase chain helices of the HEAT motif form convex and reaction and subsequent direct DNA se- concave faces, respectively. The parallel stack- quencing. ing of adjacent HEAT repeats aligns adjacent Results—Five missense mutations pro- intrarepeat turns that form a continuous ridge, ducing amino acid substitutions were providing a platform for mediating the protein- detected in the four colon cancer cases protein interactions between PR65/A subunit 8 (13.3%; four of 30 colorectal cancers): and PP2Ac and B subunits. The PR65/A http://gut.bmj.com/ 15glycine (GGT) to alanine (GCT) and subunit binds the PP2Ac subunit through 10 499leucine (TTA) to isoleucine (ATA) in the HEAT repeats 11–15 at the C terminus and same case, and 498valine (GTG) to glutamic binding between the PR65/A and the PP2Ac 500 subunit was abolished by sequence alterations acid (GAG), valine (GTA) to glycine 5 (GGA), and 365serine (TCT) to proline of HEAT repeats 13–15. (CCT). Of these five mutations, three Here we report mutational analysis of the (60%) were located in HEAT repeat 13 and sequence of this functionally important do- on October 1, 2021 by guest. Protected copyright. four (80%) showed T to other nucleotide main (HEAT repeats 11–15), and in addition substitutions. In addition, a normal poly- HEAT repeats 1–4 and 9–10, in 30 primary morphism, 478leucine, was found. No cor- colorectal cancers. The purpose of this study relation was found between these was to determine the type of alterations in pri- mutations and clinicopathological data. mary colon and rectal cancers, and to assess Conclusion—Our results suggest that the the correlation between mutations of PPP2R1B gene is one of the true targets at PPP2R1B and clinicopathological factors. 11q23, and its inactivation is involved in the development of all types of colorectal Materials and methods PATIENT SAMPLES Second Department of cancers. Surgery, Gifu (Gut 2000;47:268–271) Thirty primary colorectal cancers and corre- University School of sponding normal tissue samples were obtained Medicine, Keywords: PPP2R1B gene; colorectal cancer; tumour from 18 male and 12 female patients, aged Tsukasa-machi, Gifu suppressor gene; protein phosphatase 24–86 years (mean age 63 years at diagnosis) 500–8705, Japan during surgery at the Gifu University School of Y Takagi Medicine from July 1997 to November 1997. M Futamura Loss of heterozygosity (LOH) is one of the According to the TNM (tumour, node, and K Yamaguchi most frequent alterations found in solid metastasis) classification,11 tumour stage S Aoki tumours and recognition of areas with high T Takahashi rates of loss of genetic material can lead to S Saji identification of chromosome regions harbour- Abbreviations used in this paper: LOH, loss of heterozygosity; RT, reverse transcriptase; PCR, Correspondence to: ing putative tumour suppressor genes. Dr Y Takagi. Email: The region 11q22-24 has moderate to high polymerase chain reaction; HEAT, Huntington yutakagi@ email.msn.com elongation A subunit TOR; Ala, alanine; Val, valine; frequencies of LOH in colorectal cancer Gly, glycine; Glu, glutamic acid; Ile, isoleucine; Leu, 12 3 Accepted for publication (29–34%), breast cancer (40–50%), and leucine; Ser, serine; Pro, proline; PP2A, protein 8 February 2000 lung cancer (63%).4 The PPP2R1B gene was phosphatase 2A. www.gutjnl.com PPP2R1B alterations in colorectal cancers 269 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 S1–AS1 (472 bp) S2–AS2 (445 bp) Gut: first published as 10.1136/gut.47.2.268 on 1 August 2000. Downloaded from S3–AS3 (452 bp) Figure 1 Schematic view of PPP2R1B cDNAs. Three sets of polymerase chain reaction primers were used to amplify a portion of the gene. Numbers indicate the internal repeats (HEAT repeats) and shaded numbers indicate the sequence of binding sites for the PP2Ac subunit on the PR65/A subunit. showed four stage I, seven stage II, 12 stage III, S3 (5'-TTA TGT ATG GCT TGG CTC and seven stage IV cases. With regard to GTG G) and AS3 (5'-TTC CCT CCT GCT tumour site, there were 15 cases in the ascend- CCT CAT TAT G) (452 bp). The reactions ing colon, two in the transverse colon, five in were programmed for thermal cycling as the sigmoid colon, and eight in the rectum. The follows (Takara, PCR thermal cycler MP): the tumours were diagnosed histologically as initial denaturing step was for one minute at colorectal cancers. In all cases tissue samples 94°C, followed by 35 cycles of 30 seconds at were rapidly frozen in liquid nitrogen and 94°C for denaturation, 30 seconds at 55°C for stored at −80°C until analysis. annealing, and one minute at 72°C for extension. The final extension for all PCR REVERSE TRANSCRIPTION-POLYMERASE CHAIN reactions was at 72°C for 10 minutes. REACTION Total RNA (2 µg), isolated and purified by standard procedures, was reverse transcribed SEQUENCE ANALYSIS FOR MUTATIONS using 0.3 µg of random primers, 20 U of RNase PCR amplified products were electrophoret- inhibitor, 10 mM of deoxynucleoside triphos- ically separated on a 2% agarose gel. Bands of phates, and 20 U of reverse transcriptase appropriate size were cut from the gel, purified (Takara Biomedicals Co., Kyoto, Japan) under with the GENE Clean III Kit (Bio101, Vista, the manufacturer’s suggested reaction condi- California, USA), and sequenced using the tions. The polymerase chain reaction (PCR) ABI PRISM Dye Termination Cycle Sequenc- was performed in 25 µl of reaction mixtures ing Kit (Perkin-Elmer, Foster City, California, containing the following: 1 µl of the comple- USA) and an ABI Prism 377 automated DNA mentary DNA mix, 2.5 µl of 10 X PCR buVer sequencer (ABI, Foster City, California, USA). (50 mM KCl, 10 mM Tris HCl, pH 8.3, and Sequences from tumour cases were aligned and 1.5 mM MgCl2), 4.0 mM deoxynucleoside tri- compared with the normal PPP2R1B se- phosphates, 1.25 U of Taq polymerase quence. When changes were identified they (Takara), and 0.5 mM of each PCR primer. were confirmed by repeating the PCR and Primers for PPP2R1B were designed to sequencing the new amplification product. http://gut.bmj.com/ amplify three regions (fig 1). The primer pairs used were as follows: HEAT repeats 1–4, S1 (5'- CAG CAG GAG GAG AAA GAA CAT CLINICOPATHOLOGICAL DATA G) and AS1 (5'-ATC CCC ACT TGC TAA Data, including sex, age, stage of disease, and GCG TTT C) (472 bp); HEAT repeats 9–12, histopathological findings were available from S2 (5'-GCC CAT TGA AGA TAG AGA GAC the clinical and pathological records. The clin- C) and AS2 (5'- AGC TTC TCG TAG GGC icopathological staging was carried out accord- on October 1, 2021 by guest. Protected copyright. GTA TAC A) (445 bp); HEAT repeats 12–15, ing to the UICC staging system. Case No 2 Case No 11 Case No 22 Case No 25 Tumour Control 73 G > C1524 T > A 1522 T > A 1528 T > G 1122 T > C Figure 2 DNA sequence electropherograms showing the PPP2R1B gene mutations identified in patients with colorectal cancer. Individual electropherograms for the tumour are shown in the upper panels and the corresponding normal tissues (controls) are shown in the lower panels. The relevant nucleotide is indicated by an arrow. www.gutjnl.com 270 Takagi, Futamura, Yamaguchi,et al Table 1 PPP2R1B sequence changes in colorectal cancers Table 2 Clinical and pathological characteristics of the patient population Tumour specimen Stage Codon Predicted eVect Nucleotide substitution Mutation (−) Mutation (+) Case No 2 III 15 Gly to Ala GGTtoGCT (n=26) (n=4)* p Value Gut: first published as 10.1136/gut.47.2.268 on 1 August 2000.
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