Table 2.

Incidence and prognostic significance of PTEN alterations in PHTS and sporadic human cancers.

Malignancy type	Increased risk in PHTS	Molecular mechanism(s) of PTEN alteration	Prognostic/therapeutic implications of PTEN loss	References
Breast cancer	Yes (85 vs. 12% LR)	Mutations <5%, LOH 40%, methylation 50%, and loss of expression ~40%	Resistance to endocrine and HER2-targeted therapy	(34–39)
Thyroid cancer	Yes (35 vs. 1% LR)	Homozygous deletion <10%, methylation >50%, rearrangement in most papillary thyroid carcinomas	PTEN loss cooperates with other genetic alterations and is more frequent in aggressive cancers (ATC)	(34, 35, 40)
Kidney cancer	Yes (34 vs. 1.6% LR)	Homozygous deletion or somatic mutations 1–5% of ccRCC and 6.4% of chRCC	High PTEN expression correlates with better DSS and better response to VEGFR-TKI	(34, 35, 41–43)
Endometrial cancer	Yes (28 vs. 2.6% LR)	Mutations 15–88% depending on specific subtype, methylation 18%, and loss of expression 20%	Favorable or unfavorable prognostic implications depending on mutation type and association with obesity and/or other factors	(34, 35, 44, 45)
Colorectal cancer	Yes (9 vs. 5% LR)	Up to 18% mutated and up to 19% LOH depending on tumor type, concomitant promoter hypermethylation	Inconsistent negative prognostic impact; lack of response to EGFR-targeted mAbs	(34, 35, 46–49)
Melanoma	Yes (6 vs. 2% LR)	LOH 30–60%, mutation 10–20% (metastases), and >50% frequent promoter methylation in patients with XP	Inconsistent association with prognosis; subcellular localization important; decreased response to BRAF-selective inhibitors	(34, 35, 50–53)
Glioma	Dysplastic gangliocytoma of the cerebellum in LD	LOH >70%, mutation 44% (coincident with LOH) and miR-26a amplification	Mutations associated with shorter OS	(34, 35, 54, 55)
Prostate cancer	NR	Homozygous deletion and mutation in up to 20%, miR-22 and miR-106b-25 cluster overexpression	Early recurrence after surgery, development of metastases, hormone refractoriness, and shorter survival	(34, 56–58)
Leukemia/lymphoma	NR	Deletion 10% of T-ALL and 27% mutation in T-ALL, aberrant RNA splicing in AML	Shorter survival and resistance to NOTCH inhibitors in T-ALL	(34, 59–70)
Lung cancer	Occasional	Mutations 6–9% (predominantly squamous), promoter methylation 24%, frequent miR-21 upregulation, and loss of PTEN 24–44%	Inconsistent association with poor prognosis, resistance to EGFR-targeted therapies	(34, 71–75)
Bladder cancer	NR	LOH 23%, homozygous deletion 6%, mutation 23% (late stage), and decreased or absent expression 53%	Significant association with recurrence in pTa and progression in pT1	(34, 76, 77)
Liver cancer	NR	Mutation ~5%, deletion or loss of expression ~50%, and protein expression downregulated by HBV and HCV viral proteins	Association with high tumor grade, advanced stage, high αFP expression; increased recurrence, shorter OS and possibly resistance to sorafenib	(34, 78, 79)
Pancreatic cancer	NR	Hetero or homozygous deletions 15%, loss of protein expression ~70% (exocrine); LOH ~50%, altered subcellular localization (endocrine)	Significantly increased recurrence and metastases, shorter OS (exocrine); negative prognostic impact modulated by PR and mTOR expression (endocrine)	(34, 80–82)
Phaeochromocytoma	NR	Mutations rare, LOH ~40%	More frequent in malignant versus benign lesions	(34, 83)

PHTS, PTEN hamartoma tumor syndromes; LR, lifetime risk; LOH, loss of heterozygosity; ATC, anaplastic thyroid carcinoma; ccRCC, clear cell renal cell carcinoma; chRCC, chromophobe renal cell carcinoma; DSS, disease-specific survival; VEGFR-TKI, vascular endothelial growth factor receptor tyrosine kinase inhibitors; EGFR, epidermal growth factor receptor; mAbs, monoclonal antibodies; XP, xeroderma pigmentosum; LD, Lhermitte–Duclos syndrome; miR, misro-RNA; OS, overall survival; T-ALL, T-cell acute lymphoblastic leukemia; HBV, hepatitis B virus; HCV, hepatitis C virus; αFP, alpha fetoprotein; PR, progesterone receptor; mTOR, mammalian target of rapamycin.