bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒07‒26
seven papers selected by
Joanna Zawacka-Pankau
University of Warsaw


  1. Int J Mol Sci. 2020 Jul 16. pii: E5036. [Epub ahead of print]21(14):
    Brandão A, Paulo P, Teixeira MR.
      Prostate cancer (PrCa) ranks among the top five cancers for both incidence and mortality worldwide. A significant proportion of PrCa susceptibility has been attributed to inherited predisposition, with 10-20% of cases expected to occur in a hereditary/familial context. Advances in DNA sequencing technologies have uncovered several moderate- to high-penetrance PrCa susceptibility genes, most of which have previously been related to known hereditary cancer syndromes, namely the hereditary breast and ovarian cancer (BRCA1, BRCA2, ATM, CHEK2, and PALB2) and Lynch syndrome (MLH1, MSH2, MSH6, and PMS2) genes. Additional candidate genes have also been suggested, but further evidence is needed to include them in routine genetic testing. Recommendations based on clinical features, family history, and ethnicity have been established for more cost-efficient genetic testing of patients and families who may be at an increased risk of developing PrCa. The identification of alterations in PrCa predisposing genes may help to inform screening strategies, as well as treatment options, in the metastatic setting. This review provides an overview of the genetic basis underlying hereditary predisposition to PrCa, the current genetic screening recommendations, and the implications for clinical management of the disease.
    Keywords:  genetic testing; germline variants; hereditary cancer syndrome; prostate cancer
    DOI:  https://doi.org/10.3390/ijms21145036
  2. Int J Cancer. 2020 Jul 19.
    Ahadova A, Seppälä TT, Engel C, Gallon R, Burn J, Holinski-Feder E, Steinke-Lange V, Möslein G, Nielsen M, Ten Broeke S, Laghi L, Dominguez-Valentin M, Capella G, Macrae F, Scott R, Hüneburg R, Nattermann J, Hoffmeister M, Brenner H, Bläker H, von Knebel Doeberitz M, Sampson JR, Vasen H, Mecklin JP, Møller P, Kloor M.
      Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS-associated CRC. Alongside with hypotheses addressing colonoscopy quality and pace of progression from adenoma to cancer, we discuss the role of alternative precursors and of immune system in LS-associated CRC. We also identify gaps in current knowledge and make suggestions for future studies aiming at improved CRC prevention for LS individuals. This article is protected by copyright. All rights reserved.
    Keywords:  Lynch syndrome; colonoscopy surveillance; colorectal cancer; incident cancer risk; microsatellite instability; mismatch repair deficiency
    DOI:  https://doi.org/10.1002/ijc.33224
  3. Gynecol Oncol. 2020 Jul 18. pii: S0090-8258(20)32388-X. [Epub ahead of print]
    Rosa RCA, Santis JO, Teixeira LA, Molfetta GA, Dos Santos JTT, Ribeiro VDS, Chahud F, Ribeiro-Silva A, Brunaldi MO, Silva WA, Ferraz VEF.
      OBJECTIVE: To report the frequency of Lynch syndrome (LS) in a cohort of patients from Southeast Brazil bearing endometrial cancer (EC), using a tumor screening universal approach.METHODS: A total of 242 endometrial carcinomas were screened by immunohistochemistry (IHC) and microsatellite instability (MSI) for detection of DNA mismatch repair deficiency (dMMR). MLH1 methylation was assessed to identify sporadic cases. Patients with dMMR tumors were recruited for germline variant analysis by next-generation sequencing of the MLH1, MSH2, MSH6, PMS2, and EPCAM genes.
    RESULTS: Ninety-three out of 242 tumors (38.5%) were classified as dMMR based on MSI and IHC results. Of these, 54 cases were selected for germline analysis, and 37/54 (68.5%) were available for sequencing. Ten patients (10/37, 27%) harbored germline pathogenic or likely pathogenic variants, most of them in the MSH6 gene (4/10, 40%). Seven variants of uncertain significance were found. Eight novel germline variants were identified. The LS prevalence in our cohort was of at least 4.1%. LS patients presented lower mean age at cancer diagnosis compared with patients diagnosed with sporadic EC. Individuals with dMMR tumors, without germline pathogenic variants detected in LS-genes ("Lynch-like" syndrome), had an intermediate mean age at cancer diagnosis between LS and sporadic cases.
    CONCLUSION: This is the first report of the LS prevalence in EC screened by a universal approach in Brazil. Our findings contribute to a better understanding of the mutational landscape of this syndrome in Brazil, which is relevant for improved identification, genetic counseling, prevention and control of cancer in LS.
    Keywords:  Brazil; Endometrial cancer; Lynch syndrome; Lynch-like syndrome; Next-generation sequencing; Universal screening
    DOI:  https://doi.org/10.1016/j.ygyno.2020.07.013
  4. Am J Med Sci. 2020 Jun 03. pii: S0002-9629(20)30242-1. [Epub ahead of print]
    Choi G, Kimonis V, Hall K, Lau WL.
      Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare familial cancer syndrome with a germline mutation in the fumarate hydratase gene. Affected individuals are predisposed to development of cutaneous leiomyomas, uterine leiomyomas, and papillary renal cell carcinoma. We present a case of a mother and son pair affected with HLRCC, discuss clinical management, and examine potential syndromic manifestations in extended family members. Annual imaging surveillance for kidney cancer is recommended since 20-30% of individuals develop aggressive papillary type II renal cell carcinoma that can be difficult to treat once it has metastasized.
    Keywords:  HLRCC; Hereditary leiomyomatosis and renal cell cancer; Reed's syndrome
    DOI:  https://doi.org/10.1016/j.amjms.2020.05.048
  5. Fam Cancer. 2020 Jul 20.
    Adlard J.
      Activating germline mutations of the MET gene are associated with hereditary papillary renal cancer. This a very rare autosomal dominant condition, which is usually considered not to display a phenotype of multiple types of malignancy. However, this report describes the case of a man who has been affected with testicular teratoma, diffuse large B-cell lymphoma and multiple hepatic cysts, as well as multiple papillary renal cancers. There is good supporting evidence for roles of over-expression/activity of the HGF/MET ligand-receptor in development of these tumours, raising the possibility of other increased cancer risks associated with activating germline MET gene mutations.
    Keywords:  Cancer; Germline; Lymphoma; MET; Multiple; Teratoma
    DOI:  https://doi.org/10.1007/s10689-020-00196-z
  6. Gynecol Oncol. 2020 Jul 21. pii: S0090-8258(20)32335-0. [Epub ahead of print]
    Weiss AS, Swisher E, Pennington KP, Radke M, Khasnavis N, Garcia RL, Kilgore MR, Lee MK, Norquist BM.
      OBJECTIVES: Women with fallopian tube carcinoma (FTC) are reported to have a higher frequency of inherited BRCA mutations than those with ovarian carcinoma (OC) or primary peritoneal carcinoma (PPC). We hypothesized that routine serial sectioning of fallopian tubes would increase the proportion of cases designated as FTC and change the frequency of inherited mutations between carcinoma types.METHODS: Eight hundred and sixty-seven women diagnosed from 1998 to 2018 were enrolled at diagnosis into an institutional tissue bank. Germline DNA, available from 700 women with FTC (N = 124), OC (N = 511) and PPC (N = 65), was assessed using targeted capture and massively parallel sequencing for mutations in ovarian carcinoma susceptibility genes. Cases were divided between those prior to routine serial sectioning (1998-2008) and after (2009-2019), and the frequency of FTC and inherited mutations was assessed.
    RESULTS: The proportion of carcinomas attributed as FTC after 2009 was 28% (128/465), significantly higher than before 2009 [5% (21/402), p < .0001, OR 6.9, 95% CI 4.3-11.2], with subsequent decreases in OC and PPC. In the sequenced group, overall inherited mutation frequency in FTC (24/124, 19%), OC (106/511, 21%, p = .42), and PPC (16/65, 25%, p = .25) were similar. Germline mutation rates in FTC were lower after 2009,16/107 cases (15%), compared to 8/17 cases (47.1%) before 2009 (p = .005, OR 0.20, 95% CI 0.06-0.64).
    CONCLUSIONS: The prevalence of inherited mutations is similar in FTC compared to OC or PPC when using modern pathological assignment. Complete serial sectioning of fallopian tubes has significantly increased the diagnosis of FTC, and subsequently decreased the frequency of inherited mutations within this group.
    Keywords:  Fallopian tube carcinoma; Germline mutations; High grade serous carcinoma; Inherited mutations; Serial sectioning of the fallopian tube
    DOI:  https://doi.org/10.1016/j.ygyno.2020.06.509
  7. Clin Endocrinol (Oxf). 2020 Jul 19.
    MacFarlane J, Seong KC, Bisamber C, Madhu B, Allinson K, Marker A, Warren A, Park SM, Giger O, Challis BG, Maher ER, Casey RT.
      The citric acid cycle, also known as the Krebs cycle, plays an integral role in cellular metabolism and aerobic respiration. Mutations in genes encoding the citric acid cycle enzymes succinate dehydrogenase, fumarate hydratase and malate dehydrogenase all predispose to hereditary tumour syndromes. The succinate dehydrogenase enzyme complex (SDH) couples the oxidation of succinate to fumarate in the citric acid cycle and the reduction of ubiquinone to ubiquinol in the electron transport chain. A loss of function in the succinate dehydrogenase (SDH) enzyme complex is most commonly caused by an inherited mutation in one of the four SDHx genes (SDHA, SDHB, SDHC and SDHD). This mechanism was first implicated in familial phaeochromocytoma and paraganglioma. However, over the past two decades the spectrum of tumours associated with SDH deficiency has been extended to include; gastrointestinal stromal tumours (GIST), renal cell carcinoma (RCC) and pituitary adenomas. The aim of this review is to describe the extended tumour spectrum associated with SDHx gene mutations and to consider how functional tests may help to establish the role of SDHx mutations in new or unexpected tumour phenotypes.
    DOI:  https://doi.org/10.1111/cen.14289