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Charis Eng

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Lamis Yehia and Charis Eng

An average of 10% of all cancers (range 1–40%) are caused by heritable mutations and over the years have become powerful models for precision medicine practice. Furthermore, such cancer predisposition genes for seemingly rare syndromes have turned out to help explain mechanisms of sporadic carcinogenesis and often inform normal development. The tumor suppressor PTEN encodes a ubiquitously expressed phosphatase that counteracts the PI3K/AKT/mTOR cascade – one of the most critical growth-promoting signaling pathways. Clinically, individuals with germline PTEN mutations have diverse phenotypes and fall under the umbrella term PTEN hamartoma tumor syndrome (PHTS). PHTS encompasses four clinically distinct allelic overgrowth syndromes, namely Cowden, Bannayan-Riley-Ruvalcaba, Proteus and Proteus-like syndromes. Relatedly, mutations in other genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN also predispose patients to partially overlapping clinical manifestations, with similar effects as PTEN malfunction. We refer to these syndromes as ‘PTEN-opathies.’ As a tumor suppressor and key regulator of normal development, PTEN dysfunction can cause a spectrum of phenotypes including benign overgrowths, malignancies, metabolic and neurodevelopmental disorders. Relevant to clinical practice, the identification of PTEN mutations in patients not only establishes a PHTS molecular diagnosis, but also informs on more accurate cancer risk assessment and medical management of those patients and affected family members. Importantly, timely diagnosis is key, as early recognition allows for preventative measures such as high-risk screening and surveillance even prior to cancer onset. This review highlights the translational impact that the discovery of PTEN has had on the diagnosis, management and treatment of PHTS.

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Anne M Deschamps and Charis Eng

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Wouter W de Herder and Charis Eng

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William D Foulkes, Jérôme Bertherat and Charis Eng

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Victoria Byrd, Ted Getz, Roshan Padmanabhan, Hans Arora and Charis Eng

Germline PTEN mutations defining PTEN hamartoma tumor syndrome (PHTS) confer heritable predisposition to breast, endometrial, thyroid and other cancers with known age-related risks, but it remains impossible to predict if any individual will develop cancer. In the general population, gut microbial dysbiosis has been linked to cancer, yet is unclear whether these are associated in PHTS patients. In this pilot study, we aimed to characterize microbial composition of stool, urine, and oral wash from 32 PTEN mutation-positive individuals using 16S rRNA gene sequencing. PCoA revealed clustering of the fecal microbiome by cancer history (P = 0.03, R 2 = 0.04). Fecal samples from PHTS cancer patients had relatively more abundant operational taxonomic units (OTUs) from family Rikenellaceae and unclassified members of Clostridia compared to those from non-cancer patients, whereas families Peptostreptococcaceae, Enterobacteriaceae, and Bifidobacteriaceae represented relatively more abundant OTUs among fecal samples from PHTS non-cancer patients. Functional metagenomic prediction revealed enrichment of the folate biosynthesis, genetic information processing and cell growth and death pathways among fecal samples from PHTS cancer patients compared to non-cancer patients. We found no major shifts in overall diversity and no clustering by cancer history among oral wash or urine samples. Our observations suggest the utility of an expanded study to interrogate gut dysbiosis as a potential cancer risk modifier in PHTS patients.

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Yu Wang, Andres Roma, Rosalie Nolley, Fadi Abdul-Karim, Donna M Peehl and Charis Eng

Men with organ-confined prostate cancer (CaP) are often treated with radical prostatectomy. Despite similar postoperative characteristics, a significant proportion of men with an intermediate risk of progression experience prostate-specific antigen (PSA)-defined failure, while others have relapse-free survival (RFS). Additional prognostic markers are needed to predict the outcome of these patients. KLLN is a transcription factor that regulates the cell cycle and induces apoptosis in cancer cells. We have shown that KLLN is an androgen-regulated gene and that loss of KLLN expression in primary CaP is associated with high Gleason score. In this retrospective study, we evaluated KLLN expression in the high-grade malignancy components from 109 men with intermediate risk CaP. Patients with nuclear KLLN-negative tumors had significantly higher preoperative serum PSA levels (12.24±2.37 ng/ml) and larger tumor volumes (4.61±0.71 cm3) compared with nuclear KLLN-positive patients (8.35±2.45 ng/ml, P=0.03, and 2.66±0.51 cm3, P<0.0001, respectively). None of the nuclear KLLN-positive tumors had capsular penetration, whereas 34% of nuclear KLLN-negative tumors (P=0.004) had capsular penetration. Maintaining KLLN expression in tumor nuclei, but not in cytoplasm or stroma, associated with improved RFS after surgery (P=0.002). Only 7% of patients with nuclear KLLN-positive tumors had tumor recurrence, while 60% of patients in the KLLN-negative group developed PSA-defined failure with median relapse time of 6.6 months (P=0.0003). Our data suggest that KLLN expression may be used as a prognostic marker to predict outcome for intermediate risk patients, which could provide useful information for postoperative management.

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Angelica Malinoc, Maren Sullivan, Thorsten Wiech, Kurt Werner Schmid, Cordula Jilg, Joern Straeter, Serdar Deger, Michael M Hoffmann, Alexander Bosse, Gerd Rasp, Charis Eng and Hartmut P H Neumann

The etiology and pathogenesis of renal cell carcinoma (RCC) are only partially understood. Key findings in hereditary RCC, which may be site specific or a component of a syndrome, have contributed to our current understanding. Important heritable syndromes of RCC are those associated with pheochromocytoma, especially von Hippel–Lindau disease (VHL) associated with germline VHL mutations, and pheochromocytoma and paraganglioma syndrome (PGL) associated with mutations in one of the four genes (SDHA D) encoding succinate dehydrogenase. A subset of individuals with SDHB and SDHD germline DNA mutations and variants develop RCC. RCC has never been described as a component of SDHC-associated PGL3. The European–American Pheochromocytoma and Paraganglioma Registry comprises 35 registrants with germline SDHC mutations. A new registrant had carotid body tumor (CBT) and his mother had CBT and bilateral RCC. Blood DNA, paragangliomas, and RCCs were analyzed for mutations and loss-of-heterozygosity (LOH) in/flanking SDHC and VHL. The proband with unilateral CBT had a germline SDHC c.3G>A (p.M1I) mutation. His mutation-positive mother had CBT at age 42, clear cell RCC (ccRCC) at age 68, and papillary RCC (pRCC) at age 69. Both paraganglial tumors showed somatic LOH of the SDHC locus. Both ccRCC and pRCC did not have a somatic SDHC mutation but showed LOH for intragenic and flanking markers of the SDHC locus. LOH was also present for the VHL locus. Our findings suggest that RCC is a component of PGL3. Biallelic inactivation of the SDHC gene may represent a new pathway of pathogenesis of syndromic and nonsyndromic RCC, perhaps of both clear cell and papillary histologies.

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Ying Ni, Spencer Seballos, Shireen Ganapathi, Danielle Gurin, Benjamin Fletcher, Joanne Ngeow, Rebecca Nagy, Richard T Kloos, Matthew D Ringel, Thomas LaFramboise and Charis Eng

Along with breast and endometrial cancers, thyroid cancer is a major component cancer in Cowden syndrome (CS). Germline variants in SDHB/C/D (SDHx) genes account for subsets of CS/CS-like cases, conferring a higher risk of breast and thyroid cancers over those with only germline PTEN mutations. To investigate whether SDHx alterations at both germline and somatic levels occur in apparently sporadic breast cancer and differentiated thyroid cancer (DTC), we analyzed SDHx genes in the following four groups: i) 48 individuals with sporadic invasive breast adenocarcinoma for germline mutation; ii) 48 (expanded to 241) DTC for germline mutation; iii) 37 pairs DTC tumor-normal tissues for germline and somatic mutation and mRNA expression levels; and iv) data from 476 patients in the Cancer Genome Atlas thyroid carcinoma dataset for validation. No germline SDHx variant was found in a pilot series of 48 breast cancer cases. As germline SDHx variants were found in our pilot of 48 thyroid cancer cases, we expanded to three series of DTC comprising a total 754 cases, and found 48 (6%) with germline SDHx variants (P<0.001 compared with 0/350 controls). In 513 tumors, we found 27 (5%) with large somatic duplications within chromosome 1 encompassing SDHC. Both papillary and follicular thyroid tumors showed consistent loss of SDHC/D gene expression (P<0.001), which is associated with earlier disease onset and higher pathological-TNM stage. Therefore, we conclude that both germline and somatic SDHx mutations/variants occur in sporadic DTC but are very rare in sporadic breast cancer, and overall loss of SDHx gene expression is a signature of DTC.