bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒06‒14
thirteen papers selected by
Joanna Zawacka-Pankau
  1. The function of a heterozygous p53 mutation in a Li-Fraumeni syndrome patient.
  2. Germline TET2 Loss-Of-Function Causes Childhood Immunodeficiency And Lymphoma.
  3. A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection.
  4. Updates in hereditary breast cancer genetic testing and practical high risk breast management in gene carriers.
  5. Evaluation of yield and experiences of age-related molecular investigation for heritable and nonheritable causes of mismatch repair deficient colorectal cancer to identify Lynch syndrome.
  6. BRCA immunohistochemistry for screening of BRCA mutation in epithelial ovarian cancer patients.
  7. Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019.
  8. Validation of a next generation sequencing assay for BRCA1, BRCA2, CHEK2 and PALB2 genetic testing.
  9. Germline genetic factors in the pathogenesis of myeloproliferative neoplasms.
  10. Double small bowel cancers leading to the diagnosis of Lynch syndrome with germline MSH6 mutation in an elderly patient.
  11. Case report for an adolescent with germline RET mutation and alveolar rhabdomyosarcoma.
  12. Strategy for identification of a potential inherited leukemia predisposition in a 299 patient's cohort with tumor-only sequencing data.
  13. Inherited CDH1 pathogenic variant: is there a place for surveillance of esophageal gastric inlet patch?
  1. PLoS One. 2020 ;15(6): e0234262
    The function of a heterozygous p53 mutation in a Li-Fraumeni syndrome patient.
    Li Y, Li T, Tang Y, Zhan Z, Ding L, Song L, Yu T, Yang Y, Ma J, Zhang Y, Zhou Y, Gu S, Xu M, Gao Y, Li Y.
      p53 is one of the most extensively studied proteins in cancer research. Mutations in p53 generally abolish normal p53 function, and some mutants can gain new oncogenic functions. However, the mechanisms underlying p53 mutation-driven cancer remains to be elucidated. Our study investigated the function of a heterozygous p53 mutation (p.Asn268Glufs*4) in a Li-Fraumeni syndrome (LFS) patient. We used episomal technology to perform somatic reprogramming, and used molecular and cell biology methods to determine the p53 mutation levels in patient-originated induced pluripotent stem (iPS) cells at the RNA and protein levels. We found that p53 protein expression was not increased in this patient's somatic cells compared with those of a healthy control. p53 mutation facilitates the proliferation of tumor cells by inhibiting apoptosis and promoting cell division. It can inhibit the efficiency of somatic reprogramming by inhibiting OCT4 expression during reprogramming stage. Moreover, not all p53 mutant iPS cell lines have mutant p53 RNA sequences. A small percentage of mutant p53 mRNA is present in the somatic cells from the patient and his mother. In summary, this p53 mutation can promote tumor cell proliferation, inhibit somatic reprogramming, and exhibit random p53 allelic expression of heterozygous mutations in the patient and iPS cells which may be one of the reasons why the people with p53 mutations develop cancer at random. This finding suggested that mutant p53 allelic expression should be added to the risk forecasting of cancer.
    DOI:  https://doi.org/10.1371/journal.pone.0234262
  2. Blood. 2020 Jun 09. pii: blood.2020005844. [Epub ahead of print]
    Germline TET2 Loss-Of-Function Causes Childhood Immunodeficiency And Lymphoma.
    Stremenova Spegarova J, Lawless D, Mohamad SMB, Engelhardt KR, Doody GM, Shrimpton J, Rensing-Ehl A, Ehl S, Rieux-Laucat F, Cargo C, Griffin H, Mikulasova A, Acres M, Morgan NV, Poulter JA, Sheridan E, Chetcuti P, O'Riordan S, Anwar R, Carter CR, Przyborski S, Windebank K, Cant AJ, Lako M, Bacon C, Savic S, Hambleton S.
      Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied three children with an immunodysregulatory syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity and lymphoma of either B- (n=2) or T-cell (n=1) origin. All three showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole exome sequencing, we identified rare, homozygous, germline missense or nonsense variants in a known epigenetic regulator of gene expression, Ten-Eleven Translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was either absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole blood DNA hypermethylation. Circulating T-cells showed an abnormal immunophenotype including expanded double-negative but depleted follicular helper T-cell compartments, and impaired Fas-dependent apoptosis in 2/3 patients. Moreover, TET2 deficientB-cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced-pluripotent stem cells was skewed towards the myeloid lineage. These are the first reported cases of autosomal recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.
    DOI:  https://doi.org/10.1182/blood.2020005844
  3. J Transl Med. 2020 Jun 10. 18(1): 232
    A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection.
    Velázquez C, Lastra E, Avila Cobos F, Abella L, de la Cruz V, Hernando BA, Hernández L, Martínez N, Infante M, Durán M.
      BACKGROUND: In the context of our Regional Program of Hereditary Cancer, individuals fulfilling the criteria are tested for germline mutations to subsequently establish the clinical management. Our standard diagnostic approach focuses on sequencing a few classic high-risk genes, a method that frequently renders uninformative genetic results. This study aims to examine the improved yield offered by an On-Demand panel.METHODS: We designed an On-Demand panel for the analysis of 35-genes associated with inherited cancer susceptibility in a total of 128 cases of Hereditary Breast and Ovarian Cancer (HBOC) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC).
    RESULTS: Eighteen deleterious mutations were detected, in both routinely (BRCA2, MLH1, MSH2, PMS2) and non-routinely (ATM, BLM, BRIP1, CHEK2, MUTYH) tested genes. The screening extended to 35 genes rendered by patients carrying several- up to 6-Variants of Unknown Significance (VUS). Moreover, we confirmed the splicing disruption at RNA level for a not previously reported BRIP1 splicing mutation. Using an On-Demand panel, we identified 18 pathogenic mutation carriers, seven of which would have gone unnoticed with traditional analysis.
    CONCLUSIONS: Our results reinforce the utility of NGS gene panels in the diagnostic routine to increase the performance of genetic testing, especially in individuals from families with overlapping cancer phenotypes.
    Keywords:  Genetic counselling; Germline mutation; Hereditary Cancer syndrome; Next generation sequencing; On-Demand gene panel
    DOI:  https://doi.org/10.1186/s12967-020-02391-z
  4. Semin Oncol. 2020 May 26. pii: S0093-7754(20)30047-6. [Epub ahead of print]
    Updates in hereditary breast cancer genetic testing and practical high risk breast management in gene carriers.
    Pederson HJ, Noss R.
      Testing for hereditary predisposition to breast cancer is rapidly expanding in parallel with the emerging field of molecular genetics given the associated implications for screening, risk reduction and cancer therapeutics for identified gene mutation carriers. With the advent of next generation multigene panel testing for hereditary predisposition and decreasing cost for that testing, more breast cancer patients (and unaffected family members) are undergoing cancer genetic testing. With multiple genes being tested and the myriad of possible results and implications for patients and their families, the process of genetic counseling is of paramount importance in promoting understanding by both patients and providers of risks and options for risk management. Guidelines exist to facilitate a multidisciplinary approach to management of individuals identified as being at increased risk, and there must be an appreciation for flexibility as guidelines are applied to individual families. This update summarizes recommendations regarding who may benefit from breast cancer risk assessment and genetic counseling, controversies regarding inclusion for testing and provides a framework for the practical management of high risk gene carriers.
    Keywords:  Breast cancer risk assessment and risk reduction; Genetic counseling and testing; Hereditary cancer; Next generation multi-gene panel testing
    DOI:  https://doi.org/10.1053/j.seminoncol.2020.05.008
  5. Int J Cancer. 2020 Jun 08.
    Evaluation of yield and experiences of age-related molecular investigation for heritable and nonheritable causes of mismatch repair deficient colorectal cancer to identify Lynch syndrome.
    Vos JR, Fakkert IE, Spruijt L, Willems RW, Langenveld S, Mensenkamp AR, Leter EM, Nagtegaal ID, Ligtenberg MJL, Hoogerbrugge N, .
      Universal mismatch repair deficiency (dMMR) testing of colorectal cancer (CRC) is promoted as routine diagnostics to prescreen for Lynch syndrome. We evaluated the yield and experience of age-related molecular investigation for heritable and nonheritable causes of dMMR in CRC below age 70 to identify Lynch Syndrome. In a prospective cohort of 3602 newly diagnosed CRCs below age 70 from 19 hospitals, dMMR, MLH1 promoter hypermethylation, germline MMR gene and somatic MMR gene testing was assessed in daily practice. Yield was evaluated using data from the Dutch Pathology Registry (PALGA) and two regional genetic centers. Experiences of clinicians were evaluated through questionnaires. Participating clinicians were overwhelmingly positive about the clinical workflow. Pathologists routinely applied dMMR-testing in 84% CRCs and determined 10% was dMMR, largely due to somatic MLH1 hypermethylation (66%). Of those, 69% with dMMR CRC below age 70 without hypermethylation were referred for genetic testing, of which 55% was due to Lynch syndrome (hereditary) and 43% to somatic biallelic pathogenic MMR (nonhereditary). The prevalence of Lynch syndrome was 18% in CRC < 40, 1.7% in CRC age 40-64 and 0.7% in CRC age 65-69. Age 65-69 represents most cases with dMMR, in which dMMR due to somatic causes (13%) is 20 times more prevalent than Lynch syndrome. In conclusion, up to age 65 routine diagnostics of (non-)heritable causes of dMMR CRCs effectively identifies Lynch syndrome and reduces Lynch-like diagnoses. Above age 64, the effort to detect one Lynch syndrome patient in dMMR CRC is high and germline testing rarely needed.
    Keywords:  Lynch syndrome; colorectal cancer; germline mutation; mismatch repair deficiency; somatic mutation
    DOI:  https://doi.org/10.1002/ijc.33117
  6. Gynecol Oncol Rep. 2020 Aug;33 100582
    BRCA immunohistochemistry for screening of BRCA mutation in epithelial ovarian cancer patients.
    Manchana T, Tantbirojn P, Pohthipornthawat N.
      To evaluate BRCA1/2 immunohistochemistry (IHC) as a screening test for germline BRCA1/2 in epithelial ovarian cancer (EOC), tumor tissue from 105 EOC patients who had germline BRCA mutations, including 9 BRCA1 mutations, 6 BRCA2 mutations and 90 no BRCA mutations, were studied. Paraffin-embedded tissue blocks were stained for BRCA1 and BRCA2. Tumors were indicated as a loss of BRCA expression when neoplastic nuclear stained less than 10%. Loss of BRCA1 and/or BRCA2 expression was found in 36 patients (34.3%). BRCA1 IHC loss was found in 21 patients (20%) while 24 patients (22.9%) had BRCA2 IHC loss. There were no significant differences in patient characteristics between both groups. Loss of BRCA1 expression had 66.7% sensitivity, 84.3% specificity, 28.6% positive predictive value (PPV), and 96.4% negative predictive value (NPV) for detection of germline BRCA1 mutation. Meanwhile, loss of BRCA2 expression had 50% sensitivity, 78.8% specificity, 12.5% PPV, and 96.3% NPV for detection of germline BRCA2 mutation. There was no significant difference in survival outcomes between both groups. Based on high NPV, BRCA IHC may be useful to exclude patients without BRCA dysfunction if IHC showed intact expression. Only patients with BRCA IHC loss should be offered further genetic testing.
    Keywords:  BRCA mutation; Immunohistochemistry; Ovarian cancer
    DOI:  https://doi.org/10.1016/j.gore.2020.100582
  7. J Clin Oncol. 2020 Jun 09. JCO2000046
    Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019.
    Giri VN, Knudsen KE, Kelly WK, Cheng HH, Cooney KA, Cookson MS, Dahut W, Weissman S, Soule HR, Petrylak DP, Dicker AP, AlDubayan SH, Toland AE, Pritchard CC, Pettaway CA, Daly MB, Mohler JL, Parsons JK, Carroll PR, Pilarski R, Blanco A, Woodson A, Rahm A, Taplin ME, Polascik TJ, Helfand BT, Hyatt C, Morgans AK, Feng F, Mullane M, Powers J, Concepcion R, Lin DW, Wender R, Mark JR, Costello A, Burnett AL, Sartor O, Isaacs WB, Xu J, Weitzel J, Andriole GL, Beltran H, Briganti A, Byrne L, Calvaresi A, Chandrasekar T, Chen DYT, Den RB, Dobi A, Crawford ED, Eastham J, Eggener S, Freedman ML, Garnick M, Gomella PT, Handley N, Hurwitz MD, Izes J, Karnes RJ, Lallas C, Languino L, Loeb S, Lopez AM, Loughlin KR, Lu-Yao G, Malkowicz SB, Mann M, Mille P, Miner MM, Morgan T, Moreno J, Mucci L, Myers RE, Nielsen SM, O'Neil B, Pinover W, Pinto P, Poage W, Raj GV, Rebbeck TR, Ryan C, Sandler H, Schiewer M, Scott EMD, Szymaniak B, Tester W, Trabulsi EJ, Vapiwala N, Yu EY, Zeigler-Johnson C, Gomella LG.
      PURPOSE: Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services.METHODS: A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider).
    RESULTS: Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches.
    CONCLUSION: This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.
    DOI:  https://doi.org/10.1200/JCO.20.00046
  8. Exp Mol Pathol. 2020 Jun 09. pii: S0014-4800(20)30404-4. [Epub ahead of print] 104483
    Validation of a next generation sequencing assay for BRCA1, BRCA2, CHEK2 and PALB2 genetic testing.
    Sim WC, Lee CY, Richards R, Karolien B, Mottier V, Goh LL.
      BRCA1, BRCA2, CHEK2 and PALB2 genes are associated with hereditary breast and ovarian cancer syndrome. Genetic testing of these genes is of increasing importance to guide therapeutic and management decisions. In this study, we evaluated the performance of a next generation sequencing (NGS) assay for the complete analysis of BRCA1, BRCA2, CHEK2 and PALB2 genes using Agilent's SureMASTR BRCA Screen that enabled the detection of single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variations (CNVs) in a single-tube PCR based library preparation. The results showed 100% sensitivity and specificity on a set of 52 known samples from de-identified patients and external quality assessment program. A concordance rate of 87.5% was achieved in the comparison of variant classification with the external laboratories. The high accuracy of the assay supports the use of SureMASTR BRCA Screen in clinical diagnostic laboratories (SureMASTR BRCA Screen is for research use only, not for use in diagnostic procedures).
    Keywords:  ACMG guidelines; Hereditary breast and ovarian cancer syndrome; NGS sequencing
    DOI:  https://doi.org/10.1016/j.yexmp.2020.104483
  9. Blood Rev. 2020 May 29. pii: S0268-960X(20)30060-6. [Epub ahead of print] 100710
    Germline genetic factors in the pathogenesis of myeloproliferative neoplasms.
    Bellanné-Chantelot C, Rabadan Moraes G, Schmaltz-Panneau B, Marty C, Vainchenker W, Plo I.
      Myeloproliferative neoplasms (MPN) are clonal hematological malignancies that lead to overproduction of mature myeloid cells. They are due to acquired mutations in genes encoding for AK2, MPL and CALR that result in the activation of the cytokine receptor/JAK2 signaling pathway. In addition, it exists germline variants that can favor the initiation of the disease or may affect its phenotype. First, they can be common risk alleles, which correspond to frequent single nucleotide variants present in control population and that contribute to the development of either sporadic or familial MPN. Second, some variants predispose to the onset of MPN with a higher penetrance and lead to familial clustering of MPN. Finally, some extremely rare genetic variants can induce MPN-like hereditary disease. We will review these different subtypes of germline genetic variants and discuss how they impact the initiation and/or development of the MPN disease.
    Keywords:  CNV; Germline variants; Risk allele; SNV; Sporadic and familial MPN
    DOI:  https://doi.org/10.1016/j.blre.2020.100710
  10. Clin J Gastroenterol. 2020 Jun 09.
    Double small bowel cancers leading to the diagnosis of Lynch syndrome with germline MSH6 mutation in an elderly patient.
    Ohwada S, Yamashita K, Kazama T, Mitsuhashi K, Ichiyanagi A, Nakachi K, Yamano HO, Nobuoka T, Ito T, Sasao W, Nakase H.
      A female patient in her 80s was referred to our hospital because of an ileal tumor identified by capsule endoscopy. FDG-PET suggested double intestinal tumors not only in the ileum but also in the jejunum. The patient has cancer past history including sigmoid colon, rectum, and endometrium, and also had cancer family history fulfilling the revised Amsterdam criteria. Double balloon enteroscopy disclosed two ulcerated tumors in the jejunum and the ileum. Biopsy was diagnosed as adenocarcinoma pathologically, and microsatellite instability-high (MSI-H) genetically. Surgical resection was performed, and the jejunal and the ileal tumors were tubular (T2N0M0) and mucinous adenocarcinoma (T4N0M0), respectively. Germline mutation analysis revealed a pathogenic splice-site mutation in MSH6.
    Keywords:  Capsule endoscopy; Lynch syndrome; Small bowel cancer
    DOI:  https://doi.org/10.1007/s12328-020-01147-y
  11. Cold Spring Harb Mol Case Stud. 2020 Jun;pii: a004853. [Epub ahead of print]6(3):
    Case report for an adolescent with germline RET mutation and alveolar rhabdomyosarcoma.
    Crawford KA, Berlow NE, Tsay J, Lazich M, Mancini M, Noakes C, Huang T, Keller C.
      In this case report we evaluate the genetics of and scientific basis of therapeutic options for a 14-yr-old male patient diagnosed with metastatic PAX3-FOXO1 fusion positive alveolar rhabdomyosarcoma. A distinguishing genetic feature of this patient was a germline RET C634F mutation, which is a known driver of multiple endocrine neoplasia type 2A (MEN2A) cancer. Through sequential DNA and RNA sequencing analyses over the patient's clinical course, a set of gene mutations, amplifications, and overexpressed genes were identified and biological hypotheses generated to explore the biology of RET and coexisting signaling pathways in rhabdomyosarcoma. Somatic genetic abnormalities identified include CDK4 amplification and FGFR4 G388R polymorphism. Because of the initial lack of patient-derived primary cell cultures, these hypotheses were evaluated using several approaches including western blot analysis and pharmacological evaluation with molecularly similar alveolar rhabdomyosarcoma cell lines. Once a primary cell culture became available, the RET inhibitor cabozantinib was tested but showed no appreciable efficacy in vitro, affirming with the western blot negative for RET protein expression that RET germline mutation could be only incidental. In parallel, the patient was treated with cabozantinib without definitive clinical benefit. Parallel chemical screens identified PI3K and HSP90 as potential tumor-specific biological features. Inhibitors of PI3K and HSP90 were further validated in drug combination synergy experiments and shown to be synergistic in the patient-derived culture. We also evaluated the use of JAK/STAT pathway inhibitors in the context of rhabdomyosarcomas bearing the FGFR4 G388R coding variant. Although the patient succumbed to his disease, study of the patient's tumor has generated insights into the biology of RET and other targets in rhabdomyosarcoma.
    Keywords:  alveolar rhabdomyosarcoma
    DOI:  https://doi.org/10.1101/mcs.a004853
  12. Leuk Res. 2020 May 24. pii: S0145-2126(20)30091-6. [Epub ahead of print]95 106386
    Strategy for identification of a potential inherited leukemia predisposition in a 299 patient's cohort with tumor-only sequencing data.
    Aguilera-Diaz A, Larrayoz MJ, Palomino-Echeverría S, Vazquez I, Ariceta B, Mañú A, Blasco-Iturri Z, Bernal Del Castillo T, Olivares Salaverri M, Olave Rubio MT, Rifon-Roca J, Alfonso-Pierola A, Prosper F, Fernandez-Mercado M, Calasanz MJ.
      Myeloid neoplasms (MN) are usually sporadic late-onset cancers; nevertheless, growing evidence suggests that ∼5% of the cases could emerge as a consequence of inherited predisposition. Distinguishing somatic from germline variants is of vital importance, in order to establish an appropriate individualized management and counsel the patients and their relatives. Since many of the genes associated with myeloid neoplasm germline predisposition (MNGP) are also affected in sporadic MN, we intended to design a strategy to identify potentially inherited variants in a tumor only NGS panel in a cohort of 299 patients with a variety of MN. We considered as indicative of potential inherited origin, variants detected in BM sample at a ∼50% VAF classified as pathogenic, likely pathogenic or of unknown significance detected in MNGP-related genes. A total of 104 suspicious variants from 90 patients were filtered-in in tumor samples. Mutational patterns, follow-up data, and sequencing of a range of non-myeloid tissues were used for narrowing down the list of suspicious variants, and ultimately discriminate their nature. Our data supports the importance of considering variants found upon tumor-only sequencing as potentially of germline origin, and we offer a pipeline to define the nature of the variants.
    Keywords:  Genetic counseling; Germline; Myeloid; Myeloid neoplasms predisposition; NGS
    DOI:  https://doi.org/10.1016/j.leukres.2020.106386
  13. Therap Adv Gastroenterol. 2020 ;13 1756284820916399
    Inherited CDH1 pathogenic variant: is there a place for surveillance of esophageal gastric inlet patch?
    Leclercq P, Jadot V, Bours V, Oliveira C, Neumann H, Bisschops R.
      
    Keywords:  CDH1; Hereditary diffuse gastric cancer; Signet ring cell carcinoma
    DOI:  https://doi.org/10.1177/1756284820916399
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