Germline PIK3CA and AKT1 Mutations in Cowden and Cowden-like Syndromes

Orloff, Mohammed S.; He, Xin; Peterson, Charissa; Chen, Fusong; Chen, Jin Lian; Mester, Jessica L.; Eng, Charis

doi:10.1016/j.ajhg.2012.10.021

Cited by 174 publications

(115 citation statements)

References 22 publications

(18 reference statements)

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“…Although they both cause hamartomas and several other characteristics, individuals carrying the Cowden syndrome are also prone to elevated cancer risk, in particular cancers of the thyroid and breast. 144 While germline mutations in PIK3CA and AKT3 (the Akt isoform expressed in neural tissue) may cause megalencephaly, 145 a most recent study 146 reported PI3KCA, but also AKT1 germline mutations in some families revealing the Cowden or a Cowden-like syndrome. Breast cancer patients with oestrogen receptor-positive tumours revealing HER-2 amplification have been shown to respond poorly to endocrine therapy with aromatase inhibitors as well as tamoxifen.…”

Section: Activating Mutations In the Pten/pi3k/mtor Pathway As A Causmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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Section: Activating Mutations In the Pten/pi3k/mtor Pathway As A Causmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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“…For instance, the inherited disease Cowden syndrome/multiple hamartoma syndrome is caused by either germline heterozygous inactivating mutations in the PtdIns(3,4,5)P 3 phosphatase PTEN (OMIM #158350, CWS1), or germline activating mutations or amplifi cations of the PtdIns(3,4,5)P 3 -synthesizing enzyme PIK3CA (OMIM #615108, CWS5; ref. 7 ). Patients with Cowden syndrome show a predisposition to developing breast, thyroid, and endometrial cancers, and about 70% of these individuals have benign thyroid abnormalities, such as multinodular goiter, adenomatous nodules, and follicular adenoma ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

INPP4B Is a PtdIns(3,4,5)P3 Phosphatase That Can Act as a Tumor Suppressor

et al. 2015

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Inositol polyphosphate 4-phosphatase B (INPP4B) has been identified as a tumor suppressor mutated in human breast, ovary, and prostate cancers. The molecular mechanism underlying INPP4B's tumor-suppressive role is currently unknown. Here, we demonstrate that INPP4B restrains tumor development by dephosphorylating the PtdIns(3,4,5)P3 that accumulates in situations of PTEN deficiency. In vitro, INPP4B directly dephosphorylates PtdIns(3,4,5)P3. In vivo, neither inactivation of Inpp4b (Inpp4bΔ/Δ) nor heterozygous deletion of Pten (Pten+/−) in mice causes thyroid abnormalities, but a combination of these mutations induces malignant thyroid cancers with lung metastases. At the molecular level, simultaneous deletion of Inpp4b and Pten synergistically increases PtdIns(3,4,5)P3 levels and activates AKT downstream signaling proteins in thyroid cells. We propose that the PtdIns(3,4,5)P3 phosphatase activity of INPP4B can function as a “back-up” mechanism when PTEN is deficient, making INPP4B a potential novel therapeutic target for PTEN-deficient or PIK3CA-activated cancers. Significance: Although INPP4B expression is reduced in several types of human cancers, our work on Inpp4B-deficient mice provides the first evidence that INPP4B is a bona fide tumor suppressor whose function is particularly important in situations of PTEN deficiency. Our biochemical data demonstrate that INPP4B directly dephosphorylates PtdIns(3,4,5)P3. Cancer Discov; 5(7); 730–9. ©2015 AACR. See related commentary by Vo and Fruman, p. 697. See related article by Chew et al., p. 740. This article is highlighted in the In This Issue feature, p. 681

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“…16 Of note, mosaic mutations of these genes cause CLOVES 17 and Proteus syndrome, 18 respectively. Because Sanger sequencing is still the mainstay of clinical genetic testing, it is likely that many patients with low-level mosaicism in the peripheral blood remain undiagnosed.…”

Section: Discussionmentioning

confidence: 99%