bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒02‒14
fourteen papers selected by
Joanna Zawacka-Pankau
University of Warsaw

  1. Cancers (Basel). 2021 Jan 25. pii: 447. [Epub ahead of print]13(3):
    Baughan S, Tainsky MA.
      Whole genome analysis and the search for mutations in germline and tumor DNAs is becoming a major tool in the evaluation of risk as well as the management of hereditary cancer syndromes. Because of the identification of cancer predisposition gene panels, thousands of such variants have been catalogued yet many remain unclassified, presenting a clinical challenge for the management of hereditary cancer syndromes. Although algorithms exist to estimate the likelihood of a variant being deleterious, these tools are rarely used for clinical decision-making. Here, we review the progress in classifying K3326X, a rare truncating variant on the C-terminus of BRCA2 and review recent literature on other novel single nucleotide polymorphisms, SNPs, on the C-terminus of the protein, defined in this review as the portion after the final BRC repeat (amino acids 2058-3418).
    Keywords:  BRCA2; HBOC; HBOPC; K33326X; hereditary breast and ovarian cancer syndrome; hereditary breast ovarian and pancreatic cancer syndrome
  2. Int J Gynecol Pathol. 2021 Feb 11.
    Kurpiel B, Thomas MS, Mubeen M, Ring KL, Modesitt SC, Moskaluk CA, Mills AM.
      MLH1/PMS2 loss due to epigenetic hypermethylation of the MLH1 promoter is the most common cause of mismatch repair deficiency in endometrial carcinoma, and typically provides reassurance against an associated germline mutation. To further characterize the genetic features of MLH1/PMS2-deficient endometrial cancers, the departmental database was searched for cases with dual MLH1/PMS2 loss and retained MSH2/6 expression which underwent MLH1 hypermethylation testing. Genetic testing results were obtained when available. One hundred seventeen endometrial cancers met inclusion criteria: 100 (85%) were MLH1-hypermethylated, 3 (3%) were low-level/borderline, 7 (6%) were nonmethylated, and 7 (6%) were insufficient for testing. Sixteen cases (12 MLH1-hypermethylated, 3 nonmethylated, and 1 insufficient for testing) underwent germline testing, 6 of which (37.5%) demonstrated germline variants of unknown significance (VUS) (MSH6, PMS2, POLD1, BRIP1, RAD51D, CHEK2) but no known deleterious mutations. Notably, however, the patients harboring the MSH6 and PMS2 germline VUS had clinical features concerning for Lynch syndrome. One nonmethylated, germline-normal case underwent somatic tumor testing, and demonstrated a somatic MLH1 mutation. In summary, MLH1-hypermethylation accounts for the vast majority of MLH1/PMS2-deficient cancers in a universally screened population, although MLH1 somatic and germline mutations can occur. Occasionally, patients with MLH1-hypermethlated tumors also bear germline VUS in other mismatch repair genes as well as genes implicated in other hereditary cancer syndromes, but their clinical relevance is unclear. Family and personal cancer histories must always be evaluated to determine the need for germline testing in women with loss of MLH1/PMS2, even in the setting of hypermethylation.
  3. Hered Cancer Clin Pract. 2021 Feb 12. 19(1): 18
    Bernstedt SW, Björk J, Fritzell K, Spigelman AD, Björck E, Backman AS.
      BACKGROUND: Lynch syndrome is caused by germline mutations in the mismatch repair genes and is characterised by a familial accumulation of colorectal and other cancers. Earlier identification of Lynch syndrome patients enables surveillance and might reduce the risk of cancer. It is important to explore whether today's clinical care discovers patients with Lynch syndrome suitable for surveillance in time. This study aimed to describe what led to a diagnosis of Lynch syndrome in the cohort referred to the Hereditary Gastrointestinal Cancer Unit, Karolinska University Hospital, Solna, Sweden for gastrointestinal surveillance.METHODS: This was a descriptive study. Data from 1975 to 2018 were collected and compiled as a database. Age at diagnosis was calculated from the date when a pathogenic MMR gene mutation was confirmed, from the period June 1994-September 2018. Data were collected from patient protocols prospectively during patient consultations and medical records retrospectively. Criteria for inclusion were registration at the outpatient clinic and a confirmed mismatch repair gene mutation.
    RESULTS: A total of 305 patients were eligible for inclusion. Three major reasons for diagnosis were identified: 1. Predictive testing of a previously known mutation in the family (62%, mean age 37), 2. A family history of Lynch associated tumours (9%, mean age 37), 3. A diagnosis of cancer (29%, mean age 51). The proportion diagnosed due to cancer has not changed over time.
    CONCLUSION: A high proportion of patients (29%) were identified with Lynch syndrome after they had been diagnosed with an associated cancer, which suggests that there is significant room for improvement in the diagnosis of patients with Lynch syndrome before cancer develops.
    Keywords:  Cancer prevention; Colorectal cancer; Genetic testing; Lynch syndrome; Mismatch repair genes
  4. Front Oncol. 2020 ;10 614541
    Caroleo AM, De Ioris MA, Boccuto L, Alessi I, Del Baldo G, Cacchione A, Agolini E, Rinelli M, Serra A, Carai A, Mastronuzzi A.
      DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the DICER1 gene. The risk to present a neoplasm before the age of 10 years is 5.3 and 31.5% before the age of 60. DICER1 variants have been associated with a syndrome involving familial pleuropulmonary blastoma (PPB), a rare malignant tumor of the lung, which occurs primarily in children under the age of 6 years and represents the most common life-threatening manifestation of DICER1 syndrome. Type I, II, III, and Ir (type I regressed) PPB are reported with a 5-year overall survival ranging from 53 to 100% (for type Ir). DICER1 gene should be screened in all patients with PPB and considered in other tumors mainly in thyroid neoplasms (multinodular goiter, thyroid cancer, adenomas), ovarian tumors (Sertoli-Leydig cell tumor, sarcoma, and gynandroblastoma), and cystic nephroma. A prompt identification of this syndrome is necessary to plan a correct follow-up and screening during lifetime.
    Keywords:  DICER1; PPB; cancer predisposition; cystic nephroma; pediatric
  5. Blood Adv. 2021 Jan 12. 5(1): 216-223
    Vasta LM, Khan NE, Higgs CP, Harney LA, Carr AG, Harris AK, Schultz KAP, McMaster ML, Stewart DR.
      Pathogenic germline variants in DICER1 underlie an autosomal dominant, pleiotropic tumor-predisposition disorder. Murine models with the loss of DICER1 in hematopoietic stem cell progenitors demonstrate hematologic aberrations that include reductions in red and white blood cell counts, hemoglobin volume, and impaired maturation resulting in dysplasia. We investigated whether hematologic abnormalities such as those observed in DICER1-deficient mice were observed in humans with a pathogenic germline variant in DICER1. A natural history study of individuals with germline pathogenic DICER1 variants and family controls conducted through the National Cancer Institute (NCI) evaluated enrollees at the National Institutes of Health Clinical Center during a comprehensive clinical outpatient visit that included collecting routine clinical laboratory studies. These were compared against normative laboratory values and compared between the DICER1 carriers and controls. There were no statistical differences in routine clinical hematology laboratory studies observed in DICER1 carriers and family controls. A review of the medical history of DICER1 carriers showed that none of the individuals in the NCI cohort developed myelodysplastic syndrome or leukemia. Query of the International Pleuropulmonary Blastoma/DICER1 Registry revealed 1 DICER1 carrier who developed a secondary leukemia after treatment of pleuropulmonary blastoma. We found limited evidence that the hematologic abnormalities observed in murine DICER1 models developed in our cohort of DICER1 carriers. In addition, no cases of myelodysplastic syndrome were observed in either the NCI cohort or the International Pleuropulmonary Blastoma/DICER1 Registry; 1 case of presumed secondary leukemia was reported. Abnormalities in hematologic indices should not be solely attributed to DICER1. This trial was registered at as #NCT01247597.
  6. Hum Mutat. 2021 Feb 10.
    Li H, Liu S, Wang S, Zeng Q, Chen Y, Fang T, Zhang Y, Zhou Y, Zhang Y, Wang K, Yan Z, Qiang C, Xu M, Chai X, Yuan Y, Huang M, Zhang H, Xiong Y.
      Cancer is one of the most important health issues globally and the accuracy of interpretation of cancer-related variants is critical for the clinical management of hereditary cancer. ClinGen Sequence Variant Interpretation (SVI) Working Groups have developed many adaptations of ACMG-AMP guidelines to improve the consistency of interpretation. We combined the most recent adaptations to expand the number of the criteria from 28 to 48 and developed a tool called Cancer SIGVAR to help genetic counselors interpret the clinical significance of cancer germline variants. Our tool can accept VCF files as input and realize fully automated interpretation based on 21 criteria and semi-automated interpretation based on 48 criteria. We validated the performance of our tool with the ClinVar and CLINVITAE benchmark databases, achieving an average consistency for pathogenic and benign assessment up to 93.71% and 79.38%, respectively. We compared Cancer SIGVAR with two similar tools, InterVar and PathoMAN, and analyzed the main differences in criteria and implementation. Furthermore, we selected 911 variants from another two in-house benchmark databases and semi-automated interpretation reached an average classification consistency of 98.35%. Our findings highlight the need to optimize automated interpretation tools based on constantly updated guidelines. Cancer SIGVAR is publicly available at This article is protected by copyright. All rights reserved.
    Keywords:  ACMG-AMP guidelines; ClinGen Sequence Variant Interpretation; automated interpretation; hereditary cancer; variant
  7. J Med Genet. 2021 Feb 09. pii: jmedgenet-2020-107230. [Epub ahead of print]
    Jiang W, Li L, Ke CF, Wang W, Xiao BY, Kong LH, Tang JH, Li Y, Wu XD, Hu Y, Guo WH, Wang SZ, Wan DS, Xu RH, Pan ZZ, Ding PR.
      PURPOSE: Universal germline testing in patients with colorectal cancer (CRC) with a multigene panel can detect various hereditary cancer syndromes. This study was performed to understand how to choose a testing panel and whether the result would affect clinical management.METHODS: We prospectively enrolled 486 eligible patients with CRC, including all patients with CRC diagnosed under age 70 years and patients with CRC diagnosed over 70 years with hereditary risk features between November 2017 and January 2018. All participants received germline testing for various hereditary cancer syndromes.
    RESULTS: The prevalence of germline pathogenic variants (PVs) in cancer susceptibility genes was 7.8% (38/486), including 25 PVs in genes with high-risk CRC susceptibility (the minimal testing set) and 13 PVs in genes with moderate-risk CRC susceptibility or increased cancer risk other than CRC (the additional testing set). All the clinically relevant PVs were found in patients diagnosed under age 70 years. Among them, 11 patients would not have been diagnosed if testing reserved to present guidelines. Most (36/38) of the patients with PVs benefited from enhanced surveillance and tailored treatment. PVs in genes from the minimal testing set were found in all age groups, while patients carried PVs in genes from the additional testing set were older than 40 years.
    CONCLUSION: Universal germline testing for cancer susceptibility genes should be recommended among all patients with CRC diagnosed under age 70 years. A broad panel including genes from the additional testing set might be considered for patients with CRC older than 40 years to clarify inheritance risks.
    Keywords:  and neonatal diseases and abnormalities; congenital; gastroenterology; genetic carrier screening; genetic counseling; hereditary
  8. NPJ Genom Med. 2020 Mar 23. 5(1): 12
    Tesch ME, Pater JA, Vandekerkhove G, Wang G, Binnington K, So AI, Wyatt AW, Eigl BJ.
      Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (TPDS). BAP1 TPDS is associated with an increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma, and several other cancer subtypes. Here, we report a germline nonsense BAP1 variant (c.850G>T, p.Glu284Ter) in a patient with bladder cancer and a strong family history of malignancy. Concurrently, we identified a somatic frameshift BAP1 variant, and as expected, immunostaining validated the loss of BAP1 protein in patient-derived tumor specimens. Together, these data provide strong evidence of pathogenicity in this case. With the addition of bladder cancer to the tumor types reported with germline BAP1 mutations, our understanding of the BAP1 TPDS continues to evolve, and may affect future screening and surveillance guidelines.
  9. Cancer Genet. 2021 Jan 20. pii: S2210-7762(21)00008-9. [Epub ahead of print]254-255 18-24
    Norris GA, Tsai AC, Schneider KW, Wu YH, Caulfield T, Green AL.
      CBL is a mammalian gene encoding the protein CBL, which is an E3 ubiquitin-protein ligase involved in cell signaling and protein ubiquitination. Pathogenic variants in this gene have been implicated in a number of human cancers, particularly acute myeloid leukemia (AML). Here, we present a 5-year-old male patient with a history of AML, diffuse midline glioma, and left brain lesion with histiocytic features. A variant of uncertain significance (VUS): p.L493F was detected in his CBL gene via clinical evaluation. Protein modeling predicts this variant to be pathogenic. Details of the clinical evaluation and modeling assay are discussed.
    Keywords:  Acute myeloid leukemia; CBL; Cancer; Cancer predisposition; Cell signaling; Diffuse midline glioma; Germline; Protein modeling; Protein ubiquitination; Variant
  10. Hered Cancer Clin Pract. 2021 Feb 09. 19(1): 17
    Akhtar S, Rauf MS, Al-Kofide A, Elshenawy MA, Mushtaq AH, Maghfoor I.
      BACKGROUND: Familial clustering of lymphoid and/or hematological malignancies (FHM) provides an opportunity to study the responsible genes. The data is limited in patients with lymphoid and hematological malignancies.METHODS: The lymphoma database was used to identify patients seen in our institution from 1998 to 2019 with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). We studied FHM by collecting detailed history of any malignancy in the family (FM).
    RESULTS: Two hundred NLPHL patients were identified. Contacting was not possible in 30 patients due to no response to the phone calls (22) and death [1]. 170/200 patients were interviewed; represented 167 families (3 patients with a family member with NLPHL). These 170 patients provided information about 8225 family members. These 167 families had a total of 329 family members with 334 malignancies (including 167 NLPHL patients and 5 members with 2 malignancies each). Of these 167 patients, 77 (46.1%) had no FM while 90 (53.9%) patients had a positive FM; 162 family members with 167 malignancies. Among these 167 families, 31 families (18.6%) had members with FHM +/- solid cancers. These 31 families had 35 family members (25 males:10 females) with 16 lymphomas: diffuse large B cell lymphoma [2], follicular center cell lymphoma [3], chronic lymphocytic leukemia/small lymphocytic lymphoma [3], non-Hodgkin lymphoma [2], classical HL [2], and NLPHL [4]. Total of 8 leukemia: acute lymphoblastic leukemia [4], acute myeloid leukemia [3], and leukemia - no subtyping [5]. These 35 FHM members are 1st [6], 2nd (16), and 3rd [7] degree relatives of 31 NLPHL patients. There are 4 families with NLPHL in family members; all these 8 NLPHL patients are male and are alive. The median total number of 1st + 2nd +3rd degree members are 81. The decrease in the age of diagnosis from 1st generation to the 2nd generation (anticipation) was noted in 13/17 patients; 2nd generation median age at diagnosis was 29.7 years vs 1st generation age 53 years (developed malignancy 23.3 years earlier).
    CONCLUSION: FHM is frequent in NLPHL. This study provided us many important insights for planning future studies in terms of interviewing technique, time, and resource allocation and genetic testing.
    Keywords:  Familial hematological malignancy; Familial lymphoma; Familial malignancy; Hereditary malignancy; Hodgkin lymphoma; Nodular lymphocyte-predominant Hodgkin lymphoma
  11. Eur J Cancer. 2021 Feb 09. pii: S0959-8049(20)31448-9. [Epub ahead of print]146 30-47
    Pujol P, Barberis M, Beer P, Friedman E, Piulats JM, Capoluongo ED, Garcia Foncillas J, Ray-Coquard I, Penault-Llorca F, Foulkes WD, Turnbull C, Hanson H, Narod S, Arun BK, Aapro MS, Mandel JL, Normanno N, Lambrechts D, Vergote I, Anahory M, Baertschi B, Baudry K, Bignon YJ, Bollet M, Corsini C, Cussenot O, De la Motte Rouge T, Duboys de Labarre M, Duchamp F, Duriez C, Fizazi K, Galibert V, Gladieff L, Gligorov J, Hammel P, Imbert-Bouteille M, Jacot W, Kogut-Kubiak T, Lamy PJ, Nambot S, Neuzillet Y, Olschwang S, Rebillard X, Rey JM, Rideau C, Spano JP, Thomas F, Treilleux I, Vandromme M, Vendrell J, Vintraud M, Zarca D, Hughes KS, Alés Martínez JE.
      BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices.
    Keywords:  BRCA-related cancer; BRCA1 and BRCA2 testing; Guidelines; PARP inhibitors
  12. NPJ Breast Cancer. 2020 Jul 24. 6(1): 31
    Kuemmel S, Harrach H, Schmutzler RK, Kostara A, Ziegler-Löhr K, Dyson MH, Chiari O, Reinisch M.
      There is a strong biologic rationale that poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors may benefit a broader range of metastatic breast cancer (MBC) patients than covered by current approvals, which require a germline BRCA1/2 sequence variant affecting function. We report a patient with germline/somatic BRCA1/2 wild-type MBC, who had a dramatic response to the PARP inhibitor olaparib of at least 8 months' duration. The patient is a 37-year-old woman with recurrent, hormone receptor-positive, HER2-negative MBC that had progressed despite hormonal therapy and palbociclib. Sensitivity to olaparib was likely conferred by a germline sequence variant affecting function in PALB2 (exon 1, c.18G>T, p.(=)). This case documenting activity of olaparib monotherapy in germline/somatic BRCA1/2 wild-type MBC illustrates that the clinical potential of PARP inhibition in MBC extends beyond currently approved indications to additional patients whose tumors have (epi)genetic changes affecting homologous recombination repair.
  13. Cancer Res. 2021 Feb 08. pii: canres.0177.2020. [Epub ahead of print]
    Zhang P, Kitchen-Smith I, Xiong L, Stracquadanio G, Brown K, Richter PH, Wallace MD, Bond E, Sahgal N, Moore S, Nornes S, De Val S, Surakhy M, Sims D, Wang X, Bell DA, Zeron-Medina J, Jiang Y, Ryan AJ, Selfe JL, Shipley J, Kar S, Pharoah PDP, Loveday C, Jansen R, Grochola LF, Palles C, Protheroe A, Millar V, Ebner DV, Pagadala M, Blagden SP, Maughan TS, Domingo E, Tomlinson I, Turnbull C, Carter H, Bond GL.
      Insights into oncogenesis derived from cancer susceptibility loci (single nucleotide polymorphisms, SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, while both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic TP53 mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of pro-survival p53 target gene KITLG and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacological inhibition of the pro-survival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies.