bims-lifras 2020-06-28 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2020–06–28
eightteen papers selected by
Joanna Zawacka-Pankau

Lung adenocarcinoma in a patient with Li-Fraumeni syndrome bearing a novel germ-line mutation, TP53R333Vfs*12.
Patterns of Prior and Subsequent Neoplasms in Children and Adolescents With Soft Tissue Sarcomas.
TP53 p.Arg337His geographic distribution correlates with adrenocortical tumor occurrence.
UKCGG Consensus Group guidelines for the management of patients with constitutional TP53 pathogenic variants.
Hereditary Predisposition to Hematopoietic Neoplasms: When Bloodline Matters for Blood Cancers.
Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes.
Clinicopathologic features of endometrial cancer with mismatch repair deficiency.
Deleterious mis-splicing of STK11 caused by a novel single-nucleotide substitution in the 3' polypyrimidine tract of intron five.
PTEN hamartoma tumour syndrome: What happens when there is no PTEN germline mutation?
Germline PTEN mutations are associated with a skewed peripheral immune repertoire in humans and mice.
Co-occurrence of germline BRCA1 and CDH1 pathogenic variants.
Germline mutations in MEN1 are associated with the tumorigenesis of pituitary adenoma associated with meningioma.
Genotype of CDC73 germline mutation determines risk of parathyroid cancer.
Germline BRCA2 Truncating Mutation in Familial Esophageal Squamous Cell Carcinoma: A Case Controlled Study in China.
Rare Tumor-Normal Matched Whole Exome Sequencing Identifies Novel Genomic Pathogenic Germline and Somatic Aberrations.
Large Copy-Number Variants in UK Biobank Caused by Clonal Hematopoiesis May Confound Penetrance Estimates.
Germline Mutation in KIF1Bβ Gene Associated with Loss of Heterozygosity: Usefulness of Next-Generation Sequencing in the Genetic Screening of Patients with Pheochromocytoma.
Genomic profiling of multiple primary cancers including synchronous lung adenocarcinoma and bilateral malignant mesotheliomas: Identification of a novel BAP1 germline variant.

Jpn J Clin Oncol. 2020 Jun 24. pii: hyaa095. [Epub ahead of print]

Lung adenocarcinoma in a patient with Li-Fraumeni syndrome bearing a novel germ-line mutation, TP53R333Vfs*12.

Shodai Takahashi, Kazuhiro Shimazu, Koya Kodama, Koji Fukuda, Taichi Yoshida, Daiki Taguchi, Tsutomu Takahashi, Hiroshi Nanjyo, Hiroyuki Shibata.

  Germline mutations of TP53 are responsible for Li-Fraumeni syndrome in its 60-80%. We found a novel germline mutation, TP53: c.997del:p.R333Vfs*12 (NM_000546.6, GRCh, 17:7670713..7670713). The proband is a 40-year-old female, who was suffered from osteosarcoma in her right forearm at her age of 11. She was also suffered from lung adenocarcinoma in her right upper lobe and bone metastasis in her right scapula at her age of 37. She was treated with gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) because of EGFR mutation (L747-S752 del). Her bone metastasis became resistant after 1-year treatment. Bone metastasis had an additional EGFR mutation (T790M). The secondary treatment with osimertinib, an another EGFR-TKI, can successfully control the tumors for over 2 years. This TP53 mutation (R333Vfs*12) was first found in lung adenocarcinomas. The therapeutic effect of osimertinib for this triple mutant lung adenocarcinoma is better than the previous report.

Keywords:  Li–Fraumeni syndrome; TP53; epidermal growth factor receptor-tyrosine kinase inhibitor; lung adenocarcinoma

DOI:  https://doi.org/10.1093/jjco/hyaa095
J Pediatr Hematol Oncol. 2020 Jul;42(5): e265-e270

Patterns of Prior and Subsequent Neoplasms in Children and Adolescents With Soft Tissue Sarcomas.

Oliver Uckunkaya, Peter Nöllke, Erika Hallmen, Cornelia Becker, Sabine Stegmaier, Monika Sparber-Sauer, Christian Vokuhl, Ewa Koscielniak, Simone Hettmer.

BACKGROUND: The occurrence of prior, concurrent and subsequent neoplasms (SN) represents a serious problem in children and adolescents with soft tissue sarcomas. Pathogenic germline variants contribute to the diagnosis of multiple neoplasms in sarcoma survivors.
MATERIALS AND METHODS: The records of 748 children and adolescents, diagnosed with soft tissue sarcomas and registered in trials/registries by the cooperative soft tissue sarcoma (Cooperative Weichteilsarkom Studie) group, were reviewed for the occurrence of SNs. Reference histology review was available for all cases; the presence of oncogenic fusions known at the time of diagnosis was confirmed for fusion-positive (F+) entities.
RESULTS: Concurrent or subsequent SNs developed in 13 of 473 survivors of fusion-negative (F-) sarcomas, for an 8-year cumulative SN incidence of 5% in survivors of F- sarcomas. In contrast, only 1 of 278 survivors of F+ sarcoma developed an SN. Twenty of 748 patients with soft tissue sarcomas had a history of prior neoplasms. Six of 14 patients who developed SNs after their index sarcomas met Chompret criteria for Li-Fraumeni syndrome. Nine of 20 patients who had tumors before their index sarcoma diagnosis had neurofibromatosis type 1 or neurofibromatosis type 1 spectrum tumors.
CONCLUSION: Sarcoma phenotype/genotype and the sequence and nature of prior and subsequent neoplasms provide a window into underlying germline genetic susceptibilities in children and adolescents with soft tissue sarcomas.

DOI: https://doi.org/10.1097/MPH.0000000000001837
Mol Genet Genomic Med. 2020 Jun 27. e1168

TP53 p.Arg337His geographic distribution correlates with adrenocortical tumor occurrence.

Ana L Seidinger, Isabel P Caminha, Maria J Mastellaro, Carmen S Gabetta, Alexandre E Nowill, Vitória R P Pinheiro, José A Yunes.

   BACKGROUND: The p.Arg337His mutation of the TP53 is the most frequent germline missense variant associated with cancer described so far in this gene. It is mainly found in the South and Southeastern regions of Brazil, where it has been associated with a high incidence of pediatric adrenocortical (ACT) and choroid plexus tumors. The frequency and geographic distribution of this mutation is largely unknown, except for the Parana State, where a mean prevalence of 0.27% was reported. In the present study, we developed a high-throughput method for p.Arg337His genotyping, what allowed us to determine the frequency and geographic distribution of this mutation in a cohort from the most populous state in Brazil.
METHODS: Consecutive samples from 31,612 newborns from São Paulo State were screened for p.Arg337His. The allelic discrimination was done by real-time polymerase chain reaction (PCR) and the presence of haplotype A3 in carriers was examined by using allele-specific oligonucleotide PCR, followed by nested-PCR to detect the SNP rs9894946.
RESULTS: We found 67 (0.21%) samples positive for this mutation. The highest p.Arg337His frequencies were found in the cities close to the boundary between São Paulo and Minas Gerais State. No association could be found between p.Arg337His and gender, ethnicity, premature birth or twinning. Remarkably, a trend was found between the geographic distribution of p.Arg337His carriers and occurrence of ACT.
CONCLUSION: We presented for the first time the p.Arg337His frequency among individuals unselected for any disease from a subset of the São Paulo State, the most populous in Brazil. The allele discrimination assay we presented here has proven to be a reliable and efficient method for high-throughput genotyping. ACT was found to be a good sentinel cancer to suppose p.Arg337His presence in our region.

Keywords:   TP53 ; genetic counseling; high-throughput genotyping; p.Arg337His; pediatric oncology

DOI:  https://doi.org/10.1002/mgg3.1168
J Med Genet. 2020 Jun 22. pii: jmedgenet-2020-106876. [Epub ahead of print]

UKCGG Consensus Group guidelines for the management of patients with constitutional TP53 pathogenic variants.

Consensus Group Members

  Constitutional pathogenic variants in TP53 are associated with Li-Fraumeni syndrome or the more recently described heritable TP53-related cancer syndrome and are associated with increased lifetime risks of a wide spectrum of cancers. Due to the broad tumour spectrum, surveillance for this patient group has been limited. To date, the only recommendation in the UK has been for annual breast MRI in women; however, more recently, a more intensive surveillance protocol including whole-body MRI (WB-MRI) has been recommended by International Expert Groups. To address the gap in surveillance for this patient group in the UK, the UK Cancer Genetics Group facilitated a 1-day consensus meeting to discuss a protocol for the UK. Using a preworkshop survey followed by structured discussion on the day, we achieved consensus for a UK surveillance protocol for TP53 carriers to be adopted by UK Clinical Genetics services. The key recommendations are for annual WB-MRI and dedicated brain MRI from birth, annual breast MRI from 20 years in women and three-four monthly abdominal ultrasound in children along with review in a dedicated clinic.

Keywords:  clinical genetics; genetics; guidelines; paediatric oncology; screening

DOI:  https://doi.org/10.1136/jmedgenet-2020-106876
Mayo Clin Proc. 2020 Jun 19. pii: S0025-6196(19)31089-4. [Epub ahead of print]

Hereditary Predisposition to Hematopoietic Neoplasms: When Bloodline Matters for Blood Cancers.

Abhishek A Mangaonkar, Mrinal M Patnaik.

With the advent of precision genomics, hereditary predisposition to hematopoietic neoplasms- collectively known as hereditary predisposition syndromes (HPS)-are being increasingly recognized in clinical practice. Familial clustering was first observed in patients with leukemia, which led to the identification of several germline variants, such as RUNX1, CEBPA, GATA2, ANKRD26, DDX41, and ETV6, among others, now established as HPS, with tendency to develop myeloid neoplasms. However, evidence for hereditary predisposition is also apparent in lymphoid and plasma--cell neoplasms, with recent discoveries of germline variants in genes such as IKZF1, SH2B3, PAX5 (familial acute lymphoblastic leukemia), and KDM1A/LSD1 (familial multiple myeloma). Specific inherited bone marrow failure syndromes-such as GATA2 haploinsufficiency syndromes, short telomere syndromes, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, severe congenital neutropenia, and familial thrombocytopenias-also have an increased predisposition to develop myeloid neoplasms, whereas inherited immune deficiency syndromes, such as ataxia-telangiectasia, Bloom syndrome, Wiskott Aldrich syndrome, and Bruton agammaglobulinemia, are associated with an increased risk for lymphoid neoplasms. Timely recognition of HPS is critical to ensure safe choice of donors and/or conditioning-regimen intensity for allogeneic hematopoietic stem-cell transplantation and to enable direction of appropriate genomics-driven personalized therapies. The purpose of this review is to provide a comprehensive overview of HPS and serve as a useful reference for clinicians to recognize relevant signs and symptoms among patients to enable timely screening and referrals to pursue germline assessment. In addition, we also discuss our institutional approach toward identification of HPS and offer a stepwise diagnostic and management algorithm.

DOI: https://doi.org/10.1016/j.mayocp.2019.12.013
J Clin Med. 2020 Jun 23. pii: E1954. [Epub ahead of print]9(6):

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes.

Mariona Terradas, Gabriel Capellá, Laura Valle.

  In the past two decades, multiple studies have been undertaken to elucidate the genetic cause of the predisposition to mismatch repair (MMR)-proficient nonpolyposis colorectal cancer (CRC). Here, we present the proposed candidate genes according to their involvement in specific pathways considered relevant in hereditary CRC and/or colorectal carcinogenesis. To date, only pathogenic variants in RPS20 may be convincedly linked to hereditary CRC. Nevertheless, accumulated evidence supports the involvement in the CRC predisposition of other genes, including MRE11, BARD1, POT1, BUB1B, POLE2, BRF1, IL12RB1, PTPN12, or the epigenetic alteration of PTPRJ. The contribution of the identified candidate genes to familial/early onset MMR-proficient nonpolyposis CRC, if any, is extremely small, suggesting that other factors, such as the accumulation of low risk CRC alleles, shared environmental exposures, and/or gene-environmental interactions, may explain the missing heritability in CRC.

Keywords:  cancer genetics; cancer predisposition; cancer susceptibility; colorectal cancer; familial colorectal cancer type X; gene identification; hereditary cancer; mismatch repair proficiency; molecular pathways

DOI:  https://doi.org/10.3390/jcm9061954
Ecancermedicalscience. 2020 ;14 1061

Clinicopathologic features of endometrial cancer with mismatch repair deficiency.

Sushmita Gordhandas, Ryan M Kahn, Charlotte Gamble, Nizam Talukdar, Brandon Maddy, Becky Baltich Nelson, Gulce Askin, Paul J Christos, Kevin Holcomb, Thomas A Caputo, Eloise Chapman-Davis, Melissa K Frey.

  The inclusion of DNA mismatch repair (MMR) evaluation as a standard of care for endometrial cancer management will result in a growing population of patients with MMR deficiency and negative germline Lynch syndrome testing (MMR-deficient). In this systematic review and study, the clinicopathologic features of endometrial cancer in patients with MMR-intact, MLH1 methylation positive, MMR-deficient or Lynch syndrome are evaluated. A systematic search of online databases between 1990 and 2018 identified studies of endometrial cancer patients with tumour testing (MMR protein immunohistochemistry or microsatellite instability) and germline assessment for Lynch syndrome. Extracted data included tumour testing, germline genetic testing, age, body mass index (BMI), family history, tumour stage, grade and histologic type. Associations between MMR-intact, MLH1 methylation positive, MMR-deficient and Lynch syndrome groups were analysed using descriptive statistics. The comprehensive search produced 4,400 publications, 29 met inclusion criteria. A total of 7,057 endometrial cancer cases were identified, 1,612 with abnormal immunohistochemistry, 977 with microsatellite instability. Nine-hundred patients underwent germline genetic testing, identifying 212 patients with Lynch syndrome. Patients in the Lynch syndrome and MMR-deficient groups were significantly younger than patients in the MMR-intact and MLH1 methylation positive groups. Patients with MMR-intact tumours had the highest BMI, followed by MMR-deficient, then Lynch syndrome. MMR-intact tumours were more likely to be grade I at diagnosis than other groups. Patients with Lynch syndrome and MMR-deficient tumours were less likely to have stage I disease as compared to patients with MMR-intact tumours. Endometrial cancer patients with MMR-deficient tumours have similar features to those with germline Lynch syndrome mutations, including age, grade, histology and stage. Even in the absence of a germline mutation, tumour evaluation for MMR status may have important clinical implications.

Keywords:  DNA; DNA mismatch repair; EPCAM protein; MLH1 protein; MutL protein homolog 1; MutS homolog 2 protein; endometrial neoplasms; epithelial cell adhesion molecule; hereditary; human; immunohistochemistry; microsatellite instability; mismatch repair endonuclease PMS2; neoplastic syndromes; risk assessment

DOI:  https://doi.org/10.3332/ecancer.2020.1061
Mol Genet Genomic Med. 2020 Jun 23. e1381

Deleterious mis-splicing of STK11 caused by a novel single-nucleotide substitution in the 3' polypyrimidine tract of intron five.

Thorkild Terkelsen, Ole H Larsen, Søren Vang, Uffe B Jensen, Friedrik Wikman.

   BACKGROUND: Pathogenic variants in STK11, also designated as LKB1, cause Peutz-Jeghers syndrome, which is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation changes, polyposis, and a high risk of cancer.
METHODS: A male meeting the clinical diagnostic criteria for Peutz-Jeghers syndrome underwent next-generation sequencing. To validate the predicted splicing impact of a detected STK11 variant, we performed RNA-Seq on mRNA extracted from patient-derived Epstein-Barr virus-transformed lymphocytes treated with cycloheximide to inhibit nonsense-mediated decay ex vivo.
RESULTS: Blood testing identified a novel single-nucleotide substitution, NM_000455.4:c.735-10C>A, at the end of the 3' polypyrimidine tract of intron five in STK11. RNA-Seq confirmed a predicted eight base pair insertion in the mRNA transcript. Following inhibition of nonsense-mediated decay, the out-of-frame insertion was detected in 50% of all RNA-Seq reads. This confirmed a strong, deleterious splicing impact of the variant.
CONCLUSION: We characterized a novel likely pathogenic germline variant in intron five of STK11 associated with Peutz-Jeghers syndrome. The study highlights RNA-Seq as a useful supplement in hereditary cancer predisposition testing.

Keywords:   LKB1 ; STK11 ; Peutz-Jeghers syndrome; RNA-Seq; germline mutation; splice variant

DOI:  https://doi.org/10.1002/mgg3.1381
Hum Mol Genet. 2020 Jun 22. pii: ddaa127. [Epub ahead of print]

PTEN hamartoma tumour syndrome: What happens when there is no PTEN germline mutation?

Lamis Yehia, Charis Eng.

Hereditary cancer syndromes represent ~10% of all incident cancers. It is important to identify individuals having these disorders because, unlike patients with sporadic cancer, these patients require specialised life-long care, with implications for their families. Importantly, the identification of alterations in cancer-predisposing genes facilitates gene-informed molecular diagnosis, cancer risk assessment and gene-specific clinical management. Moreover, knowledge about gene function in the inherited cancers offers insights towards biological processes pertinent to the more common sporadic cancers. Conversely, without a known gene, clinical management is less precise and it is impossible to offer predictive testing of family members. PTEN hamartoma tumour syndrome (PHTS) is an umbrella term encompassing four overgrowth and cancer predisposition disorders associated with germline PTEN mutations. With time, it became evident that only a finite subset of individuals with PHTS-associated phenotypes harbour germline PTEN mutations. Therefore, non-PTEN aetiologies exist in PTEN wildtype patients. Indeed, gene discovery efforts over the last decade elucidated multiple candidate cancer predisposition genes. While a subset of genes (e.g. AKT1, PIK3CA) are biologically plausible as being key effectors within the PTEN signalling cascade, other genes required meticulous functional interrogation to explain their contribution to PHTS-related phenotypes. Collectively, the extensive phenotypic heterogeneity of the clinical syndromes typically united by PTEN is reflected by the genetic heterogeneity revealed through gene discovery. Validating these gene discoveries is critical because while PTEN wildtype patients can be diagnosed clinically, they do not have the benefit of specific gene-informed risk assessment and subsequent management.

DOI: https://doi.org/10.1093/hmg/ddaa127
Hum Mol Genet. 2020 Jun 26. pii: ddaa118. [Epub ahead of print]

Germline PTEN mutations are associated with a skewed peripheral immune repertoire in humans and mice.

Ritika Jaini, Matthew G Loya, Alexander T King, Stetson Thacker, Nicholas B Sarn, Qi Yu, George R Stark, Charis Eng.

Individuals with germline mutations in the gene encoding Phosphatase and Tensin Homolog on chromosome Ten (PTEN) are diagnosed with PTEN Tumor Hamartoma Syndrome (PHTS) and are at high risk for developing breast, thyroid and other cancers and/or autoimmunity or neurodevelopmental issues including autism spectrum disorders (ASD). Although well recognized as a tumor suppressor, involvement of PTEN mutations in mediating such a diverse range of phenotypes indicates a more central involvement for PTEN in immunity than previously recognized. To address this, sequencing of the T-cell receptor variable-region β-chain (TCRVB) was performed on peripheral blood from PHTS patients. Based on patient findings, we performed mechanistic studies in two Pten knock-in murine models, distinct from each other in cell compartment-specific predominance of Pten. We found that PTEN mutations in humans and mice are associated with a skewed T- and B-cell gene repertoire, characterized by increased prevalence of high frequency clones. Immunological characterization showed that Pten mutants have increased B-cell proliferation and a proclivity towards increased T-cell reactivity upon Toll-like-receptor stimulation. Furthermore, decreases in nuclear but not cytoplasmic Pten levels associated with a reduction in expression of the Autoimmune Regulator (Aire), a critical mediator of central immune tolerance. Mechanistically, we show that nuclear PTEN most likely regulates Aire expression via its emerging role in splicing regulation. We conclude that germline disruption of PTEN, both in human and mouse, results in compromised central immune tolerance processes that may significantly impact individual stress-responses and therefore predisposition to autoimmunity and cancer.

DOI: https://doi.org/10.1093/hmg/ddaa118
J Med Genet. 2020 Jun 23. pii: jmedgenet-2020-106972. [Epub ahead of print]

Co-occurrence of germline BRCA1 and CDH1 pathogenic variants.

Marie-Charlotte Villy, Emmanuelle Mouret-Fourme, Lisa Golmard, Véronique Becette, Nasrine Callet, Gilles Marx, Chrystelle Colas, Dominique Lamarque, Etienne Rouleau, Dominique Stoppa-Lyonnet.

   INTRODUCTION: We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the first report of such an association.Family description: The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer. She was tested for several genes associated with hereditary breast cancer.
RESULTS: A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified.
CONCLUSION: This complex situation is challenging for genetic counselling and management of at-risk individuals.

Keywords:  cancer: breast; cancer: gastric; clinical genetics; genetic screening/counselling; molecular genetics

DOI:  https://doi.org/10.1136/jmedgenet-2020-106972
Oncol Lett. 2020 Jul;20(1): 561-568

Germline mutations in MEN1 are associated with the tumorigenesis of pituitary adenoma associated with meningioma.

Haibo Zhu, Yazhou Miao, Yutao Shen, Jing Guo, Weiyan Xie, Sida Zhao, Wei Dong, Yazhuo Zhang, Chuzhong Li.

  Pituitary adenoma and meningioma are two of the most common benign tumors in the central nervous system. Pituitary adenoma associated with meningioma (PAM) is a rare disease, the tumorigenesis of which remains unclear. Therefore, the aim of the present study was to investigate the tumorigenesis of PAM. A total of 8,197 patients with pituitary adenoma were analyzed. Furthermore, the clinical data of 57 patients with PAM were compared with patients with multiple endocrine neoplasia 1 (MEN-1) syndrome. Whole exome sequencing (WES) was performed on 23 samples from patients with PAM and the germline mutation was verified by Sanger sequencing. The age of tumor penetrance (age of patients at diagnosis) for PAM was significantly higher than that for patients with MEN-1. Compared with MEN-1 patients, there was a significant association between PAM and female sex (P=0.004). Clonal analysis and phylogenetic tree construction suggested that the pituitary adenoma and meningioma in PAM don't originate from a common progenitor. WES revealed that 5/23 PAM samples had the recurrent germline mutation MEN1 c.1523G>A; p.G508D, which may be a genetic risk factor for PAM. Compared with patients with sporadic pituitary adenoma, the difference was statistically significant (P=0.0004). Compared with wild-type MEN1, there was a significant association between the MEN1 mutation and recurrence of pituitary adenoma, young age and larger diameter of the meningioma. The present study indicated that germline mutations in MEN1 may be associated with the tumorigenesis of PAM.

Keywords:  MEN1; PAM; germline mutation

DOI:  https://doi.org/10.3892/ol.2020.11601
Endocr Relat Cancer. 2020 Jun 01. pii: ERC-20-0149.R1. [Epub ahead of print]

Genotype of CDC73 germline mutation determines risk of parathyroid cancer.

Yulong Li, Jianhua Zhang, Poorni R Adikaram, James Welch, Bin Guan, Lee Weinstein, Haobin Chen, William F Simonds.

Mutation of the CDC73 gene, which encodes parafibromin, has been linked with parathyroid cancer. However, no correlation between genotypes of germline CDC73 mutations and the risk of parathyroid cancer has been known. In this study, subjects with germline CDC73 mutations were identified from the participants of two clinical protocols at National Institutes of Health (Discovery Cohort) and from the literature (Validation Cohort). The relative risk of developing parathyroid cancer was analyzed as a function of CDC73 genotype, and the impact of representative mutations on structure of parafibromin was compared between genotype groups. A total of 419 subjects, 68 in Discovery Cohort and 351 in Validation Cohort, were included. In both cohorts, percentages of CDC73 germline mutations that predicted significant conformational disruption or loss of expression of parafibromin (referred as 'high-impact mutations') were significantly higher among the subjects with parathyroid cancers compared to all other subjects. The Kaplan-Meier analysis showed that high-impact mutations were associated with a 6.6-fold higher risk of parathyroid carcinoma compared to low-impact mutations, despite a similar risk of developing primary hyperparathyroidism between two groups. Disruption of the C-terminal domain (CTD) of parafibromin is directly involved in predisposition to parathyroid carcinoma, since only the mutations impacting this domain were associated with an increased risk of parathyroid carcinoma. Structural analysis revealed that a conserved surface structure in the CTD is universally disrupted by the mutations affecting this domain. In conclusion, high-impact germline CDC73 mutations were found to increase risk of parathyroid carcinoma by disrupting the CTD of parafibromin.

DOI: https://doi.org/10.1530/ERC-20-0149
Med Sci Monit. 2020 Jun 24. 26 e923926

Germline BRCA2 Truncating Mutation in Familial Esophageal Squamous Cell Carcinoma: A Case Controlled Study in China.

Zhong Liang, Weidong Hu, Shuping Li, Zhenhong Wei, Zijiang Zhu.

BACKGROUND Germline mutations of BRCA2 have been reported in various malignancies. We investigated BRCA2 germline mutations in familial clusters with esophageal squamous cell carcinoma (ESCC). MATERIAL AND METHODS We screened the DNA of familial ESCC patients for BRCA2 germline mutations with whole gene sequencing. Multiple BRCA2 mutations including one novel splice variant, c.426-2A>G were identified. Other family members, sporadic ESCC patients, and controls were also assessed for the novel mutation. RESULTS The mutation c.426-2A>G was found in 2 affected ESCC sisters and 7 other family members. The splice variant mutation results in exon 5 skipping with a frame shift leading to a premature stop codon in exon 6 and truncation. Novel mutation tracking ruled out single nucleotide polymorphism (SNP) in 100 chromosomes of healthy individuals. CONCLUSIONS BRCA2 germline mutation in ESCC patients may play a role in genetic susceptibility to familial ESCC. Genetic analysis of BRCA2 in patients with familial ESCC could provide opportunities for targeted therapies.

DOI: https://doi.org/10.12659/MSM.923926
Cancers (Basel). 2020 Jun 18. pii: E1618. [Epub ahead of print]12(6):

Rare Tumor-Normal Matched Whole Exome Sequencing Identifies Novel Genomic Pathogenic Germline and Somatic Aberrations.

Ryan Sprissler, Bryce Perkins, Laurel Johnstone, Hani M Babiker, Pavani Chalasani, Branden Lau, Michael Hammer, Daruka Mahadevan.

  Whole exome sequencing (WES) of matched tumor-normal pairs in rare tumors has the potential to identify genome-wide mutations and copy number alterations (CNAs). We evaluated 27 rare cancer patients with tumor-normal matching by WES and tumor-only next generation sequencing (NGS) as a comparator. Our goal was to: 1) identify known and novel variants and CNAs in rare cancers with comparison to common cancers; 2) examine differences between germline and somatic variants and how that functionally impacts rare tumors; 3) detect and characterize alleles in biologically relevant genes-pathways that may be of clinical importance but not represented in classical cancer genes. We identified 3343 germline single nucleotide variants (SNVs) and small indel variants-1670 in oncogenes and 1673 in tumor suppressor genes-generating an average of 124 germline variants/case. The number of somatic SNVs and small indels detected in all cases was 523:306 in oncogenes and 217 in tumor suppressor genes. Of the germline variants, six were identified to be pathogenic or likely pathogenic. In the 27 analyzed rare cancer cases, CNAs are variable depending on tumor type, germline pathogenic variants are more common. Cell fate pathway mutations (e.g., Hippo, Notch, Wnt) dominate pathogenesis and double hit (mutation + CNV) represent ~18% cases.

Keywords:  copy number alteration (CNA); double hits; inherited variants; rare tumors; tumor-germline matched sequencing; whole exome sequencing

DOI:  https://doi.org/10.3390/cancers12061618
Am J Hum Genet. 2020 Jun 17. pii: S0002-9297(20)30189-0. [Epub ahead of print]

Large Copy-Number Variants in UK Biobank Caused by Clonal Hematopoiesis May Confound Penetrance Estimates.

Marcus Tuke, Jessica Tyrrell, Katherine S Ruth, Robin N Beaumont, Andrew R Wood, Anna Murray, Timothy M Frayling, Michael N Weedon, Caroline F Wright.

  Large copy-number variants (CNVs) are strongly associated with both developmental delay and cancer, but the type of disease depends strongly on when and where the mutation occurred, i.e., germline versus somatic. We used microarray data from UK Biobank to investigate the prevalence and penetrance of large autosomal CNVs and chromosomal aneuploidies using a standard CNV detection algorithm not designed for detecting mosaic variants. We found 160 individuals that carry >10 Mb copy number changes, including 56 with whole chromosome aneuploidies. Nineteen (12%) individuals had a diagnosis of Down syndrome or other developmental disorder, while 84 (52.5%) individuals had a diagnosis of hematological malignancies or chronic myeloproliferative disorders. Notably, there was no evidence of mosaicism in the blood for many of these large CNVs, so they could easily be mistaken for germline alleles even when caused by somatic mutations. We therefore suggest that somatic mutations associated with blood cancers may result in false estimates of rare variant penetrance from population biobanks.

Keywords:  aneuploidy; biobank; cnv; germline; mosaic; penetrance; somatic

DOI:  https://doi.org/10.1016/j.ajhg.2020.06.001
Int J Endocrinol. 2020 ;2020 3671396

Germline Mutation in KIF1Bβ Gene Associated with Loss of Heterozygosity: Usefulness of Next-Generation Sequencing in the Genetic Screening of Patients with Pheochromocytoma.

Giuseppina De Filpo, Elisa Contini, Viola Serio, Andrea Valeri, Massimiliano Chetta, Daniele Guasti, Daniele Bani, Massimo Mannelli, Elena Rapizzi, Michaela Luconi, Mario Maggi, Tonino Ercolino, Letizia Canu.

The genetic approach of pheochromocytomas and paragangliomas has changed in the last two decades. Nowadays, we know that more than 40% of patients have a germline mutation in one of the susceptibility genes identified to date. Our aim is to underline how genetic diagnosis by next-generation sequencing (NGS) can improve the management of patients affected by pheochromocytomas and paragangliomas in our routine diagnostic screening. We reported a case presentation and next-generation sequencing analysis supported by in silico studies and evaluation of mitochondrial status in KIF1Bβ tissue. A 46-year-old male affected by a left secreting pheochromocytoma underwent surgery in 2017. After surgery, the normetanephrine levels decreased very slowly and a suspected abdominal lymph node was detected. We found a novel germline KIF1Bβ gene mutation, c.4052C > T, p. Pro1351Leu associated with tumor loss of heterozygosity, and resulted likely-pathogenetic by in silico studies. This mutation was also associated with an increased number of mitochondria through the electron microscopy compared with wild-type tissues as suggestive for mitochondria neoformation compensatory to the mitochondrial autophagic figures observed. Our results underline the usefulness of next-generation sequencing in the presence of multiple tumor predisposition genes and how, at the same time, its use may result challenging for the clinicians. To date, performing the genetic analysis according to the latest Consensus Statement is mandatory in patients affected by PHEO/PGL.

DOI: https://doi.org/10.1155/2020/3671396
Pathol Int. 2020 Jun 24.

Genomic profiling of multiple primary cancers including synchronous lung adenocarcinoma and bilateral malignant mesotheliomas: Identification of a novel BAP1 germline variant.

Aya Shinozaki-Ushiku, Shinji Kohsaka, Hidenori Kage, Katsutoshi Oda, Kiyoshi Miyagawa, Jun Nakajima, Hiroyuki Aburatani, Hiroyuki Mano, Tetsuo Ushiku.

  We report a case with a rare combination of synchronous lung adenocarcinoma and bilateral malignant pleural mesotheliomas in a 70-year-old male without asbestos exposure. He metachronously developed peritoneal malignant mesothelioma, intrahepatic cholangiocarcinoma, urothelial carcinoma of the bladder and prostatic adenocarcinoma. Immunohistochemistry revealed complete loss of BAP1 expression in all seven lesions. Targeted next generation sequencing using Todai OncoPanel identified a novel germline variant (c.1565_1566del, p.P522Rfs*14) of BAP1. Additionally, different nonsynonymous somatic mutations of BAP1 were identified in four lesions including lung adenocarcinoma, malignant pleural and peritoneal mesotheliomas, and bladder cancer. The remaining two lesions had different somatic mutations in genes other than BAP1. Multiple BAP1-deficient cancers that developed in a single patient suggest the newly identified germline variant of BAP1 gene to be pathogenic and this case expands the clinical spectrum of BAP1-tumor predisposition syndrome. Screening for BAP1 status is highly recommended in cases with a similar combination of cancers.

Keywords:  BAP1; BAP1-tumor predisposition syndrome; TodaiOncoPanel; lung cancer; malignant mesothelioma

DOI:  https://doi.org/10.1111/pin.12977