bims-lifras Biomed News
on Li-Fraumeni Syndrome
Issue of 2020‒01‒05
sixteen papers selected by
Joanna Zawacka-Pankau



  1. Clin Transl Oncol. 2019 Dec 30.
    González-Santiago S, Ramón Y Cajal T, Aguirre E, Alés-Martínez JE, Andrés R, Balmaña J, Graña B, Herrero A, Llort G, González-Del-Alba A, .
      Mutations in BRCA1 and BRCA2 high penetrance genes account for most hereditary breast and ovarian cancer, although other new high-moderate penetrance genes included in multigene panels have increased the genetic diagnosis of hereditary breast and ovarian cancer families by 50%. Multigene cancer panels provide new challenges related to increased frequency of variants of uncertain significance, new gene-specific cancer risk assessments, and clinical recommendations for carriers of mutations of new genes. Although clinical criteria for genetic testing continue to be largely based on personal and family history with around a 10% detection rate, broader criteria are being applied with a lower threshold for detecting mutations when there are therapeutic implications for patients with breast or ovarian cancer. In this regard, new models of genetic counselling and testing are being implemented following the registration of PARP inhibitors for individuals who display BRCA mutations. Massive sequencing techniques in tumor tissue is also driving a paradigm shift in genetic testing and potential identification of germline mutations. In this paper, we review the current clinical criteria for genetic testing, as well as surveillance recommendations in healthy carriers, risk reduction surgical options, and new treatment strategies in breast cancer gene-mutated carriers.
    Keywords:  Hereditary breast; Ovarian cancer; SEOM guidelines
    DOI:  https://doi.org/10.1007/s12094-019-02262-0
  2. Hered Cancer Clin Pract. 2019 ;17 32
    Clift KE, Macklin SK, Hines SL.
      Background: Genetic testing for hereditary cancer syndromes has been revolutionized by next-generation sequencing, which allows for simultaneous review of numerous genes. Multigene panels are regularly offered to patients because of their scope and decreased cost and turnaround time. However, many genes included on larger panels have not been studied as extensively as BRCA1 and BRCA2 (BRCA1/2), and their clinical effects are often not as well established.Methods: We identified patients who received positive test results for pathogenic variants of breast cancer genes from January 2012 through May 2018. We mailed a survey and conducted qualitative interviews to explore the personal and health care experiences of patients with pathogenic variants of BRCA1/2 and patients with "other" (ie, non-BRCA1/2 or PALB2; PTEN; ATM; TP53; NBM, RAD51C; MSH6) variants. We compared the experiences of these patients.
    Results: Fifty-nine out of 128 individuals responded to the survey (46%). Thirty-two patients had BRCA1/2 variants, and 27 had other variants. (49 women and 10 men; median [range] age, 63 [34-87] years). We interviewed 21 patients (17 women and 4 men; median [range] age, 59.6 [34-82] years). Of the interview participants, ten patients had BRCA1/2 variants, and 11 had non-BRCA1/2 variants. Patients reported receiving poor information about their genetic test results, and they often educated their physicians about their results. Some patients believed that they had been ignored or "brushed off" by health care professionals because non-BRCA1/2 genes are less understood outside the genetics research community. Patients with BRCA1/2 variants had similar problems with health care providers, despite increased awareness and established guidelines about BRCA1/2.
    Conclusions: Research is required to understand the clinical significance and proper management of diseases attributable to newly characterized hereditary cancer genes. Additional evaluation of patient and provider education should be at the forefront of efforts to improve patient care.
    Keywords:  ATM; Familial cancer; Genetic counseling; Genetic risk; Genetics; Hereditary breast cancer; MSH6; NBM, RAD51C; PALB2; PTEN; Qualitative research; TP53
    DOI:  https://doi.org/10.1186/s13053-019-0132-6
  3. J Breast Cancer. 2019 Dec;22(4): 587-598
    Yoon KH, Chae S, Kang E, Shin HC, Kim JH, Kim IA, Park SY, Kim SW, Kim EK.
      Purpose: We evaluated the risk of contralateral breast cancer (CBC) and ipsilateral breast tumor recurrence (IBTR) and investigated the predictive factors for CBC and IBTR in breast cancer patients with BRCA mutations and non-carriers at high-risk of hereditary breast and ovarian cancer (HBOC).Methods: We analyzed prospectively collected clinical data of patients with unilateral breast cancer who were at high-risk for HBOC and were tested for the BRCA mutation between 2003 and 2013.
    Results: The cohort comprised 540 patients with 45 BRCA1 carriers, 50 BRCA2 carriers, and 445 non-carriers. The median follow-up was 84.5 months. Overall, 61 patients (11.3%) developed CBC (24.4% for BRCA1 carriers, 20% for BRCA2 carriers, and 9% for non-carriers). The 10-year cumulative risk for CBC was 23.8% for BRCA1 carriers, 19.1% for BRCA2 carriers, and 9.8% for non-carriers (p = 0.174). Among the 277 patients who underwent breast-conserving surgery, 29 (10.5%) developed IBTR (9.1% for BRCA1 carriers, 16.7% for BRCA2 carriers, and 10.2% for non-carriers). The 10-year cumulative risk for IBTR for BRCA1 carriers, BRCA2 carriers, and non-carriers was 8.7%, 14.1%, and 20%, respectively (p = 0.577). BRCA1 (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.20-7.20; p = 0.019) and BRCA2 (HR, 2.88; 95% CI, 1.13-7.35; p = 0.027) mutations and negative estrogen receptor status (HR, 4.02; 95% CI, 1.60-10.08; p = 0.003) were the significant predictive factors for CBC, while tumor size ≥ 2 cm was predictive of IBTR (HR, 6.11; 95% CI, 2.03-18.33; p = 0.001).
    Conclusion: While BRCA1/2 mutation carriers had a higher risk of developing CBC compared to non-carriers at high-risk of HBOC, the risk of IBTR was similarly high across breast cancer patients irrespective of the BRCA mutation. Further preventive strategies to reduce CBC and IBTR for all patients at high-risk of HBOC should be investigated.
    Keywords:  Breast neoplasms; Genes, BRCA1; Genes, BRCA2; Hereditary breast and ovarian cancer syndrome; Risk factors
    DOI:  https://doi.org/10.4048/jbc.2019.22.e47
  4. Clin Lung Cancer. 2019 Nov 28. pii: S1525-7304(19)30329-8. [Epub ahead of print]
    Barbosa MVR, Cordeiro de Lima VC, Formiga MN, Andrade de Paula CA, Torrezan GT, Carraro DM.
      
    Keywords:  EGFR mutation; Hereditary cancer; Li-Fraumeni syndrome; Lung adenocarcinoma; p.R337H mutation
    DOI:  https://doi.org/10.1016/j.cllc.2019.11.012
  5. Gynecol Oncol. 2019 Dec 27. pii: S0090-8258(19)31802-5. [Epub ahead of print]
    Jorge S, McFaddin AS, Doll KM, Pennington KP, Norquist BM, Bennett RL, Pritchard CC, Swisher EM.
      OBJECTIVE: Germline and somatic BRCA1 and BRCA2 (BRCA) mutations predict treatment response in patients with epithelial ovarian, peritoneal or fallopian tube cancer (OC), yet only germline testing is routinely pursued or reimbursed at diagnosis. We report our experience with clinical testing of paired tumor and germline DNA for OC mutations.METHODS: Simultaneous sequencing using the BROCA assay of DNA from paired blood and neoplastic tissue became clinically available at our institution in 2017. We retrospectively reviewed the medical records of OC cases tested from 7/2017 to 7/2018. We calculated the rates of known pathogenic germline mutations and actionable somatic mutations, defined as those for which targeted therapies exist.
    RESULTS: We identified 43 women (36 new diagnoses, seven recurrences) who underwent testing. Average age at diagnosis was 60. OC samples came from surgical specimens in 31 cases (72.1%), from biopsy in 11 cases (25.6%), and from cytology in one case (2.3%). We identified pathogenic germline mutations in six cases (14%), actionable somatic mutations in 15 cases (35%), and both a somatic and germline mutation in one case (2%). BRCA mutations accounted for 59% of all mutations. Of 40 cases with sufficient follow-up, providers documented reviewing results of genetic testing in 34 (85%), which influenced clinical decisions in 12 (30%).
    CONCLUSIONS: Simultaneous germline and tumor sequencing is an efficient way to provide enhanced information to guide the care of OC patients. This approach can identify somatic BRCA mutations at diagnosis, allowing physicians to provide PARP inhibitor maintenance and improve outcomes for those patients.
    Keywords:  BRCA; BROCA; Genetic testing; Germline; Ovarian cancer; Somatic
    DOI:  https://doi.org/10.1016/j.ygyno.2019.12.010
  6. Adv Exp Med Biol. 2019 ;1210 279-300
    Arce S, Athie A, Pritchard CC, Mateo J.
      Recent studies have provided a better understanding of the molecular underpinnings of prostate cancer. Alterations in genes encoding for proteins involved in the different pathways in charge of preserving genomic integrity and repairing DNA damage are common in prostate cancer, particularly in late-stage disease. Generally, these alterations would confer a survival advantage for tumors, resulting in a more aggressive phenotype. However, DNA repair defects can also represent a vulnerability for tumors that can be exploited therapeutically, offering the possibility of precision medicine strategies. Moreover, many of these mutations are linked to hereditary risk for cancers; hence, identification of DNA repair mutations could also be relevant for cancer prevention and screening in healthy individuals, including relatives of prostate cancer patients. In this chapter, we summarize current knowledge about the prevalence of different DNA repair gene alterations across different stages of prostate cancer and review the clinical relevance of such events in terms of prognosis and treatment stratification.
    Keywords:  BRCA1; BRCA2; DNA repair; Genomics; Germline; Hereditary cancer; MMR; Mismatch repair; PARP; Precision medicine
    DOI:  https://doi.org/10.1007/978-3-030-32656-2_12
  7. J Genet Couns. 2020 Jan 02.
    Williams D, Vilar E, Shakrukh Hashmi S, Choates M, Noblin S, Mork M.
      Lynch syndrome (LS) is a hereditary cancer predisposition syndrome primarily defined by increased risk for colorectal and uterine cancers. Individuals with germline pathogenic variants in the mismatch repair (MMR) genes (MLH1, MSH2/EPCAM, MSH6, and PMS2) are diagnosed with LS and recommended high-risk screening protocols to increase prevention and early detection of LS-related cancers. Tumor testing can help identify those at high risk for LS, but sometimes creates uncertainty with discordant screening and germline results, or unexplained mismatch repair deficiency (UMMRD). Somatic testing for MMR genes may help resolve UMMRD, potentially clarifying LS status and modifying cancer surveillance. However, guidelines for such testing are currently limited. This survey of cancer genetic counselors (GCs) aimed to examine current versus preferred ordering practices and interpretation of somatic MMR testing results in LS evaluation. Two hundred eligible GCs practicing in the United States and Canada were recruited from the National Society of Genetic Counselors. Participants answered questions regarding ordering practices, barriers to somatic MMR testing, theoretical scenarios, and desire for further guidelines. Statistical analysis was performed using chi-square, Fisher's exact, and Wilcoxon rank-sum tests, while themes were identified from free-text responses. Most respondents did not include somatic MMR testing in the LS work-up, despite three-quarters reporting they were 'somewhat comfortable' or 'extremely comfortable' with interpreting these results. Approximately half of participants indicated interest in ordering concurrent somatic MMR and germline testing for each of the four theoretical scenarios. Over three-quarters of individuals reported barriers to ordering somatic MMR testing, with cost and coordinating tissue samples most commonly cited. The frequently reported laboratory- and insurance-related barriers may contribute to the gap between preferred and current ordering practices for somatic MMR testing. Nearly all respondents endorsed additional guidelines for this testing, which could reduce barriers and inform screening recommendations for patients with UMMRD and their family members.
    Keywords:  Lynch syndrome; Somatic testing; genetic counselors; genetic testing; mismatch repair genes; risk assessment
    DOI:  https://doi.org/10.1002/jgc4.1198
  8. Saudi J Biol Sci. 2020 Jan;27(1): 157-162
    Rasool M, Pushparaj PN, Mirza Z, Imran Naseer M, Abusamra H, Alquaiti M, Shaabad M, Sibiany AMS, Gauthaman K, Al-Qahtani MH, Karim S.
      Lynch syndrome is inherited in an autosomal dominant mode. Lynch syndrome is caused by impairment of one or more of the various genes (most frequently MLH1 and MSH2) involved in mismatch repair. In this study, whole genome comparative genomic hybridization array (array CGH) based genomic analysis was performed on twelve Saudi Lynch syndrome patients. A total of 124 chromosomal alterations (structural loss) were identified at mean log2 ratio cut off value of ±0.25. We also found structural loss in 2p21-p16.3, 3p23-p14.2, 7p22.1 and 1p34.1-p33 regions. These findings were subsequently validated by real time quantitative PCR showing downregulation of MSH2, MSH6, EPCAM, MLH1, PMS2 and MUTYH genes. These findings shall help in establishing database for alterations in mismatch repair genes underlying Lynch syndrome in Saudi population as well as to determine the incidence ratio of these disorders. Guided counselling will subsequently lead to the prevention and eradication of Lynch Syndrome in the local population.
    Keywords:  Familial colorectal cancer; Lynch syndrome; Mismatch repair genes; arrayCGH
    DOI:  https://doi.org/10.1016/j.sjbs.2019.06.012
  9. J Cancer. 2020 ;11(1): 208-212
    Shin S, Kim Y, Lee JK, Lee KA.
      Background: Germline mutations in CDH1 are associated with hereditary and early onset- diffuse gastric cancer. However, the frequency of CDH1 germline mutation in unselected gastric cancer cases is not well established. Aim: The aim of this study was to investigate the frequency and clinical characteristics of germline CDH1 V832M mutation carriers in unselected Korean gastric cancer cases. Methods: Direct sequencing was performed to determine the presence of CDH1 V832M in 305 unselected Korean gastric cancer patients. Lauren's histologic type, family history of gastric cancer, and age of cancer diagnosis were compared between V832M carriers and non-carriers. Results: In the study population, seven gastric cancer patients (7/305, 2.29%) were found to have the CDH1 V832M mutation. The CDH1 V832M mutation carrier state was not significantly associated with phenotypes including Lauren's histologic type, family history of gastric cancer, age of cancer diagnosis, and other cancer history in a patient. Conclusion: This study demonstrates that the germline CDH1 V832M mutation is common in sporadic, late onset, and intestinal type gastric cancer as well as familial, early onset, and diffuse type gastric cancer. Our finding suggests that guidelines for managing CDH1 mutation carriers should be refined through additional data on penetration according to CDH1 mutation type in sporadic cases.
    Keywords:   CDH1; E-cadherin; gastric cancer; germline mutation; hereditary gastric cancer
    DOI:  https://doi.org/10.7150/jca.36513
  10. Hum Mutat. 2020 Jan 03.
    Fortuno C, Pesaran T, Dolinsky J, Yussuf A, McGoldrick K, Goldgar D, James PA, Spurdle AB.
      The ACMG/AMP guidelines for variant classification are widely used for clinical interpretation of gene test results. These guidelines may be specified to genes/syndromes of interest in order to improve their utility in the clinical setting. As part of these specifications, phenotype-related criteria can be detailed and weighted depending on the personal history of disease for a given variant carrier. We investigated how ascertainment can affect the significance and/or weight of patient phenotype as predictor of germline variant pathogenicity, using the Li-Fraumeni Syndrome gene TP53 as an example. Likelihood ratios in favor of variant pathogenicity were determined for report of personal history of several TP53-related cancers, using data from 2,656 probands undergoing single-gene testing (SGT) and 15,483 undergoing multigene panel testing (MGPT). Overall, TP53-associated cancers were more predictive of pathogenicity, and demonstrated greater evidence weight, in the MGPT versus SGT dataset. This observation is almost certainly explained by differences in proband ascertainment for the two streams of testing, and these findings have implications for germline variant classification using ACMG/AMP guidelines. This article is protected by copyright. All rights reserved.
    Keywords:  ACMG; TP53; VCEP; ascertainment; variant classification
    DOI:  https://doi.org/10.1002/humu.23972
  11. Case Rep Oncol Med. 2019 ;2019 7950782
    Peterson RA, Kashyap B, Pawloski PA, Forsberg AC, Hanson LR.
      Radiation-induced sarcomas in the brain are extremely rare, usually occur with an average latency of 9 years, and are associated with poor outcomes. Latency periods shorter than 1 year may indicate a genetic predisposition such as Li-Fraumeni syndrome. A 34-year-old man underwent initial tumor resection and radiation therapy for a World Health Organization (WHO) Grade II Astrocytoma. Within 6 months, the tumor recurred as WHO Grade III and was treated with temozolomide and then bevacizumab. Despite the patient's apparent improving condition, MRI revealed new dural-based lesions 10 months after radiation therapy and identified as high-grade sarcoma. The patient resumed bevacizumab, began NovoTTF treatment for progressing glioma, and ifosfamide/doxorubicin for the sarcoma. Genetic testing revealed no pathogenic mutation in the TP53 gene. Ultimately, treatment was unsuccessful and the patient succumbed to glioma and sarcoma within 2 years of initial diagnosis. This case was unique due to the rapidly progressing glioma and sudden appearance of a high-grade sarcoma. It is unusual to have two separate intracranial primary cancers with each requiring a different chemotherapy regimen. We discuss the difficulty of simultaneously treating with separate chemotherapy regimens. It remains unclear whether the sarcoma was induced by the radiation treatment or a genetic predisposition.
    DOI:  https://doi.org/10.1155/2019/7950782
  12. J Thorac Oncol. 2019 Dec 27. pii: S1556-0864(19)33852-3. [Epub ahead of print]
    Guo R, DuBoff M, Jayakumaran G, Kris MG, Ladanyi M, Robson ME, Mandelker D, Zauderer MG.
      INTRODUCTION: Although next-generation sequencing (NGS) has brought insight into critical mutations or pathways (e.g. DNA damage sensing and repair) involved in the etiology of many cancers and directed new screening, prevention, and therapeutic approaches for patients and families, NGS has only recently been utilized in malignant pleural mesotheliomas (MPMs).METHODS: We analyzed blood samples from patients with MPM using the NGS platform MSK-IMPACT™ to explore cancer-predisposing genes. Loss of function variants or pathogenic entries were identified and clinicopathologic information was collected.
    RESULTS: Of 84 patients with MPM, 12% (10/84) had pathogenic variants. Clinical characteristics were similar between cohorts, although patients with germline pathogenic variants were more likely to have more than 2 first-degree family members with cancer than those without germline mutations (40% vs 12%; Fisher's exact test, p < 0.05). Novel deleterious variants in mesotheliomas included MSH3 (1% [1/84]; 95% CI: 0-7%), BARD1 (1% [1/84]; 95% CI: 0-7%), and RECQL4 (2% [2/84]; 95% CI: 0-9%). Pathogenic variants previously reported on germline testing in patients with mesotheliomas were BAP1 (4% [3/84]; 95% CI: 1-10%), BRCA2 (1% [1/84]; 95% CI: 0-7%), and MRE11A (1% [1/84]; 95% CI: 0-7%). One patient (1% [1/84]; 95% CI: 0-7%) had a likely pathogenic alteration in SHQ1 that has not been associated with a heritable susceptibility to cancer.
    CONCLUSIONS: Our study lends further support for the role of aberrations in DNA damage repair genes in the pathogenesis of malignant pleural mesotheliomas and suggests that targeting members of these pathways for screening and treatment warrants further studying.
    Keywords:  Biomarker; DNA damage; Genetic testing; Germline mutation; Mesothelioma
    DOI:  https://doi.org/10.1016/j.jtho.2019.12.111
  13. Cancer Genet. 2019 Dec 16. pii: S2210-7762(19)30433-8. [Epub ahead of print]
    Rinelli M, Agolini E, Milano GM, Russo I, Crocoli A, De Vito R, Giannatale AD, Paolo PLD, Novelli A.
      Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and rarely occur in pediatric patients. 85% of pediatric GISTs and 15% of adult GISTs lack of KIT or PDGFRA mutations. 40% of these "wild-type" GISTs present loss of function mutations in genes encoding for the subunits of the succinate dehydrogenase (SDH) complex. Germline mutations in SDH complex genes have been described in patients with the Carney-Stratakis syndrome (CSS), a rare inherited condition that predisposes to GIST and paraganglioma. We report two pediatric patients with multifocal GIST, harboring respectively a novel and a previously reported loss-of-function germline variant, in SDHC and SDHB genes.
    Keywords:  Cancer predisposition syndrome; Gastrointestinal stromal tumors; SDH complex deficiency; SDH genes; Succinate dehydrogenase
    DOI:  https://doi.org/10.1016/j.cancergen.2019.12.002
  14. Mod Pathol. 2020 Jan 03.
    de Kock L, Yoon JY, Apellaniz-Ruiz M, Pelletier D, McCluggage WG, Stewart CJR, Dickson BC, Rouzbahman M, Clarke BA, Foulkes WD.
      Embryonal rhabdomyosarcomas (ERMS) account for 2-3% of cancers in pediatric and adolescent populations. They are rarer in adults. We and others have reported that ERMS arising in the uterine cervix may harbor mutations in the gene encoding the microRNA biogenesis enzyme, DICER1, but a large series of cases has not been published. In the uterus, distinguishing ERMS from adenosarcoma can be very challenging, even for expert pathologists, and DICER1 alterations have been identified in a variable subset of uterine adenosarcomas. We hypothesized that DICER1 genetic testing may be useful in distinguishing between ERMS and adenosarcoma. We conducted a central pathology review-based study of 64 tumors initially thought to be uterine ERMS or adenosarcoma; 19 neoplasms had a consensus diagnosis of ERMS, 27 of adenosarcoma and for 18, no consensus diagnosis was reached. The median age at diagnosis was 30 years (range 2.5-69) for ERMS, 57.5 years (range 27-82) for adenosarcoma, and 65.5 years (range 32-86) for no consensus cases. In our series, the DICER1 mutation prevalence differed between the three groups: DICER1 alterations were present in 18/19 (95%) ERMS, 7/27 (26%) adenosarcomas (p < 0.001), and 4/18 (22%) no consensus cases. A germline alteration was present in 6/12 ERMS patients tested versus 0/6 adenosarcoma patients. Thus, although DICER1 mutations are near ubiquitous in uterine ERMS and are significantly less common in uterine adenosarcoma, DICER1 testing is only of value in distinguishing between the two neoplasms when a DICER1 mutation is absent, as this is helpful in excluding ERMS. On review of the clinical and radiological features of the single DICER1 wild-type cervical ERMS, this was thought most likely to be of vaginal origin. Given the significant prevalence of DICER1 germline pathogenic variants in uterine ERMS, all patients with this diagnosis should be referred to a genetics service.
    DOI:  https://doi.org/10.1038/s41379-019-0436-0