Tumour spectrum, distinguishing features and management recommendations for NTHL1-associated tumour syndrome: a systematic review

We report four previously undescribed families with germline BRCA1-associated protein-1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.

Children and adolescents who present with neuroendocrine tumors are at extremely high likelihood of having an underlying germline predisposition for the multiple endocrine neoplasia (MEN) syndromes, including MEN1, MEN2A and MEN2B, MEN4, and hyperparathyroid-jaw tumor (HPT-JT) syndromes. Each of these autosomal dominant syndromes results from a specific germline mutation in unique genes: MEN1 is due to pathogenic MEN1 variants (11q13), MEN2A and MEN2B are due to pathogenic RET variants (10q11.21), MEN4 is due to pathogenic CDKN1B variants (12p13.1), and the HPT-JT syndrome is due to pathogenic CDC73 variants (1q25). Although each of these genetic syndromes share the presence of neuroendocrine tumors, each syndrome has a slightly different tumor spectrum with specific surveillance recommendations based upon tumor penetrance, including the age and location for which specific tumor types most commonly present. Although the recommended surveillance strategies for each syndrome contain similar approaches, important differences do exist among them. Therefore, it is important for caregivers of children and adolescents with these syndromes to become familiar with the unique diagnostic criteria for each syndrome, and also to be aware of the specific tumor screening and prophylactic surgery recommendations for each syndrome. Clin Cancer Res; 23(13); e123-e32. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.

3627 Background: PHTS consists of a group of familial disorders associated with germline mutations of the PTEN gene. Cowden syndrome is the most common phenotype. Affected patients develop a variety of tumors, including polyposis of the gastrointestinal tract. Based on current literature, PHTS is not associated with an increased risk of colon cancer; therefore, the risk of neoplastic transformation and appropriate screening intervals for PHTS-associated colon polyposis is not well characterized. This study was performed to better define the incidence and outcomes of colon polyposis in PHTS. Methods: Patients with a clinical diagnosis of PHTS at the Mayo Clinic were identified from 1980 to 2009. Only patients that met the NCCN consortium criteria for diagnosis were included. The relevant clinical information, onco-pathology data and molecular studies were retrospectively reviewed. Results: 47 patients with PHTS were identified, of which 17 (36%) had colon studies at our institution. All met criteria for Cowden disease. Of the 14 that underwent a colonoscopy, 13 (93%) were noted to have diffuse polyposis, with 9 (64%) estimated to have > 50 polyps. 15 patients had colon biopsies reviewed (median age 47 at first biopsy). The spectrum of tumors included hamartomas (n = 12), ganglioneuromas (n = 6) and tubular adenomas (n = 6). 7 (47%) patients had low-grade dysplasia (median age 50 at first detection), including 1 patient with dysplasia within hamartomatous polyps. 2 (12%) patients, age 56 and 62, had early-stage (T1N0M0, grade II and T2N0M0, grade III) left-sided colonic adenocarcinomas. Neither showed evidence of microsatellite instability. 7 (41%) patients underwent colectomy (median age 45), of which 4 had colonic dysplasia/neoplasia and 3 had symptomatic polyposis. Conclusions: This is the largest series from a single institution to examine the colonic manifestations of PHTS. Our findings suggest that germline mutations in the PTEN gene are associated with a spectrum of colonic tumors, including hamartomas, ganglioneuromas, tubular adenomas and colon cancer. Colonic dysplasia and neoplasia were more common then expected. If confirmed, colon cancer screening recommendations should be developed for patients with PHTS. No significant financial relationships to disclose.

Background Schwannomatosis and atypical teratoid rhabdoid tumour syndrome (ATRT) are autosomal dominant disorders associated with mutations in the SMARCB1 gene on chromosome 22q, but with different age at onset and tumour predisposition. Missense mutations in the first and last exons of SMARCB1 typically cause multiple, benign schwannomas of the peripheral and spinal nerves (average age 28.3y), whereas, large deletion and frameshift mutations in exons 2–8 typically cause malignant rhabdoid tumours (before age 3y). Recently, families with both types of tumours have been described including a Newfoundland and Labrador (NL) family identified through a proband with ‘glioma’ and her brother with multiple spinal cord schwannomas. Objectives We were interested in determining the age-at-onset, type and number of tumours for NL family members in order to develop a clinical screening program. Design/method We obtained family history, and reviewed clinical records and genetic test results for 18 consenting members of this family with ‘schwannomatosis’ and a SMARCB1 missense mutation in exon 9. Results Seven family members had from 1–26 peripheral schwannomas, four had multiple spinal schwannomas, one had an ocular schwannoma, the proband (who died at 52y) had a high grade glioma with rhabdoid features, a five year old had an ATRT, and two obligate carriers in their 70s had no identified tumours. Conclusions The spectrum of tumours and age at onset was broader than expected. We recommend a complete clinical examination and, for adults, full-body MRI at diagnosis, annual clinical review, and repeat imaging to review any new pain, ‘lumps’ or dysfunction.

Replication proofreading is crucial to avoid mutation accumulation in dividing cells. In humans, proofreading and replication repair is maintained by the exonuclease domains of DNA polymerases and the mismatch repair system. Individuals harboring germline mutations in genes involved in this process are at increased risk of early cancers from multiple organs. Biallelic mutations in any of the four mismatch repair genes MSH2, MSH6, MLH1, and PMS2 result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency or constitutional mismatch repair deficiency syndrome (CMMRD). Data gathered in the last decade allow us to better define the clinical manifestations, tumor spectrum, and diagnostic algorithms for CMMRD. In this article, we summarize this information and present a comprehensive consensus surveillance protocol for these individuals. Ongoing research will allow for further definition of replication repair-deficient cancer syndromes, assessing the cost-effectiveness of such surveillance protocols and potential therapeutic interventions for these children and families. Clin Cancer Res; 23(11); e32-e37. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.

The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors. We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided. The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001). This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.

The citric acid cycle, also known as the Krebs cycle, plays an integral role in cellular metabolism and aerobic respiration. Mutations in genes encoding the citric acid cycle enzymes succinate dehydrogenase, fumarate hydratase and malate dehydrogenase all predispose to hereditary tumour syndromes. The succinate dehydrogenase enzyme complex (SDH) couples the oxidation of succinate to fumarate in the citric acid cycle and the reduction of ubiquinone to ubiquinol in the electron transport chain. A loss of function in the succinate dehydrogenase (SDH) enzyme complex is most commonly caused by an inherited mutation in one of the four SDHx genes (SDHA, SDHB, SDHC and SDHD). This mechanism was first implicated in familial phaeochromocytoma and paraganglioma. However, over the past two decades the spectrum of tumours associated with SDH deficiency has been extended to include gastrointestinal stromal tumours (GIST), renal cell carcinoma (RCC) and pituitary adenomas. The aim of this review is to describe the extended tumour spectrum associated with SDHx gene mutations and to consider how functional tests may help to establish the role of SDHx mutations in new or unexpected tumour phenotypes.

Review: Clinical aspects of hereditary DNA Mismatch repair gene mutations.

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

Paediatric renal tumors are rare and accounts for about 7% of all paediatric malignant tumors. The spectrum of paediatric renal tumors ranges from benign to malignant. Benign tumors include cystic nephroma, metanephric tumors and ossifying renal tumor of infancy. Tumor with low grade malignancy includes mesoblastic nephroma. Malignant tumors are nephroblastoma, clear cell sarcoma, malignant rhabdoid tumor, anaplastic sarcoma and Ewing sarcoma. Additionally, there are molecularly defined renal tumors, which includes renal cell carcinoma (RCC) with MiT translocations, ALK-rearranged RCC, eosinophilic solid and cystic RCC and SMARCB1- deficient renal medullary carcinoma. These tumors apart from having characteristic clinical presentation and histomorphology, also carry typical molecular mutations and translocations. Certain renal tumors have association with various genetic syndromes such as Beckwith-Weidmann syndrome, Wilm’s tumor, aniridia, genitourinary anomalies and mental retardation syndrome, Denys-Drash syndrome, rhabdoid tumor predisposition syndrome and DICER syndrome. This review article focusses on molecular characteristics, histomorphology and syndromic association of pediatric renal tumors, their immunohistochemical approach to diagnosis with recent updates in molecularly defined renal tumors.

DICER1 syndrome, arising from a mutation in the DICER1 gene mapped to chromosome 14q32, is associated with an increased risk of a range of benign and malignant neoplasms. To determine the spectrum of abnormalities and imaging characteristics in patients with DICER1 syndrome at a tertiary pediatric hospital. This retrospective analysis evaluated imaging in patients ≤18years with DICER1 germline variants between January 2004 and July 2016. An imaging database search including keywords pleuropulmonary blastoma, cystic nephroma, pineoblastoma, embryonal rhabdomyosarcoma, ovarian sex cord-stromal tumor, ovarian Sertoli-Leydig cell tumor and DICER1 syndrome, was cross-referenced against the institutional Cancer Genetics Program database, excluding patients with negative/unknown DICER1 gene testing. Sixteen patients were included (12 females; mean age at presentation: 4.2years, range: 14days to 17years), with surveillance imaging encompassing the following modalities: chest X-ray and CT; abdominal, pelvic and neck US; and brain and whole-body MRI. Malignant lesions (68.8% of patients) included pleuropulmonary blastoma (5), pineoblastoma (3), ovarian Sertoli-Leydig cell tumor (1), embryonal rhabdomyosarcoma (1) and renal sarcoma (1); benign lesions (37.5% of patients) included thyroid cysts (2), thyroid nodules (2), cystic nephroma (2), renal cysts (1) and pineal cyst (1). A common lesional appearance observed across modalities and organs was defined as the "cracked windshield" sign. The spectrum of DICER1-related tumors and the young age at presentation suggest early surveillance of at-risk patients is critical, while minimizing exposure to ionizing radiation.

Syndromes de prédisposition aux tumeurs neuroendocrines gastro-entéro-pancréatiques et thoraciques

Germline PTEN Mutation Cowden Syndrome: An Underappreciated Form of Hereditary Kidney Cancer

A total of 1 out of 10 patients with primary hyperparathyroidism (PHP) presents an underlying genetic form, such as multiple endocrine neoplasia types 1, 2A, etc., as well as hyperparathyroidism-jaw tumour syndrome (HJT). We aimed to summarise the recent data, thus raising more awareness regarding HJT, from the clinical perspective of PHP in association with the challenges and pitfalls of CDC73 genetic testing and parafibromin staining. This narrative review included a sample-focused analysis from the past decade according to a PubMed search. We identified 17 original human studies (≥4 patients per article). The mean age at disease onset was between 20.8 and 39.5 years, while the largest study found that 71% of patients had HJT recognised before the age of 30. Males and females seemed to be equally affected, in contrast with sporadic PHP. PHP represented the central manifestation of HJT, occurring as the first manifestation in up to 85% of HJT cases. A biochemistry panel found a mean serum calcium level above the level of 12 mg/dL in PHP. PTH was elevated in HJT as well, with average values of at least 236.6 pg/mL. The most frequent pathological type in PHP was a parathyroid adenoma, but the incidence of a parathyroid carcinoma was much higher than in non-HJT cases (15% of all parathyroid tumours), with the diagnosis being established between the age of 15 and 37.5. In some families up to 85% of carriers suffered from a parathyroid carcinoma thus indicating that certain CDC73 pathogenic variants may harbour a higher risk. An important issue in HJT was represented by the parafibromin profile in the parathyroid tumours since in HJT both parathyroid adenomas and carcinomas might display a deficient immunoreactivity. Another frequent manifestation in HJT was ossifying fibromas of the jaw (affecting 5.4% to 50% of patients; the largest study found a prevalence of 15.4%). HJT was associated with a wide variety of kidney lesion (mostly: kidney cysts, with a prevalence of up to 75%, and renal tumours involved in 19% of patients). The risk of uterine lesions seemed increased in HJT, especially with concern to leiomyomas, adenofibromas, and adenomyosis. The underlying pathogenic mechanisms and the involvement of CDC73 pathogenic variants and parafibromin expression are yet to be explored. Currently, the heterogeneous expression of parafibromin status and, the wide spectrum of CDC73 mutations including the variety of clinical presentations in HJT, make it difficult to predict the phenotype based on the genotype. The central role of HJT-PHP is, however, the main clinical element, while the elevated risk of parathyroid carcinoma requires a special awareness.

Carcinoids are neuroendocrine tumours of the gut which may also be found in the bronchus, pancreatic islets and retroperitoneum. They probably arise from gastrointestinal or bronchopulmonary pluripotential stem cells. Carcinoid tumours derived from these cells are potentially malignant; the strength of the tendency for aggressive growth correlates with the site of origin, depth of local penetration and the size of the tumour. Carcinoids occur sporadically or result from specific hereditary tumour syndromes. Mutations and/or aberrant expression of specific genes induce and promote tumour growth. Clinical features include local symptoms due to angulation or obstruction and hepatomegaly due to liver metastases. The carcinoid syndrome commonly involves flushing, diarrhoea, bronchospasm and hypotension. Other distinct syndromes may be caused by tumour release of products that may also be used as biochemical markers in diagnosis and follow-up. Scanning using radiolabelled octreotide, an analogue of somatostatin, sensitively identifies occult primary and metastatic deposits. Localized carcinoid tumours should be resected. Some patients benefit from hepatic resection. Palliation of symptoms is best achieved with octreotide. Hepatic artery chemoembolization may produce long-acting palliation. Further genetic characterization of the different types and stages of carcinoid development as well as assessment of gene expression profiles may improve differential diagnosis, prognosis and treatment.