Vascular anomalies, including lymphatic malformations (LMs), are usually diagnosed in children or young individuals and they can present as either isolated lesions or as part of somatic or congenital syndromes. Here, the term lymphatic malformation is used to include the clinicopathologic continuum of benign tumors of lymphatic origin (https://rarediseases.org/rare-diseases/lymphatic-malformations), including cystic lymphangioma, kaposiform lymphangiomatosis (KLM), and macro/microcystic LM. In general, LMs are managed by sclerotherapy, laser, or surgical interventions when there is an indication for therapy (Perkins et al., 2010). In certain cases, LMs can attain large sizes or involve critical locations, which poses treatment challenges such as the possibility of disfigurement. Genomic sequencing has demonstrated a somatic clonal origin for a number of nonmalignant growth conditions including LMs. Activating PIK3CA mutations have been reported in most pediatric patients with isolated or syndromic LMs (Luks et al., 2015). This finding has led to the use of mammalian target of rapamycin (mTOR) inhibitors for systemic therapy of unresectable LMs, given that mTOR is a molecule downstream of the PI3K pathway (Fruman et al., 2017). However, only a subset of patients responded, and the treatment can have substantial side effects. PI3K inhibitors have also been recently approved by the FDA for treatment of adults and children with severe manifestations PIK3CA-related Overgrowth Spectrum (termed PROS) who require systemic therapy, but the efficacy of alpelisib in isolated sporadic LMs is not at all clear. Activating NRAS mutations have been described in a subset of LM known as KLM (Barclay et al., 2019). KLM belong to a group of complex lymphatic anomalies that exhibit histologic and clinical features distinguishing them from classic LM. It is not as yet clear which oncogenic drivers, if any, are present in LMs with wild-type PIK3CA and NRAS alleles.

To define the spectrum of genomic alterations and lesions present in LMs, here we have analyzed a patient cohort of LMs (n = 30 cases) assayed by clinical-grade genomic sequencing. Pathogenic activating mutations in PIK3CA and NRAS were the most common genetic alterations found. Strikingly, the PIK3CA and NRAS mutations were mutually exclusive with NRAS mutations being greatly enriched in LMs with kaposiform morphology. We have also performed an N-of-1 trial of the PI3Kα inhibitor alpelisib in a young man with an activating PIK3CA point mutation, presenting with a giant (unresectable) retroperitoneal and pancreatic LM, who had a dramatic and prolonged response to the drug lasting years, and we present confirmatory translational correlates in vitro.

Here, we report the mutational landscape of a patient cohort of LMs (n = 30 cases) which underwent comprehensive genomic profiling. We have confirmed prior reports that hotspot activating mutations in PIK3CA are common driver events in these lesions, seen in 20 (67%) of these cases. Interestingly, NRAS mutations were seen in an additional five (17%) cases and were particularly enriched in LMs with a kaposiform histopathology. This finding supports previous studies that have shown that LMs with kaposiform features likely represent a distinct entity (KLA) (Barclay et al., 2019; Croteau et al., 2014). KLM have distinct clinical, histologic, and genomic features. Clinically, they are more likely to occur in young patients and commonly present as generalized processes with involvement of the mediastinum, pleura, and pericardium. Histologically, they are composed of highly cellular sheet-like and nodular proliferations of spindle cells, reminiscent of Kaposi sarcoma (Croteau et al., 2014). Unlike Kaposi sarcoma, the tumor cells lack immunopositivity for human herpesvirus-8 (HHV-8) latency-associated nuclear antigen (LANA). Genomically, recent studies have shown they tend to harbor somatic activating alterations in NRAS (Barclay et al., 2019Barclay et al., 2019). As a caveat, for the one NRAS-mutant LM with classic histology, the histologic classification was based on a small biopsy, and it is certainly possible that kaposiform histology was present in the large visceral LM but not captured by the limited sampling by core needle biopsy. Importantly, three of the five patients (60%) with NRAS-mutant LMs had failed treatment with sirolimus prior to NGS. There are reports that some NRAS-mutant LMs may respond to treatment with MEK inhibitors (Dummer et al., 2017), suggesting this may be an option for LMs with kaposiform features.

Of the five cases without either PIK3CA or NRAS mutations, all of classic histology, a single case had a known pathogenic in-frame GOPC–ROS1 genetic fusion predicted to have an intact ROS1 kinase domain and thus potentially function as the driver. Similar GOPC–ROS1 fusions have been seen in pediatric gliomas and adult lung cancers and may be sensitive to ROS1 inhibitors (Davare et al., 2018; Drilon et al., 2021). These data suggest that most LMs may have a potentially actionable driver mutation, with PIK3CA mutations dominating LMs with conventional histology and NRAS mutations predominantly or exclusively seen in the minor subset of LMs with kaposiform features. It is possible that the other NRAS and KRAS wild-type LMs may also have oncogenic alterations in other members of the PIK3CA or MAPK signaling pathway members that were not profiled by targeted sequencing strategies. We appreciate that one limitation of our study is that the cohort presented in Table 1 was established from clinical information provided by the ordering physicians early in the course of diagnostic investigation. Therefore, we cannot rule out that the working clinical diagnosis and/or pathologic diagnoses were refined after genomic analyses without transmission of these data to the reference laboratory that supplied the cohort data. Comprehensive NGS analysis of LMs with PIK3CA and NRAS wild-type may be required to identify any potential actionable driver mutations. In patients without solid LM tissue available for NGS, liquid biopsy—or NGS performed on circulating tumor DNA (ctDNA) in peripheral blood—may be a possible solution for LMs, which are innately associated with the vascular system and thus potentially ‘shedding’ ctDNA into the peripheral blood.

To illustrate the potential for therapeutic intervention of the target mutations identified, we performed an N-of-1 trial of alpelisib in one young adult index patient with a giant retroperitoneal and pancreatic LM with conventional histological features and a gain-of-function H1047R somatic PIK3CA mutation. Our index patient experienced a rapid, complete, and durable clinical response with this small molecule PI3Kα inhibitor. Given the high frequency of PIK3CA mutations in pediatric LMS (Luks et al., 2015), this finding suggests that alpelisib may be highly effective for systemic, nonsurgical treatment approach to this class of disorders. Furthermore, the lack of toxicity to alpelisib in our case is promising in terms of a potential future treatment of young patients with LMs. Our patient did not experience increases in glucose levels, consistent with reported lack of alpelisib-induced hyperglycemia in most pediatric patients with PROS (Venot et al., 2018; Mayer et al., 2017). In this prior series, only one patient developed new-onset hyperglycemia and this was controlled by dietary modification (Venot et al., 2018). These findings suggest that the effect of alpelisib on inducing hyperglycemia might perhaps be less of a concern in younger patients, who may have more robust glucose homeostasis, compared with older patients who may already have subclinical insulin resistance.

Ultimately, we decided to hold alpelisib after 2 years of complete radiological response, and unfortunately the LM relapsed but the patient still achieved a major partial response on the second challenge with alpelisib. This result suggests that PI3Kα inhibitors do not completely eradicate all LM-initiating cells, and they may need to be given long term (in our young index patient case, perhaps over decades) in PIK3CA-mutant LMs for sustained control. This class of drugs can also be envisioned to be utilized in a neoaduvant approach to render large cases resectable. Our patient declined surgery after initial response and he continues on alpelisib for several years. Acquired resistance mechanisms to PI3Kα inhibitors have been reported, due to other associated compensatory or bypassing mutations such as ones involving RAS oncogene (Janku et al., 2014) or PTEN tumor suppressor gene (Juric et al., 2017), and these may conceivably arise in these patients with longer follow-up over time. Deftly balancing the potential benefits of continuing treatment with the potential for drug resistance mechanisms will require monitoring for both actionable known and novel mutations through NGS of LM tissue samples or liquid biopsy.

In a series of pediatric patients with LMs, Luks et al. identified PIK3CA gene mutations in patients with sporadic LMs in 16 out of 17 patients (94%) or syndromic LMs such as the Klippel–Trenaunay syndrome in 19 out of 21 patients (90%), fibro-adipose vascular anomaly in 5 out of 8 patients (63%), along with the CLOVES syndrome in 31 out of 33 patients (94%) (Luks et al., 2015). H1047R was one of the top 2 most frequently encountered hotspot mutations in this series. Venot et al. reported a single arm clinical trial of alpelisib in 19 patients with pediatric PROS including CLOVES (Venot et al., 2018). Alpelisib treatment-induced clinical responses in all patients, including improvement of cardiac EF as seen in our index patient. Of note, alpelisib-induced responses in patients who did not respond to prior treatment with mTOR inhibitors, such as rapamycin, similar to observations in KRAS-mutant oncology patients (Di Nicolantonio et al., 2010), similar to the recent findings of Delestre et al. (Delestre et al., 2021). Small clinical series have shown that mTOR inhibition can induce responses in a subset of unselected advanced LMs, with observed response rates of ~50–60% (Freixo et al., 2020). The on driver-oncoprotein activity, higher response rates, and tolerability suggest alpelisib may be more effective than mTOR inhibitors in this setting. It is tempting to speculate that a wide variety of PIK3CA-mutant somatic overgrowth conditions (Hucthagowder et al., 2017) may be amenable to medical treatment with FDA-approved PI3Kα inhibitors, either as neoadjuvant treatment in potentially resectable cases, or as primary treatment in unresectable cases (Juric et al., 2018; Juric et al., 2017; Bendell et al., 2012; Hong et al., 2012; Juric et al., 2015). Since our submission, the FDA-approved alpelisib for pediatric and adult patients with PROS, and several clinical trials are underway to assess safety, efficacy, and quality-of-life with alpelisib in patients with a PROS diagnosis (e.g., NCT04589650, NCT04085653, NCT04980833, and NCT05294289), demonstrating the swiftness of efforts to address this clinical need.

Furthermore, in our WGS analysis, we identified only a few somatic variants within protein-coding genetic sequences (Supplementary file 1) beyond what was reported in the cancer gene panel (Table 1). The low frequency of somatic mutations is consistent with findings in other low-grade pediatric tumors (Akhavanfard et al., 2020). In addition to detecting the PIK3CA H1047R mutation, this WGS confirmed the variant detected by the cancer gene panel in the PIK3C2B gene and demonstrated that it was germline. Although this in PIK3C2B variant has not been characterized and may be a benign polymorphism, this finding raises the issue of whether other alterations in the pathway may cooperate with activating mutations of PIK3CA to induce cell proliferation. The low VAF driver mutations in tissue derived from LMs is likely due to the fact that most pathological tissue is composed of reactive stromal elements while the clonal cells represent a relatively small portion (presumably the lymphatic channel-lining endothelial cells). Consistent with this observation, in the alpelisib-treated index patient, we observed most intense activation of the PI3Kα pathway in these lymphatic channel-lining endothelial cells (Figure 2F, G). The high representations of pathways associated with vascular development, cell motility, inflammatory response, positive regulation of response to stimuli, blood vessel morphogenesis in our gene expression analysis are consistent with a mechanistic hypothesis that most of the lesion represents an intense reactive response to the (presumably) clonal LM-LECs, although the appropriate comparator control tissues for these lesions is not clear.

Evidence is accumulating that a variety of ‘nonmalignant’ syndromes associated with abnormal tissue growth may be driven by underlying alterations in classic oncogenes (Mustjoki and Young, 2021). PIK3CA mutations are seen not only in LMs but other vascular anomalies, highlighting the role of PIK3CA activation in angiogenesis, lymphangiogenesis, and vascular neoplasms (Castel et al., 2016; Castillo et al., 2016; Limaye et al., 2015; Ren et al., 2021). Endometriosis, uterine fibroids, and seborrheic keratoses all have been found to harbor mutations in cancer-related genes (Rafnar et al., 2018; Gallagher et al., 2019; Fritsche et al., 2018; Sanders et al., 2018; Anglesio et al., 2017). These findings suggest that targeted therapies being developed for invasive cancers may also be active in proliferative lesions that are not classified as invasive cancers that harbor the targeted alteration.

In summary (Figure 5), we find that the majority of LMs have driver mutations that are potentially targetable. LMs with classic histology mostly have PIK3CA mutations that may respond to alpelisib. LMs with kaposiform histopathology are enriched in NRAS mutations, and studies are required to determine if these may respond to clinically available MEK inhibitors. LMs that are wild-type for PIK3CA and NRAS may have other actionable alterations, such as the GOPC–ROS1 fusion seen in our series and may require more comprehensive genomic analyses to identify them. Systemic treatment with targeted therapy aimed at the driver mutation in LMs may be an option for some patients who are not controlled by surgery and other conventional treatments.

Figure 5

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NGS data for this study were generated at Foundation Medicine, Inc on U.S. patients profiled during routine clinical care. Approval for this study, including a waiver of informed consent and Health Insurance Portability and Accountability Act waiver of authorization, was obtained from the Western Institutional Review Board (protocol #20152817). Due to potential for identifiability, patient-level alteration data are not available. However, extensive data supporting the findings of this study are available in Table 1 and Figure 1A.

1. 1. Akhavanfard S
   2. Padmanabhan R
   3. Yehia L
   4. Cheng F
   5. Eng C

   (2020) Comprehensive germline genomic profiles of children, adolescents and young adults with solid tumors

   Nature Communications 11:2206.

   https://doi.org/10.1038/s41467-020-16067-1

   • PubMed
   • Google Scholar
2. 1. Anglesio MS
   2. Papadopoulos N
   3. Ayhan A
   4. Nazeran TM
   5. Noë M
   6. Horlings HM
   7. Lum A
   8. Jones S
   9. Senz J
   10. Seckin T
   11. Ho J
   12. Wu R-C
   13. Lac V
   14. Ogawa H
   15. Tessier-Cloutier B
   16. Alhassan R
   17. Wang A
   18. Wang Y
   19. Cohen JD
   20. Wong F
   21. Hasanovic A
   22. Orr N
   23. Zhang M
   24. Popoli M
   25. McMahon W
   26. Wood LD
   27. Mattox A
   28. Allaire C
   29. Segars J
   30. Williams C
   31. Tomasetti C
   32. Boyd N
   33. Kinzler KW
   34. Gilks CB
   35. Diaz L
   36. Wang T-L
   37. Vogelstein B
   38. Yong PJ
   39. Huntsman DG
   40. Shih I-M

   (2017) Cancer-Associated Mutations in Endometriosis without Cancer

   The New England Journal of Medicine 376:1835–1848.

   https://doi.org/10.1056/NEJMoa1614814

   • PubMed
   • Google Scholar
3. 1. Barclay SF
   2. Inman KW
   3. Luks VL
   4. McIntyre JB
   5. Al-Ibraheemi A
   6. Church AJ
   7. Perez-Atayde AR
   8. Mangray S
   9. Jeng M
   10. Kreimer SR
   11. Walker L
   12. Fishman SJ
   13. Alomari AI
   14. Chaudry G
   15. Trenor Iii CC
   16. Adams D
   17. Kozakewich HPW
   18. Kurek KC

   (2019) A somatic activating NRAS variant associated with kaposiform lymphangiomatosis

   Genetics in Medicine 21:1517–1524.

   https://doi.org/10.1038/s41436-018-0390-0

   • PubMed
   • Google Scholar
4. 1. Bendell JC
   2. Rodon J
   3. Burris HA
   4. de Jonge M
   5. Verweij J
   6. Birle D
   7. Demanse D
   8. De Buck SS
   9. Ru QC
   10. Peters M
   11. Goldbrunner M
   12. Baselga J

   (2012) Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors

   Journal of Clinical Oncology 30:282–290.

   https://doi.org/10.1200/JCO.2011.36.1360

   • PubMed
   • Google Scholar
5. 1. Boscolo E
   2. Coma S
   3. Luks VL
   4. Greene AK
   5. Klagsbrun M
   6. Warman ML
   7. Bischoff J

   (2015) AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation

   Angiogenesis 18:151–162.

   https://doi.org/10.1007/s10456-014-9453-2

   • PubMed
   • Google Scholar
6. 1. Castel P
   2. Carmona FJ
   3. Grego-Bessa J
   4. Berger MF
   5. Viale A
   6. Anderson KV
   7. Bague S
   8. Scaltriti M
   9. Antonescu CR
   10. Baselga E
   11. Baselga J

   (2016) Somatic PIK3CA mutations as a driver of sporadic venous malformations

   Science Translational Medicine 8:332–342.

   https://doi.org/10.1126/scitranslmed.aaf1164

   • PubMed
   • Google Scholar
7. 1. Castillo SD
   2. Tzouanacou E
   3. Zaw-Thin M
   4. Berenjeno IM
   5. Parker VER
   6. Chivite I
   7. Milà-Guasch M
   8. Pearce W
   9. Solomon I
   10. Angulo-Urarte A
   11. Figueiredo AM
   12. Dewhurst RE
   13. Knox RG
   14. Clark GR
   15. Scudamore CL
   16. Badar A
   17. Kalber TL
   18. Foster J
   19. Stuckey DJ
   20. David AL
   21. Phillips WA
   22. Lythgoe MF
   23. Wilson V
   24. Semple RK
   25. Sebire NJ
   26. Kinsler VA
   27. Graupera M
   28. Vanhaesebroeck B

   (2016) Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans

   Science Translational Medicine 8:332–343.

   https://doi.org/10.1126/scitranslmed.aad9982

   • PubMed
   • Google Scholar
8. 1. Cheng Y
   2. Xu T
   3. Li S
   4. Ruan H

   (2019) GPX1, a biomarker for the diagnosis and prognosis of kidney cancer, promotes the progression of kidney cancer

   Aging 11:12165–12176.

   https://doi.org/10.18632/aging.102555

   • PubMed
   • Google Scholar
9. 1. Croteau SE
   2. Kozakewich HPW
   3. Perez-Atayde AR
   4. Fishman SJ
   5. Alomari AI
   6. Chaudry G
   7. Mulliken JB
   8. Trenor CC

   (2014) Kaposiform lymphangiomatosis: a distinct aggressive lymphatic anomaly

   The Journal of Pediatrics 164:383–388.

   https://doi.org/10.1016/j.jpeds.2013.10.013

   • PubMed
   • Google Scholar
10. 1. Davare MA
    2. Henderson JJ
    3. Agarwal A
    4. Wagner JP
    5. Iyer SR
    6. Shah N
    7. Woltjer R
    8. Somwar R
    9. Gilheeney SW
    10. DeCarvalo A
    11. Mikkelson T
    12. Van Meir EG
    13. Ladanyi M
    14. Druker BJ

    (2018) Rare but Recurrent ROS1 Fusions Resulting From Chromosome 6q22 Microdeletions are Targetable Oncogenes in Glioma

    Clinical Cancer Research 24:6471–6482.

    https://doi.org/10.1158/1078-0432.CCR-18-1052

    • PubMed
    • Google Scholar
11. 1. Delestre F
    2. Venot Q
    3. Bayard C
    4. Fraissenon A
    5. Ladraa S
    6. Hoguin C
    7. Chapelle C
    8. Yamaguchi J
    9. Cassaca R
    10. Zerbib L
    11. Magassa S
    12. Morin G
    13. Asnafi V
    14. Villarese P
    15. Kaltenbach S
    16. Fraitag S
    17. Duong JP
    18. Broissand C
    19. Boccara O
    20. Soupre V
    21. Bonnotte B
    22. Chopinet C
    23. Mirault T
    24. Legendre C
    25. Guibaud L
    26. Canaud G

    (2021) Alpelisib administration reduced lymphatic malformations in a mouse model and in patients

    Science Translational Medicine 13:614.

    https://doi.org/10.1126/scitranslmed.abg0809

    • PubMed
    • Google Scholar
12. 1. Di Nicolantonio F
    2. Arena S
    3. Tabernero J
    4. Grosso S
    5. Molinari F
    6. Macarulla T
    7. Russo M
    8. Cancelliere C
    9. Zecchin D
    10. Mazzucchelli L
    11. Sasazuki T
    12. Shirasawa S
    13. Geuna M
    14. Frattini M
    15. Baselga J
    16. Gallicchio M
    17. Biffo S
    18. Bardelli A

    (2010) Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus

    The Journal of Clinical Investigation 120:2858–2866.

    https://doi.org/10.1172/JCI37539

    • PubMed
    • Google Scholar
13. 1. Drilon A
    2. Jenkins C
    3. Iyer S
    4. Schoenfeld A
    5. Keddy C
    6. Davare MA

    (2021) ROS1-dependent cancers - biology, diagnostics and therapeutics

    Nature Reviews. Clinical Oncology 18:35–55.

    https://doi.org/10.1038/s41571-020-0408-9

    • PubMed
    • Google Scholar
14. 1. Dummer R
    2. Schadendorf D
    3. Ascierto PA
    4. Arance A
    5. Dutriaux C
    6. Di Giacomo AM
    7. Rutkowski P
    8. Del Vecchio M
    9. Gutzmer R
    10. Mandala M
    11. Thomas L
    12. Demidov L
    13. Garbe C
    14. Hogg D
    15. Liszkay G
    16. Queirolo P
    17. Wasserman E
    18. Ford J
    19. Weill M
    20. Sirulnik LA
    21. Jehl V
    22. Bozón V
    23. Long GV
    24. Flaherty K

    (2017) Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial

    The Lancet. Oncology 18:435–445.

    https://doi.org/10.1016/S1470-2045(17)30180-8

    • PubMed
    • Google Scholar
15. 1. Freixo C
    2. Ferreira V
    3. Martins J
    4. Almeida R
    5. Caldeira D
    6. Rosa M
    7. Costa J
    8. Ferreira J

    (2020) Efficacy and safety of sirolimus in the treatment of vascular anomalies: A systematic review

    Journal of Vascular Surgery 71:318–327.

    https://doi.org/10.1016/j.jvs.2019.06.217

    • PubMed
    • Google Scholar
16. 1. Fritsche LG
    2. Gruber SB
    3. Wu Z
    4. Schmidt EM
    5. Zawistowski M
    6. Moser SE
    7. Blanc VM
    8. Brummett CM
    9. Kheterpal S
    10. Abecasis GR
    11. Mukherjee B

    (2018) Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-wide Study: Results from The Michigan Genomics Initiative

    American Journal of Human Genetics 102:1048–1061.

    https://doi.org/10.1016/j.ajhg.2018.04.001

    • PubMed
    • Google Scholar
17. 1. Fruman DA
    2. Chiu H
    3. Hopkins BD
    4. Bagrodia S
    5. Cantley LC
    6. Abraham RT

    (2017) The PI3K Pathway in Human Disease

    Cell 170:605–635.

    https://doi.org/10.1016/j.cell.2017.07.029

    • PubMed
    • Google Scholar
18. 1. Gagnier JJ
    2. Kienle G
    3. Altman DG
    4. Moher D
    5. Sox H
    6. Riley D
    7. Group C

    (2013) The CARE guidelines: consensus-based clinical case reporting guideline development

    BMJ Case Reports 2013:bcr2013201554.

    https://doi.org/10.1136/bcr-2013-201554

    • PubMed
    • Google Scholar
19. 1. Gallagher CS
    2. Mäkinen N
    3. Harris HR
    4. Rahmioglu N
    5. Uimari O
    6. Cook JP
    7. Shigesi N
    8. Ferreira T
    9. Velez-Edwards DR
    10. Edwards TL
    11. Mortlock S
    12. Ruhioglu Z
    13. Day F
    14. Becker CM
    15. Karhunen V
    16. Martikainen H
    17. Järvelin MR
    18. Cantor RM
    19. Ridker PM
    20. Terry KL
    21. Buring JE
    22. Gordon SD
    23. Medland SE
    24. Montgomery GW
    25. Nyholt DR
    26. Hinds DA
    27. Tung JY
    28. Perry JRB
    29. Lind PA
    30. Painter JN
    31. Martin NG
    32. Morris AP
    33. Chasman DI
    34. Missmer SA
    35. Zondervan KT
    36. Morton CC
    37. 23andMe Research Team

    (2019) Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis

    Nature Communications 10:4857.

    https://doi.org/10.1038/s41467-019-12536-4

    • PubMed
    • Google Scholar
20. 1. Hong DS
    2. Bowles DW
    3. Falchook GS
    4. Messersmith WA
    5. George GC
    6. O’Bryant CL
    7. Vo ACH
    8. Klucher K
    9. Herbst RS
    10. Eckhardt SG
    11. Peterson S
    12. Hausman DF
    13. Kurzrock R
    14. Jimeno A

    (2012) A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors

    Clinical Cancer Research 18:4173–4182.

    https://doi.org/10.1158/1078-0432.CCR-12-0714

    • PubMed
    • Google Scholar
21. 1. Hucthagowder V
    2. Shenoy A
    3. Corliss M
    4. Vigh-Conrad KA
    5. Storer C
    6. Grange DK
    7. Cottrell CE

    (2017) Utility of clinical high-depth next generation sequencing for somatic variant detection in the PIK3CA-related overgrowth spectrum

    Clinical Genetics 91:79–85.

    https://doi.org/10.1111/cge.12819

    • PubMed
    • Google Scholar
22. 1. Janku F
    2. Hong DS
    3. Fu S
    4. Piha-Paul SA
    5. Naing A
    6. Falchook GS
    7. Tsimberidou AM
    8. Stepanek VM
    9. Moulder SL
    10. Lee JJ
    11. Luthra R
    12. Zinner RG
    13. Broaddus RR
    14. Wheler JJ
    15. Kurzrock R

    (2014) Assessing PIK3CA and PTEN in early-phase trials with PI3K/AKT/mTOR inhibitors

    Cell Reports 6:377–387.

    https://doi.org/10.1016/j.celrep.2013.12.035

    • PubMed
    • Google Scholar
23. 1. Juric D
    2. Castel P
    3. Griffith M
    4. Griffith OL
    5. Won HH
    6. Ellis H
    7. Ebbesen SH
    8. Ainscough BJ
    9. Ramu A
    10. Iyer G
    11. Shah RH
    12. Huynh T
    13. Mino-Kenudson M
    14. Sgroi D
    15. Isakoff S
    16. Thabet A
    17. Elamine L
    18. Solit DB
    19. Lowe SW
    20. Quadt C
    21. Peters M
    22. Derti A
    23. Schegel R
    24. Huang A
    25. Mardis ER
    26. Berger MF
    27. Baselga J
    28. Scaltriti M

    (2015) Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor

    Nature 518:240–244.

    https://doi.org/10.1038/nature13948

    • PubMed
    • Google Scholar
24. 1. Juric D
    2. Krop I
    3. Ramanathan RK
    4. Wilson TR
    5. Ware JA
    6. Sanabria Bohorquez SM
    7. Savage HM
    8. Sampath D
    9. Salphati L
    10. Lin RS
    11. Jin H
    12. Parmar H
    13. Hsu JY
    14. Von Hoff DD
    15. Baselga J

    (2017) Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

    Cancer Discovery 7:704–715.

    https://doi.org/10.1158/2159-8290.CD-16-1080

    • PubMed
    • Google Scholar
25. 1. Juric D
    2. Rodon J
    3. Tabernero J
    4. Janku F
    5. Burris HA
    6. Schellens JHM
    7. Middleton MR
    8. Berlin J
    9. Schuler M
    10. Gil-Martin M
    11. Rugo HS
    12. Seggewiss-Bernhardt R
    13. Huang A
    14. Bootle D
    15. Demanse D
    16. Blumenstein L
    17. Coughlin C
    18. Quadt C
    19. Baselga J

    (2018) Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study

    Journal of Clinical Oncology 36:1291–1299.

    https://doi.org/10.1200/JCO.2017.72.7107

    • PubMed
    • Google Scholar
26. 1. Limaye N
    2. Kangas J
    3. Mendola A
    4. Godfraind C
    5. Schlögel MJ
    6. Helaers R
    7. Eklund L
    8. Boon LM
    9. Vikkula M

    (2015) Somatic Activating PIK3CA Mutations Cause Venous Malformation

    American Journal of Human Genetics 97:914–921.

    https://doi.org/10.1016/j.ajhg.2015.11.011

    • PubMed
    • Google Scholar
27. 1. Luks VL
    2. Kamitaki N
    3. Vivero MP
    4. Uller W
    5. Rab R
    6. Bovée JVMG
    7. Rialon KL
    8. Guevara CJ
    9. Alomari AI
    10. Greene AK
    11. Fishman SJ
    12. Kozakewich HPW
    13. Maclellan RA
    14. Mulliken JB
    15. Rahbar R
    16. Spencer SA
    17. Trenor CC
    18. Upton J
    19. Zurakowski D
    20. Perkins JA
    21. Kirsh A
    22. Bennett JT
    23. Dobyns WB
    24. Kurek KC
    25. Warman ML
    26. McCarroll SA
    27. Murillo R

    (2015) Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA

    The Journal of Pediatrics 166:1048–1054.

    https://doi.org/10.1016/j.jpeds.2014.12.069

    • PubMed
    • Google Scholar
28. 1. Mayer IA
    2. Abramson VG
    3. Formisano L
    4. Balko JM
    5. Estrada MV
    6. Sanders ME
    7. Juric D
    8. Solit D
    9. Berger MF
    10. Won HH
    11. Li Y
    12. Cantley LC
    13. Winer E
    14. Arteaga CL

    (2017) A Phase Ib Study of Alpelisib (BYL719), A PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer

    Clinical Cancer Research 23:26–34.

    https://doi.org/10.1158/1078-0432.CCR-16-0134

    • PubMed
    • Google Scholar
29. 1. Mustjoki S
    2. Young NS

    (2021) Somatic Mutations in “Benign” Disease

    The New England Journal of Medicine 384:2039–2052.

    https://doi.org/10.1056/NEJMra2101920

    • PubMed
    • Google Scholar
30. 1. Perkins JA
    2. Manning SC
    3. Tempero RM
    4. Cunningham MJ
    5. Edmonds JL
    6. Hoffer FA
    7. Egbert MA

    (2010) Lymphatic malformations: review of current treatment

    Otolaryngology--Head and Neck Surgery 142:795–803.

    https://doi.org/10.1016/j.otohns.2010.02.026

    • PubMed
    • Google Scholar
31. 1. Qiu QC
    2. Wang L
    3. Jin SS
    4. Liu GF
    5. Liu J
    6. Ma L
    7. Mao RF
    8. Ma YY
    9. Zhao N
    10. Chen M
    11. Lin BY

    (2018) CHI3L1 promotes tumor progression by activating TGF-β signaling pathway in hepatocellular carcinoma

    Scientific Reports 8:15029.

    https://doi.org/10.1038/s41598-018-33239-8

    • PubMed
    • Google Scholar
32. 1. Rafnar T
    2. Gunnarsson B
    3. Stefansson OA
    4. Sulem P
    5. Ingason A
    6. Frigge ML
    7. Stefansdottir L
    8. Sigurdsson JK
    9. Tragante V
    10. Steinthorsdottir V
    11. Styrkarsdottir U
    12. Stacey SN
    13. Gudmundsson J
    14. Arnadottir GA
    15. Oddsson A
    16. Zink F
    17. Halldorsson G
    18. Sveinbjornsson G
    19. Kristjansson RP
    20. Davidsson OB
    21. Salvarsdottir A
    22. Thoroddsen A
    23. Helgadottir EA
    24. Kristjansdottir K
    25. Ingthorsson O
    26. Gudmundsson V
    27. Geirsson RT
    28. Arnadottir R
    29. Gudbjartsson DF
    30. Masson G
    31. Asselbergs FW
    32. Jonasson JG
    33. Olafsson K
    34. Thorsteinsdottir U
    35. Halldorsson BV
    36. Thorleifsson G
    37. Stefansson K

    (2018) Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits

    Nature Communications 9:3636.

    https://doi.org/10.1038/s41467-018-05428-6

    • PubMed
    • Google Scholar
33. 1. Ren AA
    2. Snellings DA
    3. Su YS
    4. Hong CC
    5. Castro M
    6. Tang AT
    7. Detter MR
    8. Hobson N
    9. Girard R
    10. Romanos S
    11. Lightle R
    12. Moore T
    13. Shenkar R
    14. Benavides C
    15. Beaman MM
    16. Müller-Fielitz H
    17. Chen M
    18. Mericko P
    19. Yang J
    20. Sung DC
    21. Lawton MT
    22. Ruppert JM
    23. Schwaninger M
    24. Körbelin J
    25. Potente M
    26. Awad IA
    27. Marchuk DA
    28. Kahn ML

    (2021) PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism

    Nature 594:271–276.

    https://doi.org/10.1038/s41586-021-03562-8

    • PubMed
    • Google Scholar
34. 1. Samuels Y
    2. Wang Z
    3. Bardelli A
    4. Silliman N
    5. Ptak J
    6. Szabo S
    7. Yan H
    8. Gazdar A
    9. Powell SM
    10. Riggins GJ
    11. Willson JKV
    12. Markowitz S
    13. Kinzler KW
    14. Vogelstein B
    15. Velculescu VE

    (2004) High frequency of mutations of the PIK3CA gene in human cancers

    Science (New York, N.Y.) 304:554.

    https://doi.org/10.1126/science.1096502

    • PubMed
    • Google Scholar
35. 1. Sanders MGH
    2. Pardo LM
    3. Uitterlinden AG
    4. Smith AM
    5. Ginger RS
    6. Nijsten T

    (2018) The Genetics of Seborrheic Dermatitis: A Candidate Gene Approach and Pilot Genome-Wide Association Study

    The Journal of Investigative Dermatology 138:991–993.

    https://doi.org/10.1016/j.jid.2017.11.020

    • PubMed
    • Google Scholar
36. 1. Sirois I
    2. Aguilar-Mahecha A
    3. Lafleur J
    4. Fowler E
    5. Vu V
    6. Scriver M
    7. Buchanan M
    8. Chabot C
    9. Ramanathan A
    10. Balachandran B
    11. Légaré S
    12. Przybytkowski E
    13. Lan C
    14. Krzemien U
    15. Cavallone L
    16. Aleynikova O
    17. Ferrario C
    18. Guilbert M-C
    19. Benlimame N
    20. Saad A
    21. Alaoui-Jamali M
    22. Saragovi HU
    23. Josephy S
    24. O’Flanagan C
    25. Hursting SD
    26. Richard VR
    27. Zahedi RP
    28. Borchers CH
    29. Bareke E
    30. Nabavi S
    31. Tonellato P
    32. Roy J-A
    33. Robidoux A
    34. Marcus EA
    35. Mihalcioiu C
    36. Majewski J
    37. Basik M

    (2019) A Unique Morphological Phenotype in Chemoresistant Triple-Negative Breast Cancer Reveals Metabolic Reprogramming and PLIN4 Expression as A Molecular Vulnerability

    Molecular Cancer Research 17:2492–2507.

    https://doi.org/10.1158/1541-7786.MCR-19-0264

    • PubMed
    • Google Scholar
37. 1. Subramanian A
    2. Kuehn H
    3. Gould J
    4. Tamayo P
    5. Mesirov JP

    (2007) GSEA-P: a desktop application for Gene Set Enrichment Analysis

    Bioinformatics (Oxford, England) 23:3251–3253.

    https://doi.org/10.1093/bioinformatics/btm369

    • PubMed
    • Google Scholar
38. 1. Vadivel CK
    2. Gluud M
    3. Torres-Rusillo S
    4. Boding L
    5. Willerslev-Olsen A
    6. Buus TB
    7. Nielsen TK
    8. Persson JL
    9. Bonefeld CM
    10. Geisler C
    11. Krejsgaard T
    12. Fuglsang AT
    13. Odum N
    14. Woetmann A

    (2021) JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL

    Cancers 13:280.

    https://doi.org/10.3390/cancers13020280

    • PubMed
    • Google Scholar
39. 1. Venot Q
    2. Blanc T
    3. Rabia SH
    4. Berteloot L
    5. Ladraa S
    6. Duong JP
    7. Blanc E
    8. Johnson SC
    9. Hoguin C
    10. Boccara O
    11. Sarnacki S
    12. Boddaert N
    13. Pannier S
    14. Martinez F
    15. Magassa S
    16. Yamaguchi J
    17. Knebelmann B
    18. Merville P
    19. Grenier N
    20. Joly D
    21. Cormier-Daire V
    22. Michot C
    23. Bole-Feysot C
    24. Picard A
    25. Soupre V
    26. Lyonnet S
    27. Sadoine J
    28. Slimani L
    29. Chaussain C
    30. Laroche-Raynaud C
    31. Guibaud L
    32. Broissand C
    33. Amiel J
    34. Legendre C
    35. Terzi F
    36. Canaud G

    (2018) Targeted therapy in patients with PIK3CA-related overgrowth syndrome

    Nature 558:540–546.

    https://doi.org/10.1038/s41586-018-0217-9

    • PubMed
    • Google Scholar
40. 1. Zhang Q
    2. Zhang P
    3. Li B
    4. Dang H
    5. Jiang J
    6. Meng L
    7. Zhang H
    8. Zhang Y
    9. Wang X
    10. Li Q
    11. Wang Y
    12. Liu C
    13. Li F

    (2020) The Expression of Perilipin Family Proteins can be used as Diagnostic Markers of Liposarcoma and to Differentiate Subtypes

    Journal of Cancer 11:4081–4090.

    https://doi.org/10.7150/jca.41736

    • PubMed
    • Google Scholar

Author details

1. Montaser F Shaheen

   1. University of Arizona Cancer Center, Tucson, United States
   2. Division of Hematology/Oncology, Department of Medicine, University of Arizona College of Medicine, Tucson, United States

   Contribution

   Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Visualization, Writing – original draft, Writing – review and editing

   Contributed equally with

   Julie Y Tse

   For correspondence

   shaheenm@arizona.edu

   Competing interests

   reports personal fees from Illumina, BMS, and Qiagen (outside of the submitted work). The author has no other competing interests to declare

2. Julie Y Tse

   Foundation Medicine, Inc, Cambridge, United States

   Contribution

   Conceptualization, Investigation, Methodology, Project administration, Supervision, Visualization, Writing – original draft, Writing – review and editing

   Contributed equally with

   Montaser F Shaheen

   Competing interests

   is an employee of Foundation Medicine, Inc, a wholly owned subsidiary of Roche, and owns equity in Roche. The author has no other competing interests to declare

3. Ethan S Sokol

   Foundation Medicine, Inc, Cambridge, United States

   Contribution

   Conceptualization, Investigation, Methodology, Visualization, Writing – original draft, Writing – review and editing

   Competing interests

   is an employee of Foundation Medicine, Inc, a wholly owned subsidiary of Roche, and owns equity in Roche. The author has no other competing interests to declare

4. Margaret Masterson

   1. Rutgers Cancer Institute of New Jersey, New Brunswick, United States
   2. Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, United States

   Contribution

   Conceptualization, Funding acquisition, Writing – review and editing

   Competing interests

   No competing interests declared

5. Pranshu Bansal

   1. University of New Mexico Comprehensive Cancer Center, Albuquerque, United States
   2. Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, United States

   Contribution

   Investigation, Methodology, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

6. Ian Rabinowitz

   1. University of New Mexico Comprehensive Cancer Center, Albuquerque, United States
   2. Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, United States

   Contribution

   Investigation, Methodology, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

7. Christy A Tarleton

   1. University of New Mexico Comprehensive Cancer Center, Albuquerque, United States
   2. Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, United States

   Contribution

   Investigation, Methodology, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

8. Andrey S Dobroff

   1. University of New Mexico Comprehensive Cancer Center, Albuquerque, United States
   2. Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, United States

   Contribution

   Investigation, Methodology, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2162-9951

9. Tracey L Smith

   1. Rutgers Cancer Institute of New Jersey, Newark, United States
   2. Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, United States

   Contribution

   Investigation, Methodology, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

10. Thèrése J Bocklage

    1. University of New Mexico Comprehensive Cancer Center, Albuquerque, United States
    2. Department of Pathology, University of Kentucky College of Medicine and Markey Cancer Center, Lexington, United States

    Contribution

    Investigation, Methodology, Visualization, Writing – review and editing

    Competing interests

    No competing interests declared

11. Brian K Mannakee

    1. University of Arizona Cancer Center, Tucson, United States
    2. Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, United States

    Contribution

    Investigation, Methodology, Visualization, Writing – review and editing

    Competing interests

    is an employee of Foundation Medicine, Inc, a wholly owned subsidiary of Roche, and owns equity in Roche

12. Ryan N Gutenkunst

    1. University of Arizona Cancer Center, Tucson, United States
    2. Department of Molecular and Cellular Biology, College of Science, University of Arizona, Tucson, United States

    Contribution

    Investigation, Methodology, Visualization, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-8659-0579

13. Joyce Bischoff

    1. Vascular Biology Program, Boston Children’s Hospital, Boston, United States
    2. Department of Surgery, Harvard Medical School, Boston, United States

    Contribution

    Investigation, Methodology, Visualization, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-6367-1974

14. Scott A Ness

    1. University of New Mexico Comprehensive Cancer Center, Albuquerque, United States
    2. Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, United States

    Contribution

    Investigation, Methodology, Visualization, Writing – review and editing

    Competing interests

    No competing interests declared

15. Gregory M Riedlinger

    1. Rutgers Cancer Institute of New Jersey, New Brunswick, United States
    2. Department of Pathology, Rutgers Robert Wood Johnson Medical School, New Brunswick, United States

    Contribution

    Investigation, Methodology, Visualization, Writing – review and editing

    Competing interests

    No competing interests declared

16. Roman Groisberg

    1. Rutgers Cancer Institute of New Jersey, New Brunswick, United States
    2. Division of Medical Oncology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, United States

    Contribution

    Investigation, Methodology, Visualization, Writing – review and editing

    Competing interests

    reports research funding/grant support for clinical trials (to his institution) from Regeneron, BMS, Merck/EMD Serano, Amgen, Roche/Genentech, Philogen; consulting/advisory board fees from Regeneron; and speaker fees for Deciphera (all outside of the submitted work). These arrangements are managed in accordance with the established institutional conflict of interest policies of Rutgers, The State University of New Jersey. The author has no other competing interests to declare

17. Renata Pasqualini

    1. Rutgers Cancer Institute of New Jersey, Newark, United States
    2. Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, United States

    Contribution

    Conceptualization, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review and editing

    Competing interests

    Reviewing editor, eLife

18. Shridar Ganesan

    1. Rutgers Cancer Institute of New Jersey, New Brunswick, United States
    2. Division of Medical Oncology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, United States

    Contribution

    Conceptualization, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review and editing

    Competing interests

    has consulting agreements with Merck, Roche, Novartis, Foundation Medicine, EQRX, Foghorn Therapeutics, Silagene, and KayoThera and owns equity in Silagene; his spouse is an employee of Merck and owns equity in Merck (all outside of the submitted work). These arrangements are managed in accordance with the established institutional conflict of interest policies of Rutgers, The State University of New Jersey. The author has no other competing interests to declare

19. Wadih Arap

    1. Rutgers Cancer Institute of New Jersey, Newark, United States
    2. Division of Hematology/Oncology, Department of Medicine, Rutgers New Jersey Medical School, Newark, United States

    Contribution

    Conceptualization, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review and editing

    For correspondence

    wadih.arap@rutgers.edu

    Competing interests

    Reviewing editor, eLife

    "This ORCID iD identifies the author of this article:" 0000-0002-8686-4584

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