bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒04‒25
eleven papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. Multiple meningiomas arising within the same hemisphere associated with Li-Fraumeni syndrome.
  2. Alternative splicing redefines landscape of commonly mutated genes in acute myeloid leukemia.
  3. Germline variants at SOHLH2 influence multiple myeloma risk.
  4. Clinical Features of Breast Cancer in South Korean Patients with Germline TP53 Gene Mutations.
  5. Universal immunohistochemistry for Lynch Syndrome: a systematic review and meta-analysis of 58,580 colorectal carcinomas.
  6. Comprehensive Study of Germline Mutations and Double-Hit Events in Esophageal Squamous Cell Cancer.
  7. CDH1 pathogenic variants and cancer risk in an unselected patient population.
  8. Impact of Pathogenic Germline DNA Damage Repair alterations on Response to Intense Neoadjuvant Androgen Deprivation Therapy in High-risk Localized Prostate Cancer.
  9. Association of Germline BRCA Pathogenic Variants With Diminished Ovarian Reserve: A Meta-Analysis of Individual Patient-Level Data.
  10. Germline and somatic mutation profile in Cancer patients revealed by a medium-sized pan-Cancer panel.
  11. Hereditary diffuse leukoencephalopathy with spheroids mimicking primary progressive aphasia: report of a Greek case.
  1. Surg Neurol Int. 2021 ;12 99
    Multiple meningiomas arising within the same hemisphere associated with Li-Fraumeni syndrome.
    Hong CS, Erson-Omay EZ, Moliterno J.
      Background: While meningiomas are some of the most common intracranial tumors, the presence of multiple ones at the time of presentation is rare and can most commonly be observed in patients with well-described syndromes (i.e., neurofibromatosis type 2) or those with prior cranial radiation history. In others, however, the pathophysiology remains unclear.Case Description: A 49-year-old female with no significant personal or familial oncologic medical history presented with a generalized seizure and was found to have ten meningiomas arising within the right hemisphere. She underwent a two-staged resection of all tumors, with pathology revealing the World Health Organization Grade I meningioma. Whole-exome sequencing revealed somatic NF2 mutations and heterozygous deletion of chromosome 22 overlapping with NF2, and analysis of the germline uncovered mutations of TP53, rendering a diagnosis of Li-Fraumeni Syndrome.
    Conclusions: This case represents a novel presentation of multiple meningiomas in a patient with newly diagnosed Li-Fraumeni syndrome, suggesting meningioma may be considered as part of this tumor-predisposed patient population.
    Keywords:  Li-Fraumeni; Meningioma; TP53
    DOI:  https://doi.org/10.25259/SNI_125_2019
  2. Proc Natl Acad Sci U S A. 2021 Apr 13. pii: e2014967118. [Epub ahead of print]118(15):
    Alternative splicing redefines landscape of commonly mutated genes in acute myeloid leukemia.
    Rivera OD, Mallory MJ, Quesnel-Vallières M, Chatrikhi R, Schultz DC, Carroll M, Barash Y, Cherry S, Lynch KW.
      Most genes associated with acute myeloid leukemia (AML) are mutated in less than 10% of patients, suggesting that alternative mechanisms of gene disruption contribute to this disease. Here, we find a set of splicing events that alter the expression of a subset of AML-associated genes independent of known somatic mutations. In particular, aberrant splicing triples the number of patients with reduced functional EZH2 compared with that predicted by somatic mutation alone. In addition, we unexpectedly find that the nonsense-mediated decay factor DHX34 exhibits widespread alternative splicing in sporadic AML, resulting in a premature stop codon that phenocopies the loss-of-function germline mutations observed in familial AML. Together, these results demonstrate that classical mutation analysis underestimates the burden of functional gene disruption in AML and highlight the importance of assessing the contribution of alternative splicing to gene dysregulation in human disease.
    Keywords:  AML; DHX34; EZH2; alternative splicing; cancer
    DOI:  https://doi.org/10.1073/pnas.2014967118
  3. Blood Cancer J. 2021 Apr 19. 11(4): 76
    Germline variants at SOHLH2 influence multiple myeloma risk.
    Duran-Lozano L, Thorleifsson G, Lopez de Lapuente Portilla A, Niroula A, Went M, Thodberg M, Pertesi M, Ajore R, Cafaro C, Olason PI, Stefansdottir L, Bragi Walters G, Halldorsson GH, Turesson I, Kaiser MF, Weinhold N, Abildgaard N, Andersen NF, Mellqvist UH, Waage A, Juul-Vangsted A, Thorsteinsdottir U, Hansson M, Houlston R, Rafnar T, Stefansson K, Nilsson B.
      Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10-14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.
    DOI:  https://doi.org/10.1038/s41408-021-00468-6
  4. J Breast Cancer. 2021 Mar 12.
    Clinical Features of Breast Cancer in South Korean Patients with Germline TP53 Gene Mutations.
    Alyami H, Yoo TK, Cheun JH, Lee HB, Jung SM, Ryu JM, Bae SJ, Jeong J, Yoon CI, Ahn J, Paik PS, Cho MK, Park WC.
      PURPOSE: Li-Fraumeni syndrome (LFS) is a rare autosomal cancer syndrome caused by a germline mutation in the TP53 gene. Breast cancer in LFS patients is of various subtypes; however, limited data are available on the clinicopathological features of these subtypes and their appropriate treatments. This study aimed to review the clinical features and treatments for breast cancer in South Korean patients with germline TP53 mutations.METHODS: Data on the clinicopathological features and treatment of all breast cancer patients with LFS were collected retrospectively from the available database of 4 tertiary hospitals in the Republic of Korea.
    RESULTS: Twenty-one breast cancer cases in 12 unrelated women with confirmed germline TP53 mutations were included in the study. The median age at diagnosis was 33.5 years. The histopathological diagnosis included invasive ductal carcinoma (n = 16), ductal carcinoma in situ (n = 3), and malignant phyllodes tumor (n = 2). While 42% and 31% of the cases were positive for estrogen and progesterone receptors, respectively, 52.6% were human epidermal growth factor receptor 2 (HER2) positive, and 21% were triple-negative. The treatments included mastectomy (52%) and breast-conserving surgery (38%). Five patients underwent radiotherapy (RT). The median follow-up period was 87.5 (8-222) months. There were 3 ipsilateral and 4 contralateral breast recurrences during the follow-up, and 8 patients developed new primary cancers. In the post-RT subgroup, there were 2 ipsilateral and 2 contralateral breast recurrences in 1 patient, and 4 patients had a new primary cancer.
    CONCLUSION: As reported in other countries, breast cancer in LFS patients in South Korea had an early onset and were predominantly but not exclusively positive for HER2. A multidisciplinary approach with adherence to the treatment guidelines, considering mastectomy, and avoiding RT is encouraged to prevent RT-associated sequelae in LFS patients.
    Keywords:  Breast neoplasms; Genes, erbB-2; Genes, p53; Li-Fraumeni syndrome
    DOI:  https://doi.org/10.4048/jbc.2021.24.e16
  5. Clin Gastroenterol Hepatol. 2021 Apr 19. pii: S1542-3565(21)00455-9. [Epub ahead of print]
    Universal immunohistochemistry for Lynch Syndrome: a systematic review and meta-analysis of 58,580 colorectal carcinomas.
    Eikenboom EL, van der Werf-'t Lam AS, Rodríguez-Girondo M, Van Asperen CJ, Dinjens WNM, Hofstra RMW, Van Leerdam ME, Morreau H, Spaander MCW, Wagner A, Nielsen M.
      BACKGROUND AND AIMS: Lynch Syndrome is a form of hereditary colorectal cancer (CRC), caused by pathogenic germline variants (PV) in DNA mismatch repair genes. Currently, many Western countries perform universal immunohistochemistry testing on CRC to increase the identification of LS patients and their relatives. For a clear understanding of health benefits and costs, data on its outcomes are required: proportions of LS, sporadic MMR-deficient (MMRd) cases, and unexplained MMRd cases.METHODS: Ovid Medline, Embase and Cochrane CENTRAL were searched for studies reporting on universal MMR IHC, followed by MMR germline analysis, until March 20, 2020. Proportions were calculated, subgroup analyses were performed based on age and diagnostics used, and random effects meta-analyses were conducted. Quality was assessed using the Joanna Briggs Critical Appraisal Tool for Prevalence Studies.
    RESULTS: Of 2723 identified articles, 56 studies covering 58,580 CRCs were included. In 6.22% (95% CI 5.08%-7.61%; I2=96%) MMRd was identified. An MMR germline PV was present in 2.00% (95% CI 1.59%-2.50%, I2=92%), ranging from 1.80% to 7.27% based on completeness of diagnostics and age restriction. IHC outcomes were missing in 11.81%, germline testing was performed in 76.30% of eligible patients. In seven studies, including 6848 CRCs completing all diagnostic stages, germline PV and biallelic somatic MMR inactivation were found in 3.01% and 1.75%, respectively; 0.61% remained unexplained MMRd.
    CONCLUSION: Age, completeness and type of diagnostics affect the percentage of MMR PV and unexplained MMRd percentages. Complete diagnostics explain almost all MMRd CRCs, reducing the amount of subsequent multi-gene panel testing. This contributes to optimising testing and surveillance in MMRd CRC patients and relatives.
    Keywords:  Colorectal cancer; Immunohistochemistry; Lynch syndrome; Mismatch repair deficiency; Universal tumor screening
    DOI:  https://doi.org/10.1016/j.cgh.2021.04.021
  6. Front Oncol. 2021 ;11 637431
    Comprehensive Study of Germline Mutations and Double-Hit Events in Esophageal Squamous Cell Cancer.
    Zeng B, Huang P, Du P, Sun X, Huang X, Fang X, Li L.
      Esophageal squamous cell cancer (ESCC) is the eighth most common cancer around the world. Several reports have focused on somatic mutations and common germline mutations in ESCC. However, the contributions of pathogenic germline alterations in cancer susceptibility genes (CSGs), highly frequently mutated CSGs, and pathogenically mutated CSG-related pathways in ESCC remain unclear. We obtained data on 571 ESCC cases from public databases and East Asian from the 1000 Genomes Project database and the China Metabolic Analytics Project database to characterize pathogenic mutations. We detected 157 mutations in 75 CSGs, accounting for 25.0% (143/571) of ESCC cases. Six genes had more than five mutations: TP53 (n = 15 mutations), GJB2 (n = 8), BRCA2 (n = 6), RECQL4 (n = 6), MUTYH (n = 6), and PMS2 (n = 5). Our results identified significant differences in pathogenic germline mutations of TP53, BRCA2, and RECQL4 between the ESCC and control cohorts. Moreover, we identified 84 double-hit events (16 germline/somatic double-hit events and 68 somatic/somatic double-hit events) occurring in 18 tumor suppressor genes from 83 patients. Patients who had ESCC with germline/somatic double-hit events were diagnosed at younger ages than patients with the somatic/somatic double-hit events, though the correlation was not significant. Fanconi anemia was the most enriched pathway of pathogenically mutated CSGs, and it appeared to be a primary pathway for ESCC predisposition. The results of this study identified the underlying roles that pathogenic germline mutations in CSGs play in ESCC pathogenesis, increased our awareness about the genetic basis of ESCC, and provided suggestions for using highly mutated CSGs and double-hit features in the early discovery, prevention, and genetic counseling of ESCC.
    Keywords:  cancer susceptibility gene; double-hit; esophageal squamous cell cancer; germline mutation; pathogenicity
    DOI:  https://doi.org/10.3389/fonc.2021.637431
  7. Fam Cancer. 2021 Apr 22.
    CDH1 pathogenic variants and cancer risk in an unselected patient population.
    Bar-Mashiah A, Soper ER, Cullina S, Belbin GM, Kenny EE, Lucas AL, Abul-Husn NS.
      CDH1 pathogenic variants confer a markedly elevated lifetime risk of developing diffuse gastric cancer (DGC) and lobular breast cancer (LBC). The aim of this study was to evaluate the prevalence and clinical impact of CDH1 pathogenic variants in the unselected and ancestrally diverse BioMe Biobank. We evaluated exome sequence data from 30,223 adult BioMe participants to identify CDH1 positive individuals, defined as those harboring a variant previously classified as pathogenic or likely pathogenic or a predicted loss-of-function variant in CDH1. We reviewed electronic health records and BioMe enrollment surveys for personal and family history of malignancy and evidence of prior clinical genetic testing. Using a genomics-first approach, we identified 6 CDH1 positive individuals in BioMe (~ 1 in 5000). CDH1 positive individuals had a median age of 42 years (range 35-62 years), all were non-European by self-report, and one was female. None had evidence of either a personal or family history of DGC or LBC. Our findings suggest a low risk of DGC and LBC in unselected patients harboring a pathogenic variant in CDH1. Knowledge of CDH1-related cancer risk in individuals with no personal or family history may better inform surveillance and prophylactic measures.
    Keywords:  CDH1; Diffuse gastric cancer; Genomic risk; Hereditary diffuse gastric cancer
    DOI:  https://doi.org/10.1007/s10689-021-00257-x
  8. Eur Urol. 2021 Apr 19. pii: S0302-2838(21)00237-2. [Epub ahead of print]
    Impact of Pathogenic Germline DNA Damage Repair alterations on Response to Intense Neoadjuvant Androgen Deprivation Therapy in High-risk Localized Prostate Cancer.
    Berchuck JE, Zhang Z, Silver R, Kwak L, Xie W, Lee GM, Freedman ML, Kibel AS, Van Allen EM, McKay RR, Taplin ME.
      BACKGROUND: Intense neoadjuvant androgen deprivation therapy (ADT) before radical prostatectomy (RP) is an investigational approach to reduce recurrence rates in men with high-risk localized prostate cancer (PCa). The impact of germline DNA damage repair (gDDR) gene alterations on response to intense neoadjuvant ADT is not known.OBJECTIVE: To evaluate the prevalence of gDDR alterations among men with localized PCa at high risk of recurrence and evaluate their impact on response to intense neoadjuvant ADT.
    DESIGN, SETTING, AND PARTICIPANTS: We performed germline panel sequencing for 201 men with intermediate- and high-risk localized PCa from five randomized multicenter clinical trials of intense neoadjuvant ADT before RP.
    INTERVENTION: Intense neoadjuvant ADT followed by RP.
    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The prevalence of pathogenic gDDR alterations and their association with exceptional pathologic response (complete response or minimal residual disease, defined as residual tumor with the largest cross-section dimension ≤5 mm) to intense neoadjuvant ADT and rates of post-RP biochemical recurrence.
    RESULTS AND LIMITATIONS: Pathogenic gDDR alterations were detected in 19 (9.5%) of the 201 PCa patients. The most frequently altered genes were BRCA2 (n = 6; 3.0%) and ATM (n = 4; 2.0%). Patients with gDDR alterations exhibited similar rates of exceptional pathologic response (26% vs 22%), pT3 disease (42% vs 53%), lymph node involvement (5.3% vs 10%), extraprostatic extension (35% vs 54%), and positive margins (5.3% vs 13%) to patients without gDDR alterations (all p > 0.05). The 3-yr biochemical recurrence-free survival was also similar at 45% (95% confidence interval 7.9-78%) for men with gDDR alterations and 55% (95% confidence interval 44-64%) for men without gDDR alterations.
    CONCLUSIONS: gDDR alterations are common among men with intermediate- and high-risk localized PCa. Men with gDDR alterations appear to have a comparable response to intense neoadjuvant ADT to that among men without gDDR alterations and should not be excluded from consideration for this treatment approach.
    PATIENT SUMMARY: Intense therapy to inhibit the production of androgen hormones (eg, testosterone) before surgery may minimize the risk of cancer recurrence for men with high-risk localized prostate cancer. Inherited mutations in certain DNA repair genes are associated with particularly high rates of recurrence. We found that men with these mutations respond equally well to this intense androgen inhibition before surgery as men without the mutations.
    Keywords:  Biochemical recurrence; Biomarkers; DNA damage repair; Germline alterations; Germline sequencing; Hormone therapy; Neoadjuvant therapy; Pathologic response; Prostate cancer
    DOI:  https://doi.org/10.1016/j.eururo.2021.03.031
  9. J Clin Oncol. 2021 Apr 23. JCO2002880
    Association of Germline BRCA Pathogenic Variants With Diminished Ovarian Reserve: A Meta-Analysis of Individual Patient-Level Data.
    Turan V, Lambertini M, Lee DY, Wang E, Clatot F, Karlan BY, Demeestere I, Bang H, Oktay K.
      PURPOSE: To determine whether germline BRCA (gBRCA) pathogenic variants are associated with decreased ovarian reserve.MATERIALS AND METHODS: An individual patient-level data meta-analysis was performed using five data sets on 828 evaluable women who were tested for gBRCA. Of those, 250 carried gBRCA, whereas 578 had tested negative and served as controls. Of the women with gBRCA, four centers studied those affected with breast cancer (n = 161) and one studied unaffected individuals (n = 89). The data were adjusted for the center, age, body mass index, smoking, and oral contraceptive pill use before the final analysis. Anti-Müllerian hormone (AMH) levels in affected women were drawn before presystemic therapy.
    RESULTS: The mean age of women with versus without gBRCA1/2 (34.1 ± 4.9 v 34.3 ± 4.8 years; P = .48) and with gBRCA1 versus gBRCA2 (33.7 ± 4.9 v 34.6 ± 4.8 years; P = .16) was similar. After the adjustments, women with gBRCA1/2 had significantly lower AMH levels compared with controls (23% lower; 95% CI, 4 to 38; P = .02). When the adjusted analysis was limited to affected women (157 with gBRCA v 524 without, after exclusions), the difference persisted (25% lower; 95% CI, 9 to 38; P = .003). The serum AMH levels were lower in women with gBRCA1 (33% lower; 95% CI, 12 to 49; P = .004) but not gBRCA2 compared with controls (7% lower; 95% CI, 31% lower to 26% higher; P = .64).
    CONCLUSION: Young women with gBRCA pathogenic variants, particularly those affected and with gBRCA1, have lower serum AMH levels compared with controls. They may need to be preferentially counseled about the possibility of shortened reproductive lifespan because of diminished ovarian reserve.
    DOI:  https://doi.org/10.1200/JCO.20.02880
  10. Genomics. 2021 Apr 17. pii: S0888-7543(21)00156-7. [Epub ahead of print]
    Germline and somatic mutation profile in Cancer patients revealed by a medium-sized pan-Cancer panel.
    Li Z, Wang H, Zhang Z, Meng X, Liu D, Tang Y.
      Gene mutation detection and the resulted precision-medicine therapy is transforming clinical practice. Here, we report the use of a custom-developed, medium-sized, pan-cancer probe panel for the detection of somatic and germline mutations. We used a hybridization capture-based NGS assay for targeted deep sequencing of all exons and selected introns of 181 key cancer driver genes, covering both inherited risks and somatic mutations. We performed paired-variant calling on tumor samples and their matched normal samples. We processed clinical patient samples of formalin-fixed, paraffin embedded tumors (FFPE samples) and cell-free peripheral blood (cfDNA samples). We found germline mutations of inherited cancer risk at 9%; and discovered a novel germline mutation in BRCA1. Somatic mutation rate in driver genes is at 73.1%, much higher than previously reported. On recommending precision-medicine therapeutics, we achieved 91.6% for patients with FFPE samples.
    Keywords:  Biomarker discovery; Cancer driver genes; Cell-free DNA; FFPE sample; Germline mutation; Inherited Cancer risk; Next-generation sequencing; Tumor mutation burden
    DOI:  https://doi.org/10.1016/j.ygeno.2021.04.029
  11. Neurol Sci. 2021 Apr 18.
    Hereditary diffuse leukoencephalopathy with spheroids mimicking primary progressive aphasia: report of a Greek case.
    Stoiloudis P, Parissis D, Smyrni N, Stardeli T, Afrantou T, Konstantinopoulou E, Grigoriadis N, Ioannidis P.
      INTRODUCTION: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an adult onset leukodystrophy, causally related to mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. We report the unique case of a Greek HDLS patient, demonstrating an unusual phenotype, reminiscent of primary progressive aphasia (PPA).METHODS: A 63-year-old woman was referred with a 2-year history of deteriorating language and memory deficits, apathy, and two generalized tonic-clonic seizures. Neurological and neuropsychological examination revealed prominent aphasia with a pattern consistent with nonfluent variant of PPA. However, brain MRI disclosed confluent T2 and FLAIR white matter hyperintensities with frontal emphasis, whereas genetic testing corroborated the diagnosis of HDLS.
    DISCUSSION: PPA-like patterns may rarely develop in the context of HDLS. Prompt diagnosis of this leukoencephalopathy is essential, since preliminary data suggest that it could represent a potentially treatable disorder.
    Keywords:  Dementia; HDLS; Hereditary diffuse leukoencephalopathy with spheroids; PPA
    DOI:  https://doi.org/10.1007/s10072-021-05257-4
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