Research progress on genotype, clinical diagnosis and treatment of Peutz-Jeghers syndrome

doi:10.3877/cma.j.issn.2095-3224.2024.01.002

Abstract

Abstract:

Peutz-Jeghers syndrome (PJS) is a clinical rare autosomal dominant genetic disease. The patients with Peutz-Jeghers syndrome are characterized by pigmented spots and multiple hamartomatous polyps in the gastrointestinal tract. The molecular pathogenesis of this disease is related to the abnormal function of the tumor suppressor gene STK11, but its genetic background is complex and its clinical heterogeneity is obvious. At present, endoscopic treatment is the main treatment, supplemented by surgery, which can significantly prolong the survival of patients, but there is no radical means. This article reviews relevant literature on this disease and provides a review of its genetic characteristics and clinical treatment progress, and prospect the future research direction.

Key words: Genetic diseases, Genotype, Peutz-Jeghers syndrome, Phenotype, STK11

Zhi Zhang, Zhiwei Dong, Zuxin Xu, Lixin Jiang, Yuhui Zhang, Guoli Gu. Research progress on genotype, clinical diagnosis and treatment of Peutz-Jeghers syndrome[J]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2024, 13(01): 6-13.

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References 78

[1]	Wang Z, Chen Y, Wu B, et al. A novel mutation in STK11 gene is associated with Peutz-Jeghers syndrome in Chinese patients[J]. BMC Med Genet, 2011, 12: 161.
[2]	Korsse SE, van Leerdam ME, Dekker E. Peutz-Jeghers syndrome[J]. Ned Tijdschr Tandheelkd, 2013, 120(1): 12-16.
[3]	Beggs AD, Latchford AR, Vasen HF, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management[J]. Gut, 2010, 59(7): 975-986.
[4]	国家卫生健康委员会,科学技术部,工业和信息化部,等.第一批罕见病目录[EB/OL].[2018-05-11]. URL
[5]	Williams CD, Grady WM, Zullig LL. Use of NCCN guidelines, other guidelines, and biomarkers for colorectal cancer screening[J]. J Natl Compr Canc Netw, 2016, 14(11): 1479-1485.
[6]	全国遗传性大肠癌协作组.中国人遗传性大肠癌筛检标准的实施方案[J].中华肿瘤杂志, 2004, 26(3): 66-67.
[7]	Shen N, Li D, Zhu Y, et al. Early genetic testing of STK11 is important for management and genetic counseling for Peutz-Jeghers syndrome[J]. Dig Liver Dis, 2019, 51(9): 1353-1355.
[8]	Banno K, Kisu I, Yanokura M, et al. Hereditary gynecological tumors associated with Peutz-Jeghers syndrome (Review)[J]. Oncol Lett, 2013, 6(5): 1184-1188.
[9]	Kuroda Y, Saito T, Nagai J, et al. Microdeletion of 19p13.3 in a girl with Peutz-Jeghers syndrome, intellectual disability, hypotonia, and distinctive features[J]. Am J Med Genet A, 2015,167A(2):389-393.
[10]	Nguyen-Tu MS, da Silva Xavier G, Leclerc I, et al. Transcription factor-7-like 2 (TCF7L2) gene acts downstream of the Lkb1/Stk11 kinase to control mTOR signaling, β cell growth, and insulin secretion[J]. J Biol Chem, 2018, 293(36):14178-14189.
[11]	Altamish M, Dahiya R, Singh AK, et al. Role of the serine/threonine kinase 11 (STK11) or liver kinase B1 (LKB1) gene in Peutz-Jeghers syndrome[J]. Crit Rev Eukaryot Gene Expr, 2020, 30(3): 245-252.
[12]	Islam MJ, Khan AM, Parves MR, et al. Prediction of deleterious non-synonymous SNPs of human STK11 gene by combining algorithms, molecular docking, and molecular dynamics simulation[J]. Sci Rep, 2019, 9(1): 16426.
[13]	van Lier MG, Westerman AM, Wagner A, et al. High cancer risk and increased mortality in patients with Peutz-Jeghers syndrome[J]. Gut, 2011, 60(2): 141-147.
[14]	Hawley SA, Boudeau J, Reid JL, et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade[J]. J Biol, 2003, 2(4): 28.
[15]	Contreras CM, Akbay EA, Gallardo TD, et al. Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy[J]. Dis Model Mech, 2010, 3(3-4): 181-193.
[16]	Shorning BY, Griffiths D, Clarke AR. Lkb1 and Pten synergise to suppress mTOR-mediated tumorigenesis and epithelial-mesenchymal transition in the mouse bladder[J]. PloS One, 2011, 6(1): e16209.
[17]	Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome[J]. Clin Cancer Res, 2006, 12(10): 3209-3215.
[18]	Sanchez-Cespedes M, Parrella P, Esteller M, et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung[J]. Cancer Res, 2002, 62(13): 3659-3662.
[19]	毛旭燕,宁守斌. Peutz-Jeghers综合征发病机制和诊疗进展[J].胃肠病学, 2014, 19(8): 492-495.
[20]	van Veelen W, Korsse SE, van de Laar L, et al. The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling[J]. Oncogene, 2011, 30(20): 2289-2303.
[21]	Forcet C, Etienne-Manneville S, Gaude H, et al. Functional analysis of Peutz-Jeghers mutations reveals that the LKB1 C-terminal region exerts a crucial role in regulating both the AMPK pathway and the cell polarity[J]. Hum Mol Genet, 2005, 14(10): 1283-1292.
[22]	Katajisto P, Vaahtomeri K, Ekman N, et al. LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis[J]. Nat Genet, 2008, 40(4): 455-459.
[23]	Zeqiraj E, Filippi BM, Deak M, et al. Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation[J]. Science, 2009, 326(5960): 1707-1711.
[24]	Baas AF, Boudeau J, Sapkota GP, et al. Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD[J]. EMBO J, 2003, 22(12): 3062-3072.
[25]	Martin SG, St Johnston D. A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity[J]. Nature, 2003, 421(6921): 379-384.
[26]	Volikos E, Robinson J, Aittomäki K, et al. LKB1 exonic and whole gene deletions are a common cause of Peutz-Jeghers syndrome[J]. J Med Genet, 2006, 43(5): e18.
[27]	Alessi DR, Sakamoto K, Bayascas JR. LKB1-dependent signaling pathways[J]. Annu Rev Biochem, 2006, 75: 137-163.
[28]	Xu ZX, Jiang LX, Chen YR, et al. Clinical features, diagnosis, and treatment of Peutz-Jeghers syndrome: experience with 566 Chinese cases[J]. World J Gastroenterol, 2023, 29(10): 1627-1637.
[29]	Wu BD, Wang YJ, Fan LL, et al. Clinical and genetic analyses of 38 Chinese patients with Peutz-Jeghers syndrome[J]. Biomed Res Int, 2020, 2020: 9159315.
[30]	Latchford AR, Clark SK. Gastrointestinal aspects of Peutz-Jeghers syndrome[J]. Best Pract Res Clin Gastroenterol, 2022, 58-59: 101789.
[31]	Sullivan-Pyke C, Dokras A. Preimplantation genetic screening and preimplantation genetic diagnosis[J]. Obstet Gynecol Clin North Am, 2018, 45(1): 113-125.
[32]	Leaver M, Wells D. Non-invasive preimplantation genetic testing (niPGT): the next revolution in reproductive genetics?[J]. Hum Reprod Update, 2020, 26(1): 16-42.
[33]	Xu X, Song R, Hu K, et al. Multidisciplinary management for Peutz-Jeghers syndrome and prevention of vertical transmission to offspring using preimplantation genetic testing[J]. Orphanet J Rare Dis, 2022, 17(1): 64.
[34]	Liu BL, Ward S, Polydorides AD. Clinicopathologic comparison between sporadic and syndromic Peutz-Jeghers polyps[J]. Hum Pathol, 2023, 141:69-77.
[35]	Woo A, Sadana A, Mauger DT, et al. Psychosocial impact of Peutz-Jeghers syndrome[J]. Fam Cancer, 2009, 8(1): 59-65.
[36]	van Lier MG, Mathus-Vliegen EM, van Leerdam ME, et al. Quality of life and psychological distress in patients with Peutz-Jeghers syndrome[J]. Clin Genet, 2010, 78(3): 219-226.
[37]	Giardiello FM, Welsh SB, Hamilton SR, et al. Increased risk of cancer in the Peutz-Jeghers syndrome[J]. N Engl J Med, 1987, 316(24): 1511-1514.
[38]	Daniell J, Plazzer JP, Perera A, et al. An exploration of genotype-phenotype link between Peutz-Jeghers syndrome and STK11: a review[J]. Fam Cancer, 2018, 17(3): 421-427.
[39]	LipsaA, Kowtal P, Sarin R. Novel germline STK11 variants and breast cancer phenotype identified in an Indian cohort of Peutz-Jeghers syndrome[J]. Hum Mol Genet, 2019, 28(11): 1885-1893.
[40]	Bennett JA, Young RH, Howitt BE, et al. A Distinctive adnexal (usually paratubal) neoplasm often associated with peutz-jeghers syndrome and characterized by STK11 alterations (STK11 adnexal tumor): a report of 22 cases[J]. Am J Surg Pathol, 2021, 45(8): 1061-1074.
[41]	Wingo SN, Gallardo TD, Akbay EA, et al. Somatic LKB1 mutations promote cervical cancer progression[J]. PloS One, 2009, 4(4): e5137.
[42]	Morton JP, Jamieson NB, Karim SA, et al. LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest[J]. Gastroenterology, 2010, 139(2): 586-597, 597.e1-6.
[43]	Yoo LI, Chung DC, Yuan J. LKB1--a master tumour suppressor of the small intestine and beyond[J]. Nat Rev Cancer, 2002, 2(7): 529-535.
[44]	李白容,孙涛,蒋宇亮,等. Peutz-Jeghers综合征发病机制及临床诊治研究进展[J].世界华人消化杂志, 2019, 27(9): 576-582.
[45]	Salloch H, Reinacher-Schick A, Schulmann K, et al. Truncating mutations in Peutz-Jeghers syndrome are associated with more polyps, surgical interventions and cancers[J]. Int J Colorectal Dis, 2010, 25(1): 97-107.
[46]	Amos CI, Keitheri-Cheteri MB, Sabripour M, et al. Genotype-phenotype correlations in Peutz-Jeghers syndrome[J]. J Med Genet, 2004, 41(5): 327-333.
[47]	Resta N, Pierannunzio D, Lenato GM, et al. Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients: results of an Italian multicenter study[J]. Dig Liver Dis, 2013, 45(7): 606-611.
[48]	李冉. Peutz-Jeghers综合征STK11基因新突变及其功能研究[D].广州:南方医科大学, 2020.
[49]	Mehenni H, Resta N, Guanti G, et al. Molecular and clinical characteristics in 46 families affected with Peutz-Jeghers syndrome[J]. Dig Dis Sci, 2007, 52(8): 1924-1933.
[50]	Lim W, Hearle N, Shah B, et al. Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome[J]. Br J Cancer, 2003, 89(2): 308-313.
[51]	Scott RJ, Crooks R, Meldrum CJ, et al. Mutation analysis of the STK11/LKB1 gene and clinical characteristics of an Australian series of Peutz-Jeghers syndrome patients[J]. Clin Genet, 2002, 62(4): 282-287.
[52]	Vélez A, Gaitan MH, Marquez JR, et al. Two novel LKB1 mutations in Colombian Peutz-Jeghers syndrome patients[J].Clin Genet, 2009, 75(3): 304-306.
[53]	Mehenni H, Resta N, Park JG, et al. Cancer risks in LKB1 germline mutation carriers[J]. Gut, 2006, 55(7): 984-990.
[54]	Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome[J]. Clin Cancer Res, 2006, 12(10): 3209-3215.
[55]	De Leng WW, Jansen M, Carvalho R, et al. Genetic defects underlying Peutz-Jeghers syndrome (PJS) and exclusion of the polarity-associated MARK/Par1 gene family as potential PJS candidates[J]. Clin Genet, 2007, 72(6): 568-573.
[56]	Chen C, Zhang X, Wang D, et al. Genetic screening and analysis of LKB1 gene in chinese patients with peutz-jeghers syndrome[J]. Med Sci Monit, 2016, 22: 3628-3640.
[57]	王志青,邓秀金,冯洁,等. MLPA技术在中国Peutz-Jeghers综合征患者STK11基因突变检测中的应用[J].世界最新医学信息文摘, 2019, 19(71): 251-254.
[58]	Mehenni H, Blouin JL, Radhakrishna U, et al. Peutz-Jeghers syndrome: confirmation of linkage to chromosome 19p13.3 and identification of a potential second locus, on 19q13.4[J]. Am J Hum Genet, 1997, 61(6): 1327-1334.
[59]	毛旭燕. Peutz-Jeghers综合征患者STK11及FHIT基因突变情况分析[D].张家口:河北北方学院, 2015.
[60]	Roy D, Sin SH, Damania B, et al. Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines[J]. Blood, 2011, 118(7): e32-39.
[61]	Jelsig AM, Wullum L, Kuhlmann TP, et al. Risk of cancer and mortality in Peutz-Jeghers syndrome and juvenile polyposis syndrome-a nationwide cohort study with matched control individuals[J]. Gastroenterology, 2023, 165(6): 1565-1567.
[62]	Gu GL, Zhang Z, Zhang YH, et al. Detection and analysis of common pathogenic germline mutations in Peutz-Jeghers syndrome[J]. World J Gastroenterol, 2021, 27(39): 6631-6646.
[63]	Jacquemont C, Taniguchi T. The Fanconi anemia pathway and ubiquitin[J]. BMC Biochemistry, 2007: S10.
[64]	Stoepker C, Hain K, Schuster B, et al. SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype[J]. Nat Genet, 2011, 43(2): 138-141.
[65]	Kutler DI, Singh B, Satagopan J, et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR)[J]. Blood, 2003, 101(4): 1249-1256.
[66]	Yamamoto H, Sekine Y, Sato Y, et al. Total enteroscopy with a nonsurgical steerable double-balloon method[J]. Gastrointest Endosc, 2001, 53(2): 216-220.
[67]	Ferlitsch M, Moss A, Hassan C, et al. Colorectal polypectomy and endoscopic mucosal resection (EMR): European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline[J]. Endoscopy, 2017, 49(3): 270-297.
[68]	Yang DH, Luvsandagva B, Tran QT, et al. Colonoscopic polypectomy preferences of Asian endoscopists: results of a survey-based study[J]. Gut Liver, 2021, 15(3): 391-400.
[69]	Cao Z, Jin W, Wu X, et al. Endoscopic therapy of small bowel polyps by single-balloon enteroscopy in patients with Peutz-Jeghers syndrome[J]. Int J Clin Pract, 2022, 2022: 7849055.
[70]	Limpias Kamiya KJL, Hosoe N, Takabayashi K, et al. Feasibility and safety of endoscopic ischemic polypectomy and clinical outcomes in patients with Peutz-Jeghers syndrome (with Video)[J]. Dig Dis Sci, 2023, 68(1): 252-258.
[71]	Khurelbaatar T, Sakamoto H, Yano T, et al. Endoscopic ischemic polypectomy for small-bowel polyps in patients with Peutz-Jeghers syndrome[J]. Endoscopy, 2021, 53(7): 744-748.
[72]	Wagner A, Aretz S, Auranen A, et al. The management of Peutz-Jeghers syndrome: European Hereditary Tumour Group (EHTG) guideline[J]. J Clin Med, 2021, 10(3): 473.
[73]	van Lier MG, Mathus-Vliegen EM, Wagner A, et al. High cumulative risk of intussusception in patients with Peutz-Jeghers syndrome: time to update surveillance guidelines?[J]. Am J Gastroenterol, 2011, 106(5): 940-945.
[74]	Latchford A, Cohen S, Auth M, et al. Management of Peutz-Jeghers syndrome in children and adolescents: a position paper from the ESPGHAN polyposis working group[J]. J Pediatr Gastroenterol Nutr, 2019, 68(3): 442-452.
[75]	Yamamoto M, Iwamoto K, Suzuki R, et al. Laparoscopic-assisted disinvagination and polypectomy for multiple intussusceptions induced by small intestinal polyps in patients with Peutz-Jeghers syndrome: a case report[J]. World J Surg Oncol, 2021, 19(1): 22.
[76]	Stasinos I, Kamperidis N, Murino A, et al. Single incision laparoscopic assisted double balloon enteroscopy: a novel technique to manage small bowel pathology[J]. Surg Endosc, 2020, 34(6): 2773-2779.
[77]	Yamamoto H, Sakamoto H, Kumagai H, et al. Clinical guidelines for diagnosis and management of Peutz-Jeghers syndrome in children and adults[J]. Digestion, 2023, 104(5): 335-347.
[78]	Half E, Bercovich D, Rozen P. Familial adenomatous polyposis[J]. Orphanet J Rare Dis, 2009, 4: 22.

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