bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒05‒31
eleven papers selected by
Joanna Zawacka-Pankau



  1. Eur J Hum Genet. 2020 May 26.
    Frebourg T, Bajalica Lagercrantz S, Oliveira C, Magenheim R, Evans DG, .
      Fifty years after the recognition of the Li-Fraumeni syndrome (LFS), our perception of cancers related to germline alterations of TP53 has drastically changed: (i) germline TP53 alterations are often identified among children with cancers, in particular soft-tissue sarcomas, adrenocortical carcinomas, central nervous system tumours, or among adult females with early breast cancers, without familial history. This justifies the expansion of the LFS concept to a wider cancer predisposition syndrome designated heritable TP53-related cancer (hTP53rc) syndrome; (ii) the interpretation of germline TP53 variants remains challenging and should integrate epidemiological, phenotypical, bioinformatics prediction, and functional data; (iii) the penetrance of germline disease-causing TP53 variants is variable, depending both on the type of variant (dominant-negative variants being associated with a higher cancer risk) and on modifying factors; (iv) whole-body MRI (WBMRI) allows early detection of tumours in variant carriers and (v) in cancer patients with germline disease-causing TP53 variants, radiotherapy, and conventional genotoxic chemotherapy contribute to the development of subsequent primary tumours. It is critical to perform TP53 testing before the initiation of treatment in order to avoid in carriers, if possible, radiotherapy and genotoxic chemotherapies. In children, the recommendations are to perform clinical examination and abdominal ultrasound every 6 months, annual WBMRI and brain MRI from the first year of life, if the TP53 variant is known to be associated with childhood cancers. In adults, the surveillance should include every year clinical examination, WBMRI, breast MRI in females from 20 until 65 years and brain MRI until 50 years.
    DOI:  https://doi.org/10.1038/s41431-020-0638-4
  2. N Engl J Med. 2020 05 28. 382(22): 2103-2116
    Lee YR, Yehia L, Kishikawa T, Ni Y, Leach B, Zhang J, Panch N, Liu J, Wei W, Eng C, Pandolfi PP.
      BACKGROUND: Patients with PTEN hamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (PTEN). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative for PTEN mutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN.METHODS: In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned for WWP1 germline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representative WWP1 variants.
    RESULTS: The existence of germline WWP1 variants was first established in a family with wild-type PTEN who had oligopolyposis and early-onset colon cancers. A validation series indicated that WWP1 germline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germline WWP1 variants, particularly the WWP1 K740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including PTEN-related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritized WWP1 variants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models.
    CONCLUSIONS: In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms without PTEN germline mutations, we confirmed the function of WWP1 as a cancer-susceptibility gene through direct aberrant regulation of the PTEN-PI3K signaling axis. (Funded by the National Institutes of Health and others.).
    DOI:  https://doi.org/10.1056/NEJMoa1914919
  3. Mol Genet Genomic Med. 2020 May 28. e1293
    Breen KE, Carlo MI, Kemel Y, Maio A, Chen YB, Zhang L, Ceyhan-Birsoy O, Mandelker D.
      BACKGROUND: Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC), caused by heterozygous germline pathogenic variants in the FH, confers an increased risk for cutaneous and uterine leiomyomas and renal cancer.METHODS: About 13,722 advanced cancer patients, including 560 with renal cell carcinoma, had germline analysis performed in the context of tumor-normal sequencing under an IRB approved protocol.
    RESULTS: We report two unrelated individuals with early onset kidney cancer who both carried the c.914C > T (p.Phe305Ser) germline variant in the FH. Both tumors exhibited loss of FH staining by immunohistochemistry and/or positive 2SC staining. Subsequent familial testing discovered that a daughter of a proband who carried the variant had both cutaneous and uterine leiomyomas.
    CONCLUSION: This combination of evidence suggests that the FH c.914C > T (p.Phe305Ser) is pathogenic for HLRCC.
    Keywords:  carcinoma; fumarate hydratase; leiomyomatosis; mutation; renal cell
    DOI:  https://doi.org/10.1002/mgg3.1293
  4. Pract Radiat Oncol. 2020 May 21. pii: S1879-8500(20)30099-0. [Epub ahead of print]
    Trombetta MG, Dragun A, Mayr NA, Pierce LJ.
      PURPOSE: To develop a summary of recommendations regarding locoregional management of patients with breast cancer and germline mutations in breast cancer susceptibility genes based on the American Society of Clinical Oncology/American Society for Radiation Oncology/Society of Surgical Oncology Guideline on Management of Hereditary Breast Cancer.METHODS: The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an expert panel to develop recommendations based on a systematic review of the literature and a formal consensus process. A total of 58 articles met the eligibility criteria and formed the evidentiary basis for the locoregional therapy recommendations. Additionally, 6 randomized controlled trials of systemic therapy also met eligibility criteria.
    RESULTS: A joint evidence-based guideline was developed by a multidisciplinary panel, which has been separately published. From this guideline, the radiation-oncologist authors of the panel extracted pertinent surgical and radiation-specific recommendations of findings that are hereby presented.
    CONCLUSIONS: Patients with newly diagnosed breast cancer and BRCA1/2 mutations may be considered for breast conserving therapy (BCT), expecting similar rates of local control of the index cancer as noncarriers. The significant risk of contralateral breast cancer in these women (especially younger women), coupled with the higher risk of new cancers in the ipsilateral breast, warrant discussion of bilateral mastectomy. For women with mutations in BRCA1/2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or contralateral breast cancer events from radiation exposure in BRCA1/2 carriers. Patients with mutations in moderate-risk genes should be offered BCT as one choice after appropriate counseling. Radiation therapy should not be withheld in ATM carriers if BCT is planned. For patients with germline TP53 mutations, mastectomy is advised and radiation therapy is contraindicated except for those with a significant risk of locoregional recurrence.
    DOI:  https://doi.org/10.1016/j.prro.2020.04.003
  5. Hum Mutat. 2020 May 25.
    Belhadj S, Terradas M, Munoz-Torres PM, Aiza G, Navarro M, Capellá G, Valle L.
      Genome-wide approaches applied for the identification of new hereditary colorectal cancer (CRC) genes, identified several potential causal genes, including RPS20, IL12RB1, LIMK2, POLE2, MRE11, POT1, FAN1, WIF1, HNRNPA0, SEMA4A, FOCAD, PTPN12, LRP6, POLQ, BLM and MCM9, and the epigenetic inactivation of PTPRJ. Here we attempted to validate the association between variants in these genes and nonpolyposis CRC by performing a mutational screening of the genes and PTPRJ promoter methylation analysis in 473 familial/early-onset CRC cases, a systematic review of the published cases, and assessment of allele frequencies in control population. In the studied cohort, 24 (5%) carriers of (predicted) deleterious variants in the studied genes and no constitutional PTPRJ epimutations were identified. Assessment of allele frequencies in controls compared to familial/early-onset CRC patients showed association with increased nonpolyposis CRC risk of disruptive variants in RPS20, IL12RB1, POLE2, MRE11 and POT1, and of FAN1 c.149T>G (p.Met50Arg). Lack of association was demonstrated for LIMK2, PTPN12, LRP6, PTPRJ, POLQ, BLM, MCM9 and FOCAD variants. Additional studies are required to provide conclusive evidence for SEMA4A, WIF1, HNRNPA0 c.-110G>C, and FOCAD large deletions. This article is protected by copyright. All rights reserved.
    Keywords:  Hereditary cancer; cancer genetics; cancer predisposition; early-onset colorectal cancer; familial colorectal cancer; germline mutation
    DOI:  https://doi.org/10.1002/humu.24057
  6. Fam Cancer. 2020 May 28.
    Alhopuro P, Vainionpää R, Anttonen AK, Aittomäki K, Nevanlinna H, Pöyhönen M.
      Germline mutations in the BRCA1 and BRCA2 genes cause hereditary breast and ovarian cancer syndrome (HBOC). Mutations in these genes are usually inherited, and reports of de novo BRCA1/2 mutations are rare. To date, only one patient with low-level BRCA1 mutation mosaicism has been published. We report on a breast cancer patient with constitutional somatic mosaicism of a BRCA2 mutation. BRCA2 mutation c.9294C>G, p.(Tyr3098Ter) was detected in 20% of reads in DNA extracted from peripheral blood using next-generation sequencing (NGS). The BRCA2 mutation was subsequently observed at similar levels in normal breast tissue, adipose tissue, normal right fallopian tube tissue and ovaries of the patient, suggesting that this mutation occurred early in embryonic development. This is the first case to report constitutional mosaicism for a BRCA2 mutation and shows that BRCA2 mosaicism can underlie early-onset breast cancer. NGS for BRCA1/2 should be considered for patients whose tumors harbor a BRCA1/2 mutation and for individuals suggestive of genetic predisposition but without a family history of HBO.
    Keywords:  BRCA1; BRCA2; Breast cancer; De novo; Mosaicism; Next-generation sequencing
    DOI:  https://doi.org/10.1007/s10689-020-00186-1
  7. Clin Transl Oncol. 2020 May 25.
    Algebaly AS, Suliman RS, Al-Qahtani WS.
      BACKGROUND: About 5-10% of incidences of breast cancers have been reported as a result of germline mutations of BRCA genes. However, the mutational spectrum of BRCA1 and BRCA2 genes among breast cancer Saudi women patients is inadequate at present. Therefore, the present study aimed to report the specific germinal mutation of BRCA1 and BRCA2 in the entire coding regions, to investigate the prevalence rate of BRCA1 & BRCA2 mutations among Saudi women and the effect of these mutations, both benign and malignant tumors.METHODOLOGY: A total of 270 tissue samples of benign and malignant breast tumors were collected from Saudi women patients, Riyadh, Saudi Arabia. Examination of BRCA1 and BRCA2 germline mutations was performed using heteroduplex DNA analysis (HDA) or single-stranded conformation analysis (SSCA). 177 breast cancer women with malignant tumors and 93 with benign tumors were enrolled in the study. A total of 62 out of 177 breast cancer patients carried a BRCA1 or BRCA2 mutation (54 BRCA1 and 8 BRCA2). The analysis was done using the Sanger sequence assay.
    RESULTS: Point and frameshift mutations through the entire coding area of the two genes indicated that all the mutations were germline alterations and of early-onset breast cancers. The mean ages of diagnosed breast cancer women for BRCA1 and BRCA2 mutation carriers were 36.3 (± 3.5) and 37.9 (± 3.7) years, whereas that of benign control was 35(± 2.5) years.
    CONCLUSION: Point and frameshift mutations across the entire coding region of BRCA1 and BRCA2 are responsible for many breast cancers cases.
    Keywords:  BRCA1; BRCA2; Breast cancer; Germline mutations; Heteroduplex DNA analysis; Novel mutations; Riyadh; Sanger sequencing
    DOI:  https://doi.org/10.1007/s12094-020-02385-9
  8. Pediatr Blood Cancer. 2020 May 30. e28309
    Kebudi R, Amayiri N, Abedalthagafi M, Rana AN, Kirmani S, Musthaq N, Lamki ZA, Houdzi JE, Yazici H, El-Naggar S, Edwards M, Bianchi VJ, Durno C, Tabori U, Bouffet E, .
      Germline biallelic mutations in one of the mismatch repair genes, mutS homolog 2, mutS homolog 6, mutL homolog 1, or postmeiotic segregation increased 2, result in one of the most aggressive cancer syndromes in humans termed as constitutional mismatch repair deficiency (CMMRD). Individuals with CMMRD are affected with multiple tumors arising from multiple organs during childhood, and these individuals rarely reach adulthood without specific interventions. The most common tumors observed are central nervous system, hematological, and gastrointestinal malignancies. The incidence of CMMRD is expected to be high in low-resource settings due to a high rate of consanguinity in these regions, and it is thought to be underrecognized and consequently underdiagnosed. This position paper is therefore important to provide a summary of the current situation, and to highlight the necessity of increasing awareness, diagnostic criteria, and surveillance to improve survival for patients and family members.
    Keywords:  BMMRD; CMMRD; CNS tumors; RRD; café au lait spots; cancer genetics; hematological malignancies gastrointestinal malignancies; neurofibromatosis; surveillance
    DOI:  https://doi.org/10.1002/pbc.28309
  9. Radiographics. 2020 May 29. 190181
    Bharucha PP, Chiu KE, François FM, Scott JL, Khorjekar GR, Tirada NP.
      Professionals who specialize in breast imaging may be the first to initiate the conversation about genetic counseling with patients who have a diagnosis of premenopausal breast cancer or a strong family history of breast and ovarian cancer. Commercial genetic testing panels have gained popularity and have become more affordable in recent years. Therefore, it is imperative for radiologists to be able to provide counseling and to identify those patients who should be referred for genetic testing. The authors review the process of genetic counseling and the associated screening recommendations for patients at high and moderate risk. Ultimately, genetic test results enable appropriate patient-specific screening, which allows improvement of overall survival by early detection and timely treatment. The authors discuss pretest counseling, which involves the use of various breast cancer risk assessment tools such as the Gail and Tyrer-Cuzick models. The most common high- and moderate-risk gene mutations associated with breast cancer are also reviewed. In addition to BRCA1 and BRCA2, several high-risk genes, including TP53, PTEN, CDH1, and STK11, are discussed. Moderate-risk genes include ATM, CHEK2, and PALB2. The imaging appearances of breast cancer typically associated with each gene mutation, as well as the other associated cancers, are described. ©RSNA, 2020 See discussion on this article by Butler (pp XXX-XXX).
    DOI:  https://doi.org/10.1148/rg.2020190181
  10. Scand J Gastroenterol. 2020 May 24. 1-5
    Marques-de-Sá I, Castro R, Pita I, Dinis-Ribeiro M, Brandão C.
      Introduction: Surveillance of Lynch syndrome (LS) is recommended to reduce cancer-risk. There is an increased awareness that cancer-risk may vary with mismatch-repair mutation and family history. However, gene-specific and family-specific surveillance are not recommended. Therefore, we aimed to estimate the cumulative incidence of lesions and to assess the cancer-risk by family history and mismatch-repair mutation (MMR).Methods: Single-centre retrospective cohort of all individuals (n = 241) in a specialized institution was conducted.Results: Forty-eight percent of individuals inherited MSH2 mutations, 32% MLH1, 15% MSH6 and 5% PMS2. The calculated cumulative incidence for any cancer increased with age. By age 70, the cumulative incidence for low-risk, high-risk adenomas and CRC was estimated at 66.6%, 57.7% and 25.7%, respectively. By age 70, the cumulative incidence of endometrial cancer (EC), gastric cancer and urinary tract cancer was estimated at 17.3%, 3.3% and 12.6%, respectively. MLH1 and MSH2 mutation carriers had lower mean age of CRC diagnosis than MSH6 and PMS2 [MLH1:44(CI95% 38-50); MSH2:43(CI95% 40-47); MSH6:52(CI95% 45-59); PMS2:46(CI95% 35-57)]. The risk of EC was higher when family history was present (RR = 2.39, CI95%[1.3;4.6]). MSH6 mutation carriers had higher risk of EC comparative to other MMR mutation carriers (RR = 1.9, p = .09). The risk of urinary tract cancer was higher with MSH2 (RR = 8.4, CI95%[2.7;25.9]) and positive family history (RR = 10.8, CI95%[1.4;82.8]).Conclusion: This cohort demonstrates the effectiveness of LS surveillance and suggests possible tailored surveillance strategies by gene mutation and family history.
    Keywords:  Lynch syndrome; family history; mismatch repair mutation; surveillance
    DOI:  https://doi.org/10.1080/00365521.2020.1766553
  11. BMC Cancer. 2020 May 24. 20(1): 460
    Bucksch K, Zachariae S, Aretz S, Büttner R, Holinski-Feder E, Holzapfel S, Hüneburg R, Kloor M, von Knebel Doeberitz M, Morak M, Möslein G, Nattermann J, Perne C, Rahner N, Schmiegel W, Schulmann K, Steinke-Lange V, Strassburg CP, Vangala DB, Weitz J, Loeffler M, Engel C, .
      BACKGROUND: Individuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population.METHODS: Data was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX.
    RESULTS: The number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS than in FCCX.
    CONCLUSIONS: The characterisation of cancer risks in patients with LLS and FCCX is important to develop appropriate surveillance programmes for these specific intermediate risk groups. Larger prospective studies are needed to obtain more precise risk estimates.
    Keywords:  Cancer risk; Familial colorectal cancer type X; Lynch syndrome; Lynch-like syndrome; Prospective surveillance study
    DOI:  https://doi.org/10.1186/s12885-020-06926-x