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Article Rectal Cancer in a Patient with Bartter Syndrome: A Case Report

Shiki Fujino 1,2, Norikatsu Miyoshi 2,*, Masayuki Ohue 2, Mikio Mukai 3, Yoji Kukita 4, Taishi Hata 1, Chu Matsuda 1, Tsunekazu Mizushima 1, Yuichiro Doki 1 and Masaki Mori 1

1 Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; [email protected] (S.F.); [email protected] (T.H.); [email protected] (C.M.); [email protected] (T.M.); [email protected] (Y.D.); [email protected] (M.M.) 2 Department of Surgery, Osaka International Cancer Institute, 3-1, Otemae, Tyuou-ku, Osaka 541-8567, Japan; [email protected] 3 Department of Cardiology, Osaka International Cancer Institute, 3-1, Otemae, Tyuou-ku, Osaka 541-8567, Japan; [email protected] 4 Department of Molecular and Medical Genetics, Research Institute, Osaka International Cancer Institute, 3-1, Otemae, Tyuou-ku, Osaka 541-8567, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-6-6945-1181; Fax: +81-6-6945-1900

Academic Editor: Nora Nock Received: 22 February 2017; Accepted: 3 May 2017; Published: 12 May 2017

Abstract: A woman with rectal cancer was scheduled for surgery. However, she also had hypokalemia, hyperreninemia, and hyperaldosteronism in the absence of any known predisposing factors or endocrine tumors. She was given intravenous potassium, and her blood abnormalities stabilized after tumor resection. Genetic analysis revealed in several genes associated with Bartter syndrome (BS) and Gitelman syndrome, including SLC12A1, CLCNKB, CASR, SLC26A3, and SLC12A3. Prostaglandin E2 (PGE2) plays an important role in BS and worsens electrolyte abnormalities. The PGE2 level is reportedly increased in colorectal cancer, and in the present case, immunohistochemical examination revealed an increased PGE2 level in the tumor. We concluded that the tumor-related PGE2 elevation had worsened the patient’s BS, which became more manageable after tumor resection.

Keywords: Bartter syndrome; colorectal cancer; prostaglandin E2; whole-exome sequencing; next-generation sequencing

1. Introduction Bartter syndrome (BS) is a rare metabolic disorder that was first reported in 1962 [1]. It is characterized by persistent hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia, and hyperaldosteronism in the absence of hypertension [2]. BS is caused by impairment of sodium and chloride resorption in the thick ascending limb of Henle’s loop and is clinically classified into two phenotypes. One is neonatal BS, which presents early in life and is characterized by severe salt loss and marked prostaglandinuria. The other is classic BS, which is characterized by a milder phenotype or later disease onset [3]. It is now known that loss-of-function mutations of several genes encoding the transporters involved in salt reabsorption at the thick ascending loop cause different types of BS. BS is currently classified into five different subtypes according to the mutations involved: of SLC12A1 (Na-K-2Cl cotransporter (NKCC2)) causes type I BS [4], mutation of KCNJ1 (ATP-Regulated Potassium Channel (ROMK)) causes type II BS [4], mutation of CLCNKB (Chloride

Genes 2017, 8, 139; doi:10.3390/genes8050139 www.mdpi.com/journal/genes Genes 2017, 8, 139 2 of 7 channel Kb (CLCNKB)) causes type III BS [5], mutation of BSND (chloride channel protein ClC-Ka (CLCNKA)Genes 2017, 8 and, 139 subunit of ClC-Kb (BRTTIN)) causes type IV-A BS [6], mutation of CLCNKB2 ofand 7 CLCNKA cause type IV-B BS [7], and mutation of CASR (Calcium-Sensing Receptor) causes type V BS [8]. (CLCNKA) and subunit of ClC-Kb (BRTTIN)) causes type IV-A BS [6], mutation of CLCNKB and Gitelman syndrome (GS) is another rare metabolic disorder, and its clinical symptoms may overlap with CLCNKA cause type IV-B BS [7], and mutation of CASR (Calcium-Sensing Receptor) causes type V thoseBS [8]. of BS. Gitelman Genetic syndrome mutations (GS) in SLC12A3 is another(Solute rare Carriermetabolic Family disorder, 12 Member and its 3,clinical Na-Cl symptoms cotransporter) may [9] andoverlapCLCNKB with[10 those] have of beenBS. Genetic reported mutations in patients in SLC12A3 with GS. (Solute Additionally, CarrierSLC26A3 Family 12(Cl-HCO3 Member exchanger)3, Na-Cl hascotransporter) been reported [9] in and patients CLCNKB with [10] BS have and GSbeen [11 reported,12]. in patients with GS. Additionally, SLC26A3 (Cl-HCO3Prostaglandin exchanger) E2 (PGE2) has been levels reported are elevated in patients secondary with BS and to hypokalemia GS [11,12]. in patients with BS, and consistentProstaglandin hypokalemia E2 (PGE2) with geneticlevels are loss elevated of Na-K-2Cl secondary function to hypokalemia results in in a patients secondary with increase BS, and in PGE2consistent [13]. Several hypokalemia studies with have genetic revealed loss that of Na-K-2Cl PGE2 plays function an important results in rolea secondary in colorectal increase cancer in PGE2 [14,15 ]. [13].We Several herein studies report have a case revealed involving that PGE2 a patient plays with an important rectal cancer role in and colorectal electrolyte cancer abnormalities [14,15]. in whomWe whole-exome herein report sequencing a case involving revealed a patient BS. We with discuss rectal the cancer cause and of electr severeolyte hypokalemia abnormalities before in surgicalwhom resectionwhole-exome for advanced sequencing rectal revealed cancer BS. and We the di geneticscuss the analysis cause of BS.severe hypokalemia before surgical resection for advanced rectal cancer and the genetic analysis of BS. 2. Case Report 2. Case Report A 51-year-old Korean woman underwent colonoscopy to determine the cause of anemia. ColonoscopyA 51-year-old showed Korean a type 2woman tumor inunderwent rectum (Figure colono1A),scopy and to pathological determine the examination cause of byanemia. biopsy revealedColonoscopy colorectal showed cancer. a type Enhanced 2 tumor in computed rectum (Fig tomographyure 1A), and showedpathological a high-density examination tumor by biopsy in the rectumrevealed (Figure colorectal1B) and cancer. no metastases. Enhanced computed She was admitted tomography to our showed hospital a high-density for surgery. tumor Preoperative in the bloodrectum testing (Figure showed 1B) and hypokalemia no metastases. (1.6 She mEq/L) was admi andtted hypomagnesemia to our hospital for (1.8 surgery. mEq/L) Preoperative (Figure2A). Herblood blood testing pressure showed was hypokalemia normal despite (1.6 mEq/L) markedly and elevatedhypomagnesemia plasma renin (1.8 mEq/L) activity (Figure and aldosterone 2A). Her blood pressure was normal despite markedly elevated plasma renin activity and aldosterone levels levels (Figure2B). She had a medical history of right lobectomy for hemangioma of the liver at the age (Figure 2B). She had a medical history of right lobectomy for hemangioma of the liver at the age of of 46 years. Blood tests also showed hypokalemia at that time, but her potassium level was slightly 46 years. Blood tests also showed hypokalemia at that time, but her potassium level was slightly higher (2–3 mEq/L) than at the current presentation. The plasma renin activity and aldosterone level higher (2–3 mEq/L) than at the current presentation. The plasma renin activity and aldosterone level were also elevated at the time of the right lobectomy. She was not taking any medications such as were also elevated at the time of the right lobectomy. She was not taking any medications such as antihypertensives or diuretics, and she had no family history of hypokalemia. antihypertensives or diuretics, and she had no family history of hypokalemia.

Figure 1. Endoscopic and radiographic features of rectal cancer. (A) Endoscopic examination showed Figure 1. Endoscopic and radiographic features of rectal cancer. (A) Endoscopic examination showed type 2 cancer (white arrows); (B) Axial computed tomography scans showed the tumor (white type 2 cancer (white arrows); (B) Axial computed tomography scans showed the tumor (white arrowheads) in the rectum. arrowheads) in the rectum. She was administered intravenous potassium and underwent surgery for the rectal cancer. Her hemodynamicsShe was administered remained stable intravenous perioperatively. potassium Her serum and underwent potassium level surgery stabilized for the after rectal surgery. cancer. HerShe hemodynamics was discharged remained on postoperative stable perioperatively.day 20 with no complications. Her serum potassiumThe rectal cancer level stabilizedwas a type after 2 surgery.tumor, Sheand was pathological discharged diagnosi on postoperatives showed rectal day 20adenocarcinoma. with no complications. Rectal cancer The rectalwas stage cancer IIIb was a typeaccording 2 tumor, to the and Japanese pathological Guidelines diagnosis for showedthe Treatment rectal adenocarcinoma.of Colorectal Cancer Rectal [16], cancer and adjuvant was stage IIIbchemotherapy according to was the administered. Japanese Guidelines She was for alive the withou Treatmentt recurrence of Colorectal at the time Cancer of this [16 writing], and adjuvant(about chemotherapythree years, postoperatively). was administered. She was alive without recurrence at the time of this writing (about three years, postoperatively).

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FigureFigure 2. Graphs 2. Graphs of serum of serum potassium, potassium, renin, renin, and and aldosterone.aldosterone. (A (A) )The The serum serum potassium potassium levels levels and and potassium administered during the perioperative period are shown. After the operation, the serum potassium administered during the perioperative period are shown. After the operation, the serum potassium level improved with less administered potassium; (B) The aldosterone and renin activity potassium level improved with less administered potassium; (B) The aldosterone and renin activity in in the perioperative period is shown. The activity of both increased temporarily after surgery and the perioperativestabilized before period surgery. is shown. Referenc Thee activityranges: renin, of both 0.3–2.9 increased ng/mL/h temporarily (light blue); after aldosterone, surgery and 29.9–159 stabilized beforepg/mL surgery. (light Reference yellow). POD; ranges: postoperative renin, 0.3–2.9 day. ng/mL/h (light blue); aldosterone, 29.9–159 pg/mL (light yellow). POD; postoperative day. 3. Methods 3. MethodsThis study was approved by the institutional review board of Osaka Medical Center for Cancer Thisand Cardiovascular study was approved Diseases by (Ethical the institutional code, 15021322 review54). The board patient of Osaka gave written Medical informed Center consent for Cancer before undergoing evaluation and testing. and Cardiovascular Diseases (Ethical code, 1502132254). The patient gave written informed consent before3.1. undergoing Genetic Analyses evaluation Using a andNext-Generation testing. Sequencer 3.1. GeneticWhole-exome Analyses Using sequencing a Next-Generation was performed Sequencer using DNA from the surgically resected specimen (AllPrep DNA/RNA Mini Kit; QIAGEN, Hilden, Germany). Gene-specific analysis was carried out Whole-exomeusing an Ion Torrent sequencing Proton wassystem performed with Ion usingAmpliSeq DNA Exome from Kit the (4487084; surgically Life resected Technologies, specimen (AllPrepCarlsbad, DNA/RNA CA, USA) Mini and Kit;analyzed QIAGEN, using Ion Hilden, Reporter Germany). software (Life Gene-specific Technologies). analysis was carried out using an Ion Torrent Proton system with Ion AmpliSeq Exome Kit (4487084; Life Technologies, Carlsbad,3.2. Immunohistochemical CA, USA) and analyzed Study of usingPGE2 Ion Reporter software (Life Technologies). The surgically resected specimen was fixed in 10% buffered formalin, processed through graded 3.2. Immunohistochemicalethanol, and embedded Study in paraffin of PGE2 blocks. A 3-μm section including both normal colonic mucosa and Thecancerous surgically tissue resected was used. specimen Deparaffinized was fixed sections in 10% were buffered created, and formalin, the slide processed was boiled through for 10 min. graded ethanol, and embedded in paraffin blocks. A 3-µm section including both normal colonic mucosa and cancerous tissue was used. Deparaffinized sections were created, and the slide was boiled for 10 min. To quench endogenous peroxidase activity, the slide was immersed in mixed methanol and Genes 2017, 8, 139 4 of 7

H2O2 for 25 min at room temperature. PGE2 expression was examined using rabbit anti-human PGE2 antibody (Abcam, Cambridge, UK) and VECTASTAIN Elite ABC Rabbit IgG Kit (Vector Laboratories, Burlingame, CA, USA). The slide was blocked by blocking serum for 20 min at room temperature and incubated with a primary antibody (rabbit anti-human PGE2 antibody; Abcam, Cambridge, UK) (1:100) overnight at 4 ◦C. After overnight incubation, the slide was incubated with a secondary antibody (biotinylated goat anti-rabbit antibody) for 30 min at room temperature and incubated with Reagent A and B mixed for 20 min at room temperature. It was then incubated with Histofine (Nichirei Biosciences Inc., Tokyo, Japan) for 14 min. Finally, the slide was stained with Meyer’s hematoxylin (Wako Pure Chemical Industries, Osaka, Japan) for 3 min.

4. Results

4.1. Identification of Gene Mutations BS and/or GS was suspected based on the patient’s clinical features, and gene-specific analysis was focused on several genes that have been reported to be related to BS and/or GS: SLC12A1, KCNJ1, CLCNKB, BSND, CLCNKA, CASR, SLC26A3, and SLC12A3. Mutations were found in five genes: CLCNKB, CASR, SLC12A1, SLC26A3, and SLC12A3. Seven mutations were identified in the CLCNKB gene (Figures S1–S7 in Supplementary Materials), two mutations in CASR (Figures S8 and S9 in Supplementary Materials), three mutations in SLC12A1 (Figures S10–S12 in Supplementary Materials), two mutations in SLC26A3 (Figures S13 and S14 in Supplementary Materials), and four mutations in SLC12A3 (Figures S15–S18 in Supplementary Materials). These mutations are summarized in Table1. Genetic analysis revealed both BS and GS.

Table 1. Mutations associated with Bartter syndrome and Gitelman syndrome.

Gene Transcript Function Codon Exon Coding CLCNKB NM_000085.4 synonymous TCG 4 c.324A>G CLCNKB NM_000085.4|NM_001165945.2 synonymous GGC 5 c.492G>C| CLCNKB NM_000085.4|NM_001165945.2 missense GTG 2 c.860C>T|c.353C>T CLCNKB NM_000085.4|NM_001165945.2 synonymous TGC 3 c.876T>C|c.369T>C CLCNKB NM_000085.4|NM_001165945.2 missense ACG 9 c.1685T>C|c.1178T>C CLCNKB NM_000085.4|NM_001165945.2 missense GAG 9 c.1732A>G|c.1225A>G CLCNKB NM_000085.4|NM_001165945.2 synonymous TTG 9 c.1741C>T|c.1234C>T CASR NM_001178065.1 synonymous CCC 7 c.2274G>C CASR NM_001178065.1 missense CAG 7 c.3061G>C SLC12A1 NM_001184832.1 synonymous CAT 2 c.405C>T SLC12A1 NM_001184832.1 synonymous TAC 13 c.1614T>C SLC12A1 NM_001184832.1 missense GCA 23 c.2873T>C SLC26A3 NM_000111.2 synonymous CTC 17 c.1953T>C SLC26A3 NM_000111.2 synonymous GCA 11 c.1299G>A SLC12A3 NM_000339.2 missense GGC 6 c.791C>G SLC12A3 NM_000339.2 synonymous GCA 11 c.1392C>A SLC12A3 NM_000339.2 synonymous GCT 17 c.2142C>T SLC12A3 NM_000339.2 synonymous GGT 22 c.2625C>T CLCNKB: Chloride channel Kb; CASR: Calcium Sensing Receptor ; SLC: Solute Carrier.

4.2. Increased PGE2 Levels in the Tumor The PGE2 level is reportedly increased in patients with advanced colorectal cancer, and an increased PGE2 level worsens hypokalemia in patients with BS and/or GS. The renin-angiotensin-aldosterone (RAA) axis is stimulated, and this results in a secondary increase in PGE2. The expression of PGE2 in the colorectal cancer tissue is shown in Figure3. Immunostaining was observed in the cancer region but was scant in the normal mucosa cells. The PGE2 level was increased in the tumor but not in the normal colon. Genes 2017, 8, 139 5 of 7 Genes 2017, 8, 139 5 of 7

Figure 3. Immunohistochemistry of Prostaglandin E2 (PGE2) in rectal cancer. (A) The normal rectal Figure 3. Immunohistochemistry of Prostaglandin E2 (PGE2) in rectal cancer. (A) The normal rectal tissuetissue did not did notexpress express PGE2; PGE2; (B ()B The) The rectal rectal adenocarcinoma adenocarcinoma and and surrounding surrounding stroma stroma expressed expressed PGE2 PGE2 (scale(scale bar: bar:100 100μm).µm).

5. Discussion5. Discussion In theIn past, the past, BS and BS and GS GS were were diagnosed diagnosed by by clinical clinical features.features. These These syndromes syndromes are are now now diagnosed diagnosed by severalby several gene gene mutations. mutations. In Inrecent recent years, years, howeve however,r, these metabolicmetabolic disorders disorders have have been been considered considered hereditaryhereditary salt-losing salt-losing tubulopathies tubulopathies [17]. [17]. Recent Recent studies have have found found that that patients patients with with BS and/or BS and/or GS GS havehave several several genetic genetic mutations mutations [18,19]. [18,19]. This This is is the the first first reportedreported patient patient in in whom whom the the genes genes suspected suspected to causeto cause BS and/or BS and/or GS GSwere were examined, examined, and and several several mutations were were identified identified in CLCNKBin CLCNKB, CASR, CASR, , SLC12A3, SLC12A1, and SLC26A3. These findings suggest that BS and/or GS are hereditary salt-losing SLC12A3, SLC12A1, and SLC26A3. These findings suggest that BS and/or GS are hereditary salt-losing tubulopathies caused by not just one mutation, but several overlapped mutations. tubulopathies caused by not just one mutation, but several overlapped mutations. In patients with BS, loss of sodium and chloride stimulates the RAA axis. Aldosterone stimulates theIn patients secretion with of potassium BS, loss withof sodium sodium and uptake, chloride precipitating stimulates hypokalemia, the RAA secretionaxis. Aldosterone of hydrogen stimulates ions, the secretionand metabolic of potassium alkalosis. Hypokalemia with sodium increases uptake, the precipitating production of PGE2.hypokalemia, Furthermore, secretion PGE2 stimulates of hydrogen ions,the and RAA metabolic axis, resulting alkalosis. in a Hypokalemia secondary increase increases in PGE2 the [13 production]. In the present of PGE2. case, theFurthermore, hypokalemia PGE2 stimulatesbecame the easier RAA to controlaxis, resulting after the rectalin a cancersecondary operation. increase It was in reportedPGE2 [13]. that In surgical the present stress causes case, the hypokalemiaa renin activity became and easier aldosterone to control elevation after the in rectal non-BS cancer patients operation. [20]. However, It was reported the postoperative that surgical stressresponses causes a of renin the RAA activity axis inand BS patientsaldosterone were el notevation reported. in non-BS In this case,patients a temporal [20]. However, elevation the postoperativewas observed responses postoperatively. of the RAA axis in BS patients were not reported. In this case, a temporal elevationWe was considered observed that postoperatively. the RAA was also stimulated by the cancer-derived PGE2 (Figure4). PGE2, a proinflammatory mediator, is the most abundant prostaglandin found in colorectal cancer [21]. It is We considered that the RAA was also stimulated by the cancer-derived PGE2 (Figure 4). PGE2, associated with recurrence and metastasis, resulting in a poor prognosis [14,22]. The serum PGE2 level a proinflammatory mediator, is the most abundant prostaglandin found in colorectal cancer [21]. It could not be measured in our institution; therefore, immunohistochemical examination of PGE2 was is associatedperformed. with We recurrence found that theand PGE2 metastasis, expression resulting was higher in a poor in the prognosis rectal cancer [14,22]. than inThe the serum normal PGE2 levelcolon could mucosa. not be measured After resection in our of theinstitution; primary rectaltherefore, cancer, immunohistochemical the potassium level was examination easily controlled. of PGE2 was performed.The cancer-derived We found PGE2 that might the PGE2 increase expression renin secretion was higher in kidney in the and rectal cause cancer severe than preoperative in the normal colonhypokalemia. mucosa. After She resection was alive of without the primary recurrence rectal and cancer, the potassium the potassium level was level 2–3 was mEq/L. easily However, controlled. The thecancer-derived PGE2 level is reportedlyPGE2 might increased increase in liverrenin metastases secretion [14 in,23 kidney]. We consider and cause that ifsevere the rectal preoperative cancer hypokalemia.recurs in this She patient, was alive her without potassium recurrence level will beand more the difficultpotassium to control. level was We 2–3 plan mEq/L. to follow However, the the PGE2patient’s level clinical is reportedly course and increased examine in the liver relationship metastases between [14,23]. BS andWe colorectalconsider cancer.that if the rectal cancer recurs inIn this conclusion, patient, weher have potassi hereinum reported level will a case be ofmore colorectal difficult cancer-related to control. PGE2 We productionplan to follow that the seems to be responsible for severe preoperative hypokalemia, represented in BS syndrome. patient’s clinical course and examine the relationship between BS and colorectal cancer. Hypokalemia causes express PGE2 production that causes secondary renin secretion. In conclusion, we have herein reported a case of colorectal cancer-related PGE2 production that Th cancer-derived PGE2 might also stimulate renin secretion. seems to be responsible for severe preoperative hypokalemia, represented in BS syndrome. Hypokalemia causes express PGE2 production that causes secondary renin secretion. The cancer-derived PGE2 might also stimulate renin secretion.

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Figure 4. A scheme of mechanisms of Bartter syndrome and PGE2. TAL: thick ascending limb; ACE: Figure 4. A scheme of mechanisms of Bartter syndrome and PGE2. TAL: thick ascending limb; angiotensin-converting enzyme. ACE: angiotensin-converting enzyme.

Supplementary Materials: The following are available online at www.mdpi.com/2073-4425/8/5/139/s1.

Acknowledgments: We thank Aya Ito for technical assistance. Supplementary Materials: The following are available online at www.mdpi.com/2073-4425/8/5/139/s1. Author Contributions: S.F. wrote the report. S.F., N.M., M.M. and M.O. were the medical doctors responsible Acknowledgments: We thank Aya Ito for technical assistance. for this patient. S.F. and N.M. performed the basic experiments. Y.K. supported the gene-specific analysis using AuthorIon Contributions: Torrent Proton. S.F.N.M., wrote T.H., theC.M., report. T.M., Y.D. S.F., and N.M., M.M. M.M. analyzed and M.O. data wereor participated the medical in discussions doctors responsible of the for thisresults. patient. S.F. S.F. and and N.M. N.M. finalized performed the report. the basic experiments. Y.K. supported the gene-specific analysis using Ion Torrent Proton. N.M., T.H., C.M., T.M., Y.D. and M.M. analyzed data or participated in discussions of the results.Conflicts S.F. and of N.M. Interest: finalized The authors the report. declare they do not have any conflict of interest. Conflicts of Interest: References The authors declare they do not have any conflict of interest.

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