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This article considers the case of a 73-year-old white man who presented with synchronous gastric carcinomas and a 20-year history of mixed polyposis. Genetic-testing and molecular-pathology analyses confirmed a diagnosis of Cowden's syndrome. The case explores the diagnostic challenges of differentiating between hamartomatous and adenomatous polyposis syndromes in patients with mixed polyposis, and emphasizes the need to characterize the risk of gastrointestinal cancer in patients with this syndrome.

PTENis one of the most frequently inactivated tumour suppressor genes in cancer, and approximately 80% of patients with Cowden syndrome have mutations inPTEN. This Review discusses the different types of PTEN-mutant tumours that occur in Cowden syndrome and the mouse models that have been engineered to study them.

The authors of this Review discuss the diagnosis, clinical features and genetics of the hamartomatous polyposis syndromes, as well as the risk of malignancy associated with each syndrome and appropriate surveillance recommendations. Other disorders associated with the presence of hamartomatous polyps are briefly discussed, along with the potential for targeted therapy of hamartomatous polyposis syndromes.

Germline mutations inPTEN result in the uncommon Cowden Syndrome. Heterozygous mutations of SDH B, C and D are associated with the hereditary pheochromocytoma–paraganglioma syndrome. Zbuk et al. present the first-reported case of a woman with both PTEN and SDHCmutations, which resulted in multiple neoplasias. The authors highlight the need for predictive genetic tests and close clinical surveillance of patients with suspected Cowden or pheochromocytoma–paraganglioma syndromes.

Owen Sansom and colleagues show that conditional deletion of Pten specifically from the small intestinal epithelium in mice does not disrupt normal tissue architecture, but in the context of Apc deficiency leads to rapid development of adenocarcinoma. These findings suggest that Pten does not serve a rate-limiting, intrinsic role in regulating normal intestinal stem cell physiology.

VAMP-seq is a scalable assay that measures the effects of missense variants on intracellular protein abundance. Applying VAMP-seq to thousands of PTEN and TPMT variants helps to classify them as pathogenic or benign.

Phenomics is the systematic and meticulous collection, objective documentation and cataloguing of phenotypic data at many levels. This Review describes the possible uses of phenomics in cancer research, using the examples ofRET and PTENphenomics.

Phosphatase and tensin homologue (PTEN) governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture. Unravelling its enzymatic activities, its signalling partners, and the molecular mechanisms involved in the multiple levels of PTEN regulation will aid the design of novel PTEN-based therapeutic interventions in cancer.

Following the development of the first mTOR inhibitor that successfully improves therapeutic survival in cancer, Raymond and colleagues look at how novel biomarker identification and the use of multitargeted and multimodality therapies could advance the next generation of these drugs.

The incidence of male breast cancer is rising, and the treatment of this disease has been extrapolated from the knowledge of female breast cancer despite multiple differences in the pathogenesis, biology and genetics of these two disease entities. Although there have been major advances in hormonal manipulation for the treatment of breast cancer, an improved understanding of the potential differences between male and female breast cancer is essential to providing new opportunities for therapeutic intervention and likely improved outcome, as discussed in this review.

This Review provides a comprehensive overview of epidemiology and molecular determinants of relapsed rhabdoid and other non-nephroblastoma childhood and adolescent kidney tumours, which are usually rare and challenging to cure. The most updated results in this field are discussed to highlight how understanding tumour biology can be used to inform therapeutic strategies in these patient populations.

Three major tumour-suppressor proteins have recently been shown to undergo monoubiquitylation-mediated nuclear–cytoplasmic shuttling. Can our increasing knowledge of this mechanism be used to treat cancer?

William Dobyns and colleagues report de novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA in the sporadic overgrowth syndromes megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) and megalencephaly-capillary malformation (MCAP).

Lowry and colleagues report the potential role of stem cell quiescence as a tumour suppressive mechanism. They show that although hair follicle stem cell activation allows tumour formation in response to oncogenic stimuli, tumours are not initiated during the quiescent phase of the hair cycle. They further find that the presence of Pten is important in maintaining hair follicle stem cell quiescence in this setting.

The authors show PTEN mutations, which can cause both congenital hydrocephalus and autism spectrum disorder, disrupt CSF homeostasis and brain connectivity in mice. Reducing mTORC1 activation ameliorates ventricular enlargement and neuronal deficits.

The stability of the PTEN tumour suppressor protein is regulated by polyubiquitylation. Ma and colleagues identify USP13 as an enzyme reversing polyubiquitylation of PTEN, leading to PTEN stabilization and tumour suppression.

Experimental models of breast cancer reveal the phosphoinositide-phosphatases PIPP and PTEN play non-redundant roles in suppressing mouse mammary epithelial cell transformation, and disease progression in a subset of human breast cancers.

Mutation or deletion of PTEN is found in many cancers — however, in others, deregulation of the PI3K–PTEN network occurs in the absence of PTEN mutation. This review examines whether 'crosstalk' with other tumorigenic signalling pathways contributes to PI3K–PTEN deregulation.

Proteus syndrome is a rare hamartoma syndrome that is characterized by the presence of germlinePTEN mutations and causes benign and malignant tumors. Marsh et al. report the case of a 16-month boy who was diagnosed with Proteus syndrome, and was managed with oral rapamycin. On the basis of this patient's promising outcome, the authors discuss the rationale for rapamycin therapy for patients with disorders within the PTENhamartoma tumor syndrome spectrum.

Gene-based rare variant analyses for 601 diseases across 748,879 individuals from three biobanks identify 363 significant associations and highlight important considerations for multi-ancestry and cross-biobank sequencing studies.

Targeted therapies matched to genomics improved progression-free survival when genomic alterations were classified as level I/II (according to ESCAT), and genomics should thus be driven by target actionability in patients with metastatic breast cancer.