Somatic mosaicism for PIK3CA mutations causes various types of growth disorders, which have been summarized under the term PROS (PIK3CA related overgrowth spectrum). Targeted therapy with PI3K inhibitors seems to be a promising alternative for severe PROS cases. Therefore, PIK3CA testing may become more relevant in the future.
Methods
We report on 14 PROS patients, who had surgery for macrodactyly in the majority of cases. Clinical data were retrieved from the patient’s records. Macroscopic and microscopic findings were retrospectively reviewed. Mutational analysis was performed on formalin-fixed paraffin-embedded (FFPE) material.
Results
Patient age ranged from 7 months to 35 years. Five patients showed additional anomalies. One patient had CLOVES syndrome. The majority of the specimens were ray resections characterized by hypertrophic fat tissue. Overall, microscopy was subtle. The abnormal adipose tissue showed lobules exhibiting at least focally fibrous septa. In each case, we could detect a PIK3CA mutation.
Conclusion
Histology of affected fat tissue in PROS patients is overall nonspecific. Therefore, mutational analysis represents the key to the diagnosis, especially in unclear clinical cases. We demonstrated that FFPE material is suitable for PIK3CA testing, which can be considered as basis for targeted therapy with PI3K inhibitors.
Keppler-NoreuilKMParkerVEDarlingTNMartinez-AgostoJA. Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies. Am J Med Genet C Semin Med Genet. 2016;172(4):402-421. doi:10.1002/ajmg.c.31531
2.
BlackburnPRMilosevicDMarekT, et al.PIK3CA mutations in lipomatosis of nerve with or without nerve territory overgrowth. Mod Pathol. 2020;33(3):420-430. doi:10.1038/s41379-019-0354-1
3.
MarekTMahanMACarterJM, et al.What’s known and what's new in adipose lesions of peripheral nerves?Acta Neurochir (Wien). 2021;163(3):835-842. doi:10.1007/s00701-020-04620-2
4.
Keppler-NoreuilKMSappJCLindhurstMJ, et al.Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet Part A. Jul. 2014;164a(7):1713-1733. doi:10.1002/ajmg.a.36552
5.
MirzaaGTimmsAEContiV, et al.PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. JCI insight. 2016;1(9):1. doi:10.1172/jci.insight.87623
6.
PortaCPaglinoCMoscaA. Targeting PI3K/Akt/mTOR Signaling in Cancer. Front Oncol. 2014;4:64. doi:10.3389/fonc.2014.00064
7.
ThorpeLMYuzugulluHZhaoJJ. PI3K in cancer: Divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015;15(1):7-24. doi:10.1038/nrc3860
8.
KandothCMcLellanMDVandinFYeKNiuBLuC, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333-339.
9.
LawrenceM. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505:495-501.
10.
MillisSZ. Landscape of Phosphatidylinositol-3-Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors. Jama Oncol. 2016;2:1565-1573.
11.
ZhangYKwok-Shing NgPKucherlapatiMChenFLiuYTsangYH, et al.A pan-cancer proteogenomic atlas of PI3K/AKT/mTOR pathway alterations. Cancer Cell. 2017;31:820
12.
KurekKCLuksVLAyturkUM, et al.Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet. 2012;90(6):1108-1115. doi:10.1016/j.ajhg.2012.05.006
13.
LindhurstMJParkerVEPayneF, et al.Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet. 2012;44(8):928-933. doi:10.1038/ng.2332
14.
RiviereJBMirzaaGMO’RoakBJ, et al.De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012;44(8):934-940. doi:10.1038/ng.2331
15.
Keppler-NoreuilKMRiosJJParkerVE, et al.PIK3CA-related overgrowth spectrum (PROS): Diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet. 2015;167a(2):287-295. doi:10.1002/ajmg.a.36836
16.
DouzgouSRawsonMBaselgaE, et al.A Standard of Care for Individuals with PIK3CA-related Disorders: An International Expert Consensus Statement. Clin Genet. 2021;101:32-47. doi:10.1111/cge.14027
17.
JankuFWhelerJJNaingA, et al.PIK3CA mutations in advanced cancers: Characteristics and outcomes. Oncotarget. 2012;3(12):1566-1575. doi:10.18632/oncotarget.716
18.
SamuelsYEricsonK. Oncogenic PI3K and its role in cancer. Current opinion in oncology. 2006;18(1):77-82. doi:10.1097/01.cco.0000198021.99347.b9
19.
SamuelsYWangZBardelliA, et al.High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304(5670):554. doi:10.1126/science.1096502
20.
GrippKWBakerLKandulaV, et al.Nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation. Am J Med Genet. 2016;170(10):2559-2569. doi:10.1002/ajmg.a.37758
21.
LuksVLKamitakiNViveroMP, et al.Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr. 2015;166(4):1048e1-10545. doi:10.1016/j.jpeds.2014.12.069
22.
GriffJRDuffyKAKalishJM. Characterization and childhood tumor risk assessment of genetic and epigenetic syndromes associated with lateralized overgrowth. Frontiers in pediatrics. 2020;8:613260. doi:10.3389/fped.2020.613260
XiaPXuXY. PI3K/Akt/mTOR signaling pathway in cancer stem cells: From basic research to clinical application. American journal of cancer research. 2015;5(5):1602-1609.
25.
MirzaaGConwayRGrahamJMJr.DobynsWB. PIK3CA-Related Segmental Overgrowth. In: AdamMPArdingerHHPagonRA, et al., eds. Gene Reviews((R)). University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 2013.
26.
RiosJJPariaNBurnsDK, et al.Somatic gain-of-function mutations in PIK3CA in patients with macrodactyly. Hum Mol Genet. 2013;22(3):444-451. doi:10.1093/hmg/dds440
27.
LindhurstMJSappJCTeerJK, et al.A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med2011. 2011;365:611-619.
28.
SoeiroESMMoldovanOSousaAB. Macrodactyly in tuberous sclerosis complex: Case report and review of the literature. Am J Med Genet. 2016;170(7):1903-1907. doi:10.1002/ajmg.a.37675
29.
ChangCAPerrierRKurekKC, et al.Novel findings and expansion of phenotype in a mosaic RASopathy caused by somatic KRAS variants. Am J Med Genet. 2021;185(9):2829-2845. doi:10.1002/ajmg.a.62356
30.
SlackJCBründlerMAChangCAPerrierRLafay-CousinLKurekKC. Bilateral nephroblastic tumors and a complex renal vascular anomaly in a patient with a mosaic RASopathy: Novel histopathologic features and molecular insights. Pediatr Dev Pathol. 2021;24(3):235-240. doi:10.1177/1093526620986502
31.
KuentzPSt-OngeJDuffourdY, et al.Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing. Genet Med. 2017;19(9):989-997. doi:10.1038/gim.2016.220
32.
WuJTianWTianGSumnerKHutchinsonDTJiY. An investigation of PIK3CA mutations in isolated macrodactyly. The Journal of hand surgery, European volume. 2018;43(7):756-760. doi:10.1177/1753193418770366
33.
YeungKSIpJJChowCP, et al.Somatic PIK3CA mutations in seven patients with PIK3CA-related overgrowth spectrum. Am J Med Genet. 2017;173(4):978-984. doi:10.1002/ajmg.a.38105
34.
BieseckerL. The challenges of proteus syndrome: Diagnosis and management. Eur J Hum Genet. 2006;14(11):1151-1157. doi:10.1038/sj.ejhg.5201638
35.
EzakiMBeckwithTOishiSN. Macrodactyly: Decision-making and surgery timing. J Hand Surg Eur Vol. 2019;44(1):32-42. doi:10.1177/1753193418796441
36.
TosiLLSappJCAllenESO’KeefeRJBieseckerLG. Assessment and management of the orthopedic and other complications of proteus syndrome. Journal of children's orthopaedics. 2011;5(5):319-327. doi:10.1007/s11832-011-0350-6
37.
AlomariAI. Characterization of a distinct syndrome that associates complex truncal overgrowth, vascular, and acral anomalies: A descriptive study of 18 cases of CLOVES syndrome. Clinical dysmorphology. 2009;18(1):1-7. doi:10.1097/MCD.0b013e328317a716
38.
WuJTianGJiYHigginsJPLeeWPA. Clinical characteristics of 90 macrodactyly cases. The Journal of hand surgery. 2020;45(10):982.e1-982.e5. doi:10.1016/j.jhsa.2020.03.002
39.
Van DammeASerontEDekeuleneerVBoonLMVikkulaM. New and emerging targeted therapies for vascular malformations. Am J Clin Dermatol. 2020;21(5):657-668. doi:10.1007/s40257-020-00528-w.
40.
MarshDJTrahairTNMartinJL, et al.Rapamycin treatment for a child with germline PTEN mutation. Nat Clin Pract Oncol. 2008;5(6):357-361. doi:10.1038/ncponc1112
41.
VenotQBlancTRabiaSH, et al.Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature. 2018;558(7711):540-546. doi:10.1038/s41586-018-0217-9
