bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒03‒01
fifteen papers selected by
Joanna Zawacka-Pankau



  1. J Natl Cancer Inst. 2020 Feb 24. pii: djaa023. [Epub ahead of print]
    Hu C, Polley EC, Yadav S, Lilyquist J, Shimelis H, Na J, Hart SN, Goldgar DE, Shah S, Pesaran T, Dolinsky JS, LaDuca H, Couch FJ.
      BACKGROUND: The germline cancer predisposition genes associated with increased risk of each clinical subtype of breast cancer, defined by estrogen receptor (ER), progesterone receptor (PR), and HER2, are not well defined.METHODS: A total of 54,555 invasive breast cancer patients with 56,480 breast tumors were subjected to clinical hereditary cancer multigene panel testing. Heterogeneity for predisposition genes across clinical breast cancer subtypes was assessed by comparing mutation frequencies by gene among tumor subtypes and by association studies between each tumor subtype and reference controls.
    RESULTS: Mutations in 15 cancer predisposition genes were detected in 8.6% of patients with ER+/HER2-; 8.9% with ER+/HER2+; 7.7% with ER-/HER2+; and 14.4% of ER-/PR-/HER2- tumors. BRCA1, BRCA2, BARD1 and PALB2 mutations were enriched in ER- and HER2- tumors, RAD51C and RAD51D mutations were enriched in ER- tumors only, TP53 mutations were enriched in HER2+ tumors, and ATM and CHEK2 mutations were enriched in both ER+ and/or HER2+ tumors. All genes were associated with moderate (odds ratio (OR)>2.00) or strong (OR > 5.00) risks of at least one subtype of breast cancer in case-control analyses. Mutations in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53 had predicted lifetime absolute risks of ≥ 20.0% for breast cancer.
    CONCLUSIONS: Germline mutations in hereditary cancer panel genes confer subtype-specific risks of breast cancer. Combined tumor subtype, age at breast cancer diagnosis, and family history of breast and/or ovarian cancer information provides refined categorical estimates of mutation prevalence for women considering genetic testing.
    DOI:  https://doi.org/10.1093/jnci/djaa023
  2. Aging (Albany NY). 2020 Feb 24. 12
    Chen B, Zhang G, Li X, Ren C, Wang Y, Li K, Mok H, Cao L, Wen L, Jia M, Li C, Guo L, Wei G, Lin J, Li Y, Zhang Y, Han-Zhang H, Liu J, Lizaso A, Liao N.
      The data on the phenotypes associated with some rare germline mutations in Chinese breast cancer patients are limited. The difference in somatic mutation profiles in breast cancer patients with germline BRCA and non-BRCA mutations remains unexplored. We interrogated the germline and somatic mutational profile of 524 Chinese breast cancer patients with various stages unselected for predisposing factors using a panel consisting of 520 cancer-related genes including 62 cancer susceptibility genes. We divided the patients into three groups according to germline mutations: Germline-BRCA1/2, Germline-others (non-BRCA) and Others (non-carriers). A total of 58 patients (11.1%) carried 76 likely pathogenic or pathogenic (LP/P) germline variants in 15 cancer predisposition genes. Germline BRCA1/2 mutations were detected from 29 (5.53%) patients; with 11 (2.10%) BRCA1 carriers and 18 (3.44%) BRCA2 carriers. In addition, LP/P germline mutations were detected in other genes including MUTYH (n=4), PALB2 (n=4), ATM (n=3), BRIP1 (n=3), CDH1 (n=3), RAD51C (n=3), CHEK2 (n=2), FANCA (n=2), PMS2 (n=2), TP53 (n=2), FANCI (n=1), FANCL (n=1) and PTEN (n=1). At least one variant of uncertain significance (VUS) was identified in 490 (93.5%) patients. Young age (P=0.011), premenopausal status (P=0.013), and breast/ovarian cancer family history (P=0.001) were correlated with germline mutations. Germline-BRCA1/2 group was detected with more missense (P=0.02) and less copy-number amplification (P=0.04) than Germline-others group. Meanwhile, Germline-others group and Others group are very similar (P>0.05). The mutation rates of AKT1, CCND1, FGFR1, and PIK3CA were different among the three groups. By investigating all breast and ovarian cancer-related genes listed in the US genetic guidelines, we identified 15 cancer susceptibility genes frequently mutated in the germline of our population and must be included in cancer predisposition screening. Our study contributed a better understanding of the tumor characteristics of patients with LP/P germline mutations.
    Keywords:  BRCA; breast cancer; germline mutations; non-BRCA; somatic mutations
    DOI:  https://doi.org/10.18632/aging.102783
  3. Indian J Pathol Microbiol. 2020 Feb;63(Supplement): S7-S17
    El-Zaatari Z, Divatia MK.
      Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant syndrome wherein affected individuals are at risk for the development of cutaneous leiomyomas, early-onset multiple uterine leiomyomas, and an aggressive subtype of renal cell cancer. HLRCC is caused by germline mutations in the fumarate hydratase (FH) gene, which inactivates the enzyme and alters the function of the tricarboxylic acid/Krebs cycle. This article reviews the hitherto described morphologic features of HLRCC-associated renal cell carcinoma (RCC) and outlines the differential diagnosis and ancillary use of immunohistochemistry and molecular diagnostics for these tumors. The morphologic spectrum of HLRCC-associated RCC is wide and histologic features, including tumor cells with prominent nucleoli, perinucleolar halos, and multiple architectural patterns within the same tumor, which are suggestive of this diagnosis. FH immunohistochemistry in conjunction with genetic counseling and germline FH testing are the important parameters for detection of this entity. These kidney tumors warrant prompt treatment as even smaller sized lesions can demonstrate aggressive behavior and systemic oncologic treatment in metastatic disease should, if possible, be part of a clinical trial. Screening procedures in HLRCC families should preferably be evaluated in large cohorts.
    Keywords:  Collecting duct carcinoma; Hereditary leiomyomatosis and renal cell carcinoma; fumarate hydratase; papillary type 2 renal cancer; targeted therapy
    DOI:  https://doi.org/10.4103/IJPM.IJPM_877_19
  4. Hematol Oncol Clin North Am. 2020 Apr;pii: S0889-8588(19)30151-0. [Epub ahead of print]34(2): 333-356
    Schratz KE, DeZern AE.
      Myelodysplastic syndromes (MDSs) are a heterogeneous group of marrow failure disorders that primarily affect older persons but also occur at a lower frequency in children and young adults. There is increasing recognition of an inherited predisposition to MDS as well as other myeloid malignancies for patients of all ages. Germline predisposition to MDS can occur as part of a syndrome or sporadic disease. The timely diagnosis of an underlying genetic predisposition in the setting of MDS is important. This article delineates germline genetic causes of MDS and provides a scaffold for the diagnosis and management of patients in this context.
    Keywords:  Diagnostic testing; Germline mutations; Hematopoietic stem cell transplant; Inherited predisposition; Myelodysplastic syndrome; Somatic mutations
    DOI:  https://doi.org/10.1016/j.hoc.2019.10.002
  5. Biomed Res Int. 2020 ;2020 3289023
    Rosenthal SH, Sun W, Zhang K, Liu Y, Nguyen Q, Gerasimova A, Nery C, Cheng L, Castonguay C, Hiller E, Li J, Elzinga C, Wolfson D, Smolgovsky A, Chen R, Buller-Burckle A, Catanese J, Grupe A, Lacbawan F, Owen R.
      The use of genetic testing to identify individuals with hereditary cancer syndromes has been widely adopted by clinicians for management of inherited cancer risk. The objective of this study was to develop and validate a 34-gene inherited cancer predisposition panel using targeted capture-based next-generation sequencing (NGS). The panel incorporates genes underlying well-characterized cancer syndromes, such as BRCA1 and BRCA2 (BRCA1/2), along with more recently discovered genes associated with increased cancer risk. We performed a validation study on 133 unique specimens, including 33 with known variant status; known variants included single nucleotide variants (SNVs) and small insertions and deletions (Indels), as well as copy-number variants (CNVs). The analytical validation study achieved 100% sensitivity and specificity for SNVs and small Indels, with 100% sensitivity and 98.0% specificity for CNVs using in-house developed CNV flagging algorithm. We employed a microarray comparative genomic hybridization (aCGH) method for all specimens that the algorithm flags as CNV-positive for confirmation. In combination with aCGH confirmation, CNV detection specificity improved to 100%. We additionally report results of the first 500 consecutive specimens submitted for clinical testing with the 34-gene panel, identifying 53 deleterious variants in 13 genes in 49 individuals. Half of the detected pathogenic/likely pathogenic variants were found in BRCA1 (23%), BRCA2 (23%), or the Lynch syndrome-associated genes PMS2 (4%) and MLH1 (2%). The other half were detected in 9 other genes: MUTYH (17%), CHEK2 (15%), ATM (4%), PALB2 (4%), BARD1 (2%), CDH1 (2%), CDKN2A (2%), RAD51C (2%), and RET (2%). Our validation studies and initial clinical data demonstrate that a 34-gene inherited cancer predisposition panel can provide clinically significant information for cancer risk assessment.
    DOI:  https://doi.org/10.1155/2020/3289023
  6. Neuro Endocrinol Lett. 2019 Dec 29. 40(5): 215-221
    Fabišíková K, Behulová RL, Repiska V.
      Colorectal cancer (CRC) is currently a well-known and studied issue in experimental research. Worldwide it is the third most common cancer in men and the second most common cancer in women. 70-80% of cases occur sporadically. Most CRCs develop from adenomas. The transition from normal epithelium to adenoma and finally into carcinoma is associated with acquired molecular events. In 5-10 % of cases, CRC develops from germline mutations in cancer-predisposing genes. 15% of patients have a family history of CRC that suggests a hereditary contribution, common exposures or shared risk factors among family members. Genetic alterations in cancer-related genes represent prognostic and predictive CRC biomarkers. Genetic testing of individuals with newly diagnosed CRC as well as of asymptomatic relatives can lead to improved outcomes for the patient and at-risk family members. Discovery of circulating cell-free tumor DNA (ctDNA) promises an improvement of the CRC diagnostics. ctDNA shares common genetic alterations with the primary tumor so it allows non-invasive monitoring of the disease over time. This review is focused on the principal molecular biomarkers associated with CRC and on the key characteristics of initiation and progression of CRC including chromosomal instability, microsatellite instability and signaling pathways where this deregulation leads to tumorigenesis.
  7. Cancer Manag Res. 2020 ;12 743-758
    Llach J, Carballal S, Moreira L.
      Pancreatic cancer (PC) is a highly lethal disease, mostly incurable when detected. Thus, despite advances in PC treatments, only around 7% of patients survive 5-years after diagnosis. This morbid outcome is secondary to multifactorial reasons, such as late-stage diagnosis, rapid progression and minimal response to chemotherapy. Based on these factors, it is of special relevance to identify PC high-risk individuals in order to establish preventive and early detection measures. Although most PC are sporadic, approximately 10% cases have a familial basis. No main causative gene of PC has been identified but several known germline pathogenic mutations are related with an increased risk of this tumor. These inherited cancer syndromes represent 3% of all PC. On the other hand, in 7% of cases of PC, there is a strong family history without a causative germline mutation, a situation known as familial pancreatic cancer (FPC). In recent years, there is increasing evidence supporting the benefit of genetic germline analysis in PC patients, and periodic pancreatic screening in PC high-risk patients (mainly those with a lifetime risk greater than 5%), although there is no general agreement in the group of patients and individuals to study and screen. In the present review, we expose an update in the field of hereditary and FPC, with the aim of describing the current strategies and implications in genetic counseling, surveillance and therapeutic interventions.
    Keywords:  familial; hereditary; mutation; pancreatic cancer; personalized medicine; screening
    DOI:  https://doi.org/10.2147/CMAR.S172421
  8. Nat Commun. 2020 Feb 25. 11(1): 1044
    Rio-Machin A, Vulliamy T, Hug N, Walne A, Tawana K, Cardoso S, Ellison A, Pontikos N, Wang J, Tummala H, Al Seraihi AFH, Alnajar J, Bewicke-Copley F, Armes H, Barnett M, Bloor A, Bödör C, Bowen D, Fenaux P, Green A, Hallahan A, Hjorth-Hansen H, Hossain U, Killick S, Lawson S, Layton M, Male AM, Marsh J, Mehta P, Mous R, Nomdedéu JF, Owen C, Pavlu J, Payne EM, Protheroe RE, Preudhomme C, Pujol-Moix N, Renneville A, Russell N, Saggar A, Sciuccati G, Taussig D, Toze CL, Uyttebroeck A, Vandenberghe P, Schlegelberger B, Ripperger T, Steinemann D, Wu J, Mason J, Page P, Akiki S, Reay K, Cavenagh JD, Plagnol V, Caceres JF, Fitzgibbon J, Dokal I.
      The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.
    DOI:  https://doi.org/10.1038/s41467-020-14829-5
  9. J Clin Med. 2020 Feb 25. pii: E613. [Epub ahead of print]9(3):
    Nazaryan-Petersen L, Bjerregaard VA, Nielsen FC, Tommerup N, Tümer Z.
      Chromothripsis is a mutational mechanism leading to complex and relatively clustered chromosomal rearrangements, resulting in diverse phenotypic outcomes depending on the involved genomic landscapes. It may occur both in the germ and the somatic cells, resulting in congenital and developmental disorders and cancer, respectively. Asymptomatic individuals may be carriers of chromotriptic rearrangements and experience recurrent reproductive failures when two or more chromosomes are involved. Several mechanisms are postulated to underlie chromothripsis. The most attractive hypothesis involves chromosome pulverization in micronuclei, followed by the incorrect reassembly of fragments through DNA repair to explain the clustered nature of the observed complex rearrangements. Moreover, exogenous or endogenous DNA damage induction and dicentric bridge formation may be involved. Chromosome instability is commonly observed in the cells of patients with DNA repair disorders, such as ataxia telangiectasia, Nijmegen breakage syndrome, and Bloom syndrome. In addition, germline variations of TP53 have been associated with chromothripsis in sonic hedgehog medulloblastoma and acute myeloid leukemia. In the present review, we focus on the underlying mechanisms of chromothripsis and the involvement of defective DNA repair genes, resulting in chromosome instability and chromothripsis-like rearrangements.
    Keywords:  DNA double-strand breaks (DSBs); DNA repair; DNA repair disorders; TP53; ataxia telangiectasia and Rad3-related (ATR); ataxia telangiectasia mutated (ATM); chromosome pulverization; chromothripsis; micronuclei; structural variants
    DOI:  https://doi.org/10.3390/jcm9030613
  10. Cancers (Basel). 2020 Feb 22. pii: E506. [Epub ahead of print]12(2):
    Pinto EM, Faucz FR, Paza LZ, Wu G, Fernandes ES, Bertherat J, Stratakis CA, Lalli E, Ribeiro RC, Rodriguez-Galindo C, Figueiredo BC, Zambetti GP.
      Phosphodiesterases (PDEs) form a superfamily of enzymes that catalyze the hydrolysis of cyclic nucleotides adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) to their inactive 5' monophosphates. cAMP plays a critical role as a second messenger in endocrine tissues, and activation of cAMP signaling has been reported in endocrine tumors. Germline variants in PDEs have been associated with benign cortisol-secreting adrenocortical adenomas and testicular germ cell cancer but not adrenocortical carcinoma. We performed whole genome sequencing (WGS) and whole exome sequencing (WES) of paired blood and tumor samples from 37 pediatric adrenocortical tumors (ACTs). Germline inactivating variants in PDEs were observed in 9 of 37 (24%) patients. Tumor DNA analysis revealed loss of heterozygosity, with maintenance of the mutated allele in all cases. Our results suggest that germline variants in PDEs and other regulators of the cAMP-signaling pathway may contribute to pediatric adrenocortical tumorigenesis, perhaps by cooperating with germline hypomorphic mutant TP53 alleles and uniparental disomy of chromosome 11p15 (Beckwith-Wiedemann syndrome).
    Keywords:  11p; TP53; adrenocortical tumor; cAMP pathway; phosphodiesterase
    DOI:  https://doi.org/10.3390/cancers12020506
  11. Asian Pac J Cancer Prev. 2020 Feb 01. pii: 88966. [Epub ahead of print]21(2): 343-348
    Marcolino TF, Pimenta CAM, Artigiani Neto R, Castelo P, Silva MS, Forones NM, Oshima CTF.
      Colorectal cancer (CRC) is one of the most frequent neoplasms worldwide, and up to 15% have a family history. Lynch syndrome (LS) is a hereditary cause of CRC and gastric (GC). Individuals with LS have mutations in mismatch genes repair. p53, cyclin D1, β-catenin, APC and c-myc proteins are involved in the cell cycle and carcinogenesis.OBJECTIVE: To study the expression of p53, Cyclin D1, β-catenin, APC and c-myc proteins in patients with CRC and GC with at least one of the Bethesda positive criteria. Compare the expression of these proteins with the presence or absence of expression of the DNA repair proteins.
    PATIENTS AND METHODS: We included 70 individuals with CRC or GC with at least one of the Bethesda positive criteria. Protein expression of MLH1, MSH2, MSH6, PMS2, p53, cyclin D1, β-catenin, APC and c-myc were analized by immunohistochemistry tumours tissues.
    RESULTS: Deficient expression of MLH1, MSH2, MSH6 and PMS2 were respectively 38.7%; 17.7%; 26.22% and 48.38%. We found a negative association between deficiency of PMS2 and age, and positive association between PMS2 deficiency and APC positive. The positive imunoexpression of APC increases by 4 times the chance of having deficiency of PMS2.
    CONCLUSIONS: Patients with loss of expression of PMS2 had a higher risk of mutation or deletion of APC and tumours with positive immunoexpression of cyclin D1 had an increased risk of loss of expression of MSH2. These results suggest that tumours with loss of expression of DNA repair proteins had a higher loss of cell control cycle.<br />.
    Keywords:  Gastric cancer; Lynch syndrome; colorectal cancer; immunohistochemistry
    DOI:  https://doi.org/10.31557/APJCP.2020.21.2.343
  12. Biol Blood Marrow Transplant. 2020 Feb 20. pii: S1083-8791(20)30100-2. [Epub ahead of print]
    Hofmann I, Avagyan S, Stetson A, Guo D, Al-Sayegh H, London WB, Lehmann L.
      Germline mutations in GATA2 are associated with an inherited predisposition to bone marrow failure (BMF), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) remains the only curative therapy. However, patients may be at an increased risk for transplant-related toxicity (TRT) and mortality (TRM) due to their underlying disease biology. We performed a retrospective case-control study of pediatric BMF/MDS/AML patients with germline GATA2 mutations, comparing HSCT outcomes to randomly selected patients without germline GATA2 mutations and BMF/MDS (control A) and acute leukemia (control B). The 5-year overall and disease-free survival rates in the GATA2 cohort (65%, 51%) were similar to control A (58%, 49%) and B (45%, 43%) cohorts. In contrast, the 5-year event-free survival rate was significantly lower in the GATA2 cohort (7%±6%, 28%±10% and 33%±8% for GATA2, A, and B, respectively), due to an increased number of unique TRT. Specifically, neurologic toxicities occurred significantly more frequently in GATA2 patients than in the control groups and post-HSCT thrombotic events occurred only in the GATA2 cohort. There was no difference in TRM, infections or graft-versus-host disease (GVHD) across groups. The higher incidence of thrombotic and neurological events specific to GATA2 patients warrants further investigation and has potential treatment ramifications.
    Keywords:  Emberger syndrome; GATA2; MonoMac syndrome; bone marrow failure; myelodysplastic syndromes; pediatric MDS; stem cell transplantation
    DOI:  https://doi.org/10.1016/j.bbmt.2020.02.015
  13. Endocr Relat Cancer. 2020 Feb 01. pii: ERC-19-0454.R2. [Epub ahead of print]
    Brock PL, Geurts J, Van Galen P, Blouch E, Welch J, Kunz A, Desrosiers L, Gauerke JL, Hyde S.
      The Genetic Counseling Workgroup from the 16th International Workshop on Multiple Endocrine Neoplasia Conference (MEN 2019) convened to discuss contemporary challenges and opportunities in the area of genetic counseling for individuals and families affected by hereditary endocrine neoplasia syndromes. As healthcare professionals with multidisciplinary training in human genetics, risk assessment, patient education, psychosocial counseling, and research methodology, genetic counselors bring a unique perspective to working towards addressing these challenges and identifying their subsequent opportunities. This workgroup focused on the following broad areas: 1) genetic counseling resources for endocrine neoplasias, 2) candidate gene discovery, 3) implications of increasingly sensitive and expansive genetic testing technologies for both the germline and tumors, and 4) situating clinical diagnoses for hereditary endocrine neoplasia syndromes in the context of present-day knowledge.
    DOI:  https://doi.org/10.1530/ERC-19-0454
  14. BMC Cancer. 2020 Feb 22. 20(1): 143
    Pessôa-Pereira D, Evangelista AF, Causin RL, da Costa Vieira RA, Abrahão-Machado LF, Santana IVV, da Silva VD, de Souza KCB, de Oliveira-Silva RJ, Fernandes GC, Reis RM, Palmero EI, Marques MMC.
      BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene expression regulation and have been described as key regulators of carcinogenesis. Aberrant miRNA expression has been frequently reported in sporadic breast cancers, but few studies have focused on profiling hereditary breast cancers. In this study, we aimed to identify specific miRNA signatures in hereditary breast tumors and to compare with sporadic breast cancer and normal breast tissues.METHODS: Global miRNA expression profiling using NanoString technology was performed on 43 hereditary breast tumors (15 BRCA1, 14 BRCA2, and 14 BRCAX), 23 sporadic breast tumors and 8 normal breast tissues. These normal breast tissues derived from BRCA1- and BRCA2- mutation carriers (n = 5) and non-mutation carriers (n = 3). Subsequently, we performed receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic performance of differentially expressed miRNAs. Putative target genes of each miRNAs considered as potential biomarkers were identified using miRDIP platform and used for pathway enrichment analysis.
    RESULTS: miRNA expression analyses identified several profiles that were specific to hereditary breast cancers. A total of 25 miRNAs were found to be differentially expressed (fold change: > 2.0 and p < 0.05) and considered as potential biomarkers (area under the curve > 0.75) in hereditary breast tumors compared to normal breast tissues, with an expressive upregulation among BRCAX cases. Furthermore, bioinformatic analysis revealed that these miRNAs shared target genes involved in ErbB, FoxO, and PI3K-Akt signaling pathways.
    CONCLUSIONS: Our results showed that miRNA expression profiling can differentiate hereditary from sporadic breast tumors and normal breast tissues. These miRNAs were remarkably deregulated in BRCAX hereditary breast cancers. Therefore, miRNA signatures can be used as potential novel diagnostic biomarkers for the prediction of BRCA1/2- germline mutations and may be useful for future clinical management.
    Keywords:  Biomarker; Hereditary breast tumors; NanoString; microRNA
    DOI:  https://doi.org/10.1186/s12885-020-6640-y
  15. BMC Med Genet. 2020 Feb 27. 21(1): 42
    Liu F, Calhoun B, Alam MS, Sun M, Wang X, Zhang C, Haldar K, Lu X.
      BACKGROUND: von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL mutations include deletion, frameshift, nonsense and missense mutations. Synonymous mutations are expected to be phenotypically silent and their role in VHL disease remains poorly understood.CASE PRESENTATION: We report a Caucasian male with a family history of pheochromocytoma and the synonymous VHL mutation c.414A > G (p.Pro138Pro). At 47-years, MRI revealed pheochromocytoma in the left adrenal gland and hemangioblastomas in the spine and brain. Pheochromocytoma was treated by adrenalectomy. Radiotherapy, followed by craniotomy and resection were needed to reduce hemangioblastomas to residual lesions. Two of three of the proband's children inherited the mutation and both presented with retinal hemangioblastomas without pheochromocytoma at age 7: one twin needed four laser treatments. Primary skin fibroblasts carrying the heterozygous mutation or wild type VHL were established from the family. Mutant fibroblasts downregulated full-length VHL mRNA and protein, and upregulated the short VHL mRNA isoform (a result of exon 2 skipping in splicing) at the mRNA level but not at the protein level.
    CONCLUSIONS: Our study shows that the synonymous VHL mutation c.414A > G can within 7 years induce pediatric retinal hemangioblastoma in absence of pheochromocytoma. This highlights the need to include splicing-altering synonymous mutations into the screening for VHL disease. This is also the first report on detecting and validating a synonymous VHL mutation using patient-derived fibroblasts. The mutation c.414A > G translates to p.Pro138Pro, yet it is not functionally silent, because it causes aberrant splicing by skipping exon 2. The reduced but not completely abolished pVHL protein in a loss-of-heterozygosity genetic backdrop may underlie the etiology of VHL disease.
    Keywords:  Alternative splicing; Hemangioblastoma; Pheochromocytoma; Pro138Pro; Silent mutation; Skin fibroblast; Synonymous mutation; VHL; pVHL; von Hippel-Lindau disease
    DOI:  https://doi.org/10.1186/s12881-020-0976-7