bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒05‒30
eleven papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. Case Report of an Unusual Tumor in an Adult With a TP53 Germline Mutation.
  2. The diverse molecular profiles of lynch syndrome-associated colorectal cancers are (highly) dependent on underlying germline mismatch repair mutations.
  3. Lynch Syndrome in Thai Endometrial Cancer Patients.
  4. Sebaceous tumours: A prototypical class of skin tumour for universal germline genetic testing.
  5. Precision medicine for hereditary tumors in gynecologic malignancies.
  6. Novel Case of Isolated Peritoneal Carcinomatosis from Metastatic Prostate Cancer Carrying a Pathogenic BRCA Mutation Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.
  7. Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial.
  8. Carbon ion radiotherapy eradicates medulloblastomas with chromothripsis in an orthotopic Li-Fraumeni patient-derived mouse model.
  9. Are there monogenic hereditary forms of bladder cancer or only genetic susceptibilities?
  10. Whole Exome Sequencing in BRCA1-2 Candidate Families: The Contribution of Other Cancer Susceptibility Genes.
  11. Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population.
  1. Clin Lymphoma Myeloma Leuk. 2020 Dec 31. pii: S2152-2650(20)30552-8. [Epub ahead of print]
    Case Report of an Unusual Tumor in an Adult With a TP53 Germline Mutation.
    Castiaux J, Vandernoot I, Dallemagne J, Bruneau M, Delaunoy M, Peyrassol X, Heimann P, De Wilde V, Wolfromm A.
      
    Keywords:  Li-Fraumeni syndrome; Multiple myeloma; Mutational load; Prognosis; Thyroid carcinoma; Treatment
    DOI:  https://doi.org/10.1016/j.clml.2020.10.001
  2. Crit Rev Oncol Hematol. 2021 May 24. pii: S1040-8428(21)00126-8. [Epub ahead of print] 103338
    The diverse molecular profiles of lynch syndrome-associated colorectal cancers are (highly) dependent on underlying germline mismatch repair mutations.
    Helderman NC, Bajwa-Ten Broeke SW, Morreau H, Suerink M, Terlouw D, van der Werf-' T Lam AS, van Wezel T, Nielsen M.
      Lynch syndrome (LS) is a hereditary cancer syndrome that accounts for 3% of all new colorectal cancer (CRC) cases. Patients carry a germline pathogenic variant in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2), which encode proteins involved in a post-replicative proofreading and editing mechanism. The clinical presentation of LS is highly heterogeneous, showing high variability in age at onset and penetrance of cancer, which may be partly attributable to the molecular profiles of carcinomas. This review discusses the frequency of alterations in the WNT/B-CATENIN, RAF/MEK/ERK and PI3K/PTEN/AKT pathways identified in all four LS subgroups and how these changes may relate to the 'three pathway model' of carcinogenesis, in which LS CRCs develop from MMR-proficient adenomas, MMR-deficient adenomas or directly from MMR-deficient crypts. Understanding the specific differences in carcinogenesis for each LS subgroup will aid in the further optimization of guidelines for diagnosis, surveillance and treatment.
    Keywords:  Colorectal cancer; Lynch syndrome; Mismatch repair; Molecular profile
    DOI:  https://doi.org/10.1016/j.critrevonc.2021.103338
  3. Asian Pac J Cancer Prev. 2021 May 01. pii: 89597. [Epub ahead of print]22(5): 1477-1483
    Lynch Syndrome in Thai Endometrial Cancer Patients.
    Manchana T, Ariyasriwatana C, Triratanachat S, Phowthongkum P.
      BACKGROUND: Lynch syndrome increases lifetime risk of endometrial cancer to 40-60%. Screening with molecular tumor testing for mismatch repair (MMR) proteins have been recommended. This study aims to evaluate the incidence of MMR deficiency and germline mutation in endometrial cancer Thai patients.METHODS: Immunohistochemistry for MMR proteins, including MLH1, MSH2, MSH6 and PMS2 were tested in 166 surgical specimens. Patients who had MMR deficiencies were offered genetic counseling and a germline testing using gene-panel next generation sequencing.
    RESULTS: Fifty-eight of 166 patients (34.9%) had one or more MMR deficiencies which were: MLH1 and PMS2 in 42 patients (25.3%), MSH2 and MSH6 in 11 patients (6.6%), and MSH6 in 5 patients (3.0%). Of the 40 patients (24.1%) who met the revised Bethesda guidelines, 19 patients (47.5%) had MMR deficiency. In contrast, MMR deficiency was found in 39 of the 126 patients (31.0%) who did not meet the revised Bethesda guidelines. A total of 27 patients with MMR deficiencies agreed to have germline genetic testing. Germline MMR mutations were detected in 5 patients (18.5%) including MSH6 (n=2), PMS2 (n=2), and MLH1 mutations (n=1). Incidental germline mutations in other genes were detected in 3 patients (1 BRCA1, 1 PTEN, and 1 BARD1). Among 5 Lynch syndrome patients, 2 patients (40%) did not meet the revised Bethesda guidelines. Eight patients who met the revised Bethesda Guidelines but having MMR proficiency had genetic testing, but no germline mutation was detected.
    CONCLUSION: MMR deficiencies were detected in 34.9% of the endometrial cancer patients. Germline mutations were diagnosed in 3.0% of this cohort (5/166 patients). Lynch syndrome screening with MMR immunohistochemistry should be considered in all patients regardless of personal or family history of Lynch syndrome-related cancers.
    Keywords:  Endometrial cancer; Hereditary nonpolyposis colorectal cancer; Lynch syndrome; Mismatch repair protein; immunohistochemistry
    DOI:  https://doi.org/10.31557/APJCP.2021.22.5.1477
  4. Br J Dermatol. 2021 May 29.
    Sebaceous tumours: A prototypical class of skin tumour for universal germline genetic testing.
    Gallon R, Kibbi N, Cook S, Santibanez-Koref M, Jackson MS, Burn J, Rajan N.
      Lynch syndrome (LS) is an adult-onset cancer predisposition caused by a germline pathogenic variant affecting one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2). The vast majority of LS gene carriers are unknown yet may benefit from risk-reducing interventions such as targeted cancer screening and aspirin chemoprevention, the latter being associated with a persistent and long-term reduction in colorectal cancer (CRC) incidence.
    DOI:  https://doi.org/10.1111/bjd.20522
  5. J Obstet Gynaecol Res. 2021 May 25.
    Precision medicine for hereditary tumors in gynecologic malignancies.
    Sekine M, Enomoto T.
      Genomic medicine for gynecologic tumors is characterized by hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS). Poly ADP-ribose polymerase (PARP) inhibitor, olaparib, and the immune checkpoint inhibitor, pembrolizumab, which are drugs that show sensitivity to each hereditary tumor, have begun to spread in clinical practice for gynecologic malignancies. In clinical use, platinum sensitivity is used as a clinical surrogate marker for olaparib sensitivity, and microsatellite instability is used as a biological surrogate marker for pembrolizumab sensitivity. BRCA genetic testing and microsatellite instability test have been used as companion diagnostics before starting olaparib and pembrolizumab treatment, respectively. Homologous recombination deficiency test could be used for companion diagnostic of olaparib combination with bevacizumab in first-line maintenance treatment and niraparib without re-administration of platinum agents in the treatment of recurrence. The approval of the three drugs has been changing the treatment of gynecologic malignancies. Furthermore, preventive medical care has been covered by insurance since April 2020 for breast and/or ovarian cancer patients with germline BRCA1/2 mutation in Japan. This review article outlines the current status and future prospects of precision medicine for gynecologic hereditary tumors focusing on HBOC and LS.
    Keywords:  Hereditary Tumor; Hereditary breast and ovarian cancer; Lynch syndrome; PARP inhibitor; Risk-reducing surgery
    DOI:  https://doi.org/10.1111/jog.14861
  6. Urology. 2021 May 25. pii: S0090-4295(21)00435-0. [Epub ahead of print]
    Novel Case of Isolated Peritoneal Carcinomatosis from Metastatic Prostate Cancer Carrying a Pathogenic BRCA Mutation Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.
    King MC, Sardi A, Velez-Mejia C, Sittig M, Ledakis P.
      We present the first case of isolated peritoneal carcinomatosis (PC) from prostate cancer carrying a previously unreported pathogenic BRCA2 mutation without other organ involvement. CT showed PC with no extra-peritoneal metastases. Treatment included neoadjuvant chemotherapy, cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), and adjuvant chemotherapy. Patient is disease-free after 30-months. Germline genetic testing showed BRCA2 c.1813dupA (p.I605Nfs*11) mutation, reported in breast and ovarian cancers. Tumor genomic testing also revealed TMPRSS2, TBX3, and TP53 mutations. Given the comparable presentation and BRCA-mutation profile to ovarian cancer, BRCA2 mutations may contribute to disease phenotypes. CRS/HIPEC may provide long-term outcomes for this unique metastatic pattern.
    Keywords:  BRCA2 germline mutation; CRS/HIPEC; Peritoneal carcinomatosis; prostate cancer
    DOI:  https://doi.org/10.1016/j.urology.2021.05.026
  7. Cancer Discov. 2021 May 27. pii: candisc.0007.2021. [Epub ahead of print]
    Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial.
    Carreira S, Porta N, Arce-Gallego S, Seed G, Llop-Guevara A, Bianchini D, Rescigno P, Paschalis A, Bertan C, Baker C, Goodall J, Miranda S, Riisnaes R, Figueiredo I, Ferreira A, Pereira R, Crespo M, Gurel B, Nava Rodrigues D, Pettitt SJ, Yuan W, Serra V, Rekowski J, Lord CJ, Hall E, Mateo J, de Bono JS.
      PARP inhibitors are approved for treating advanced prostate cancers (APCs) with various defective DNA repair genes; however, further studies to clinically qualify predictive biomarkers are warranted. Herein we analyzed TOPARP-B Phase II clinical trial samples, evaluating whole exome and low-pass whole genome sequencing and immunohistochemical assays evaluating ATM and RAD51 foci (testing homologous recombination repair function). BRCA1/2 germline and somatic pathogenic mutations associated with similar benefit from olaparib; greater benefit was observed with homozygous BRCA deletion. Biallelic, but not mono-allelic, PALB2 deleterious alterations were associated with clinical benefit. In the ATM cohort, loss of ATM protein by immunohistochemistry associated with better outcome. RAD51 foci loss identified tumors with biallelic BRCA and PALB2 alteration while most ATM- and CDK12-altered APCs had higher RAD51 foci levels. Overall, APCs with homozygous BRCA2 deletion are exceptional responders; PALB2 biallelic loss and loss of ATM immunohistochemical expression associated with clinical benefit.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0007
  8. Neuro Oncol. 2021 May 28. pii: noab127. [Epub ahead of print]
    Carbon ion radiotherapy eradicates medulloblastomas with chromothripsis in an orthotopic Li-Fraumeni patient-derived mouse model.
    Simovic M, Bolkestein M, Moustafa M, Wong JKL, Körber V, Benedetto S, Khalid U, Schreiber HS, Jugold M, Korshunov A, Hübschmann D, Mack N, Brons S, Wei PC, Breckwoldt MO, Heiland S, Bendszus M, Jürgen D, Höfer T, Zapatka M, Kool M, Pfister SM, Abdollahi A, Ernst A.
      BACKGROUND: Medulloblastomas with chromothripsis developing in children with Li-Fraumeni Syndrome (germline TP53 mutations) are highly aggressive brain tumors with dismal prognosis. Conventional photon radiotherapy and DNA-damaging chemotherapy are not successful for these patients and raise the risk of secondary malignancies. We hypothesized that the pronounced homologous recombination deficiency in these tumors might offer vulnerabilities that can be therapeutically utilized in combination with high linear energy transfer carbon ion radiotherapy.METHODS: We tested high-precision particle therapy with carbon ions and protons as well as topotecan with or without PARP inhibitor in orthotopic primary and matched relapsed patient-derived xenograft models. Tumor and normal tissue underwent longitudinal morphological (MRI), cellular (markers of neurogenesis and DNA damage-repair) and molecular characterization (whole-genome sequencing).
    RESULTS: In the primary medulloblastoma model, carbon ions led to complete response in 79% of animals irrespective of PARP inhibitor within a follow-up period of 300 days post-irradiation, as detected by MRI and histology. No sign of neurologic symptoms, impairment of neurogenesis or in-field carcinogenesis was detected in repair-deficient host mice. PARP inhibitors further enhanced the effect of proton irradiation. In the post-radiotherapy relapsed tumor model, median survival was significantly increased after carbon ions (96 days) versus control (43 days, p<0.0001). No major change in the clonal composition was detected in the relapsed model.
    CONCLUSION: The high efficacy and favorable toxicity profile of carbon ions warrants further investigation in primary medulloblastomas with chromothripsis. Post-radiotherapy relapsed medulloblastomas exhibit relative resistance compared to treatment-naïve tumors, calling for exploration of multimodal strategies.
    Keywords:  PARP inhibitor; carbon ion radiotherapy; chromothripsis; medulloblastoma; synthetic lethality
    DOI:  https://doi.org/10.1093/neuonc/noab127
  9. Pharmacogenomics. 2021 May 28.
    Are there monogenic hereditary forms of bladder cancer or only genetic susceptibilities?
    Souaid T, Hindy JR, Diab E, Kourie HR.
      Bladder cancer (BC) is the most common cancer involving the urinary system and the ninth most common cancer worldwide. Tobacco smoking is the most important environmental risk factor of BC. Several single nucleotide polymorphisms have been validated by genome-wide association studies as genetic risk factors for BC. However, the identification of DNA mismatch-repair genes, including MSH2 in Lynch syndrome and MUTYH in MUTYH-associated polyposis, raises the possibility of monogenic hereditary forms of BC. Moreover, other genetic mutations may play a key role in familial and hereditary transmissions of BC. Therefore, the aim of this review is to focus on the major hereditary syndromes involved in the development of BC and to report BC genetic susceptibilities established with genome-wide significance level.
    Keywords:  Lynch; bladder cancer; genetics; hereditary; syndrome
    DOI:  https://doi.org/10.2217/pgs-2020-0165
  10. Front Oncol. 2021 ;11 649435
    Whole Exome Sequencing in BRCA1-2 Candidate Families: The Contribution of Other Cancer Susceptibility Genes.
    Doddato G, Valentino F, Giliberti A, Papa FT, Tita R, Bruno LP, Resciniti S, Fallerini C, Benetti E, Palmieri M, Mencarelli MA, Fabbiani A, Bruttini M, Orrico A, Baldassarri M, Fava F, Lopergolo D, Lo Rizzo C, Lamacchia V, Mannucci S, Pinto AM, Curr A, Mancini V, , , Mari F, Renieri A, Ariani F.
      Hereditary Breast and Ovarian Cancer (HBOC) syndrome is a condition in which the risk of breast and ovarian cancer is higher than in the general population. The prevalent pathogenesis is attributable to inactivating variants of the BRCA1-2 highly penetrant genes, however, other cancer susceptibility genes may also be involved. By Whole Exome Sequencing (WES) we analyzed a series of 200 individuals selected for genetic testing in BRCA1-2 genes according to the updated National Comprehensive Cancer Network (NCCN) guidelines. Analysis by MLPA was performed to detect large BRCA1-2 deletions/duplications. Focusing on BRCA1-2 genes, data analysis identified 11 cases with pathogenic variants (4 in BRCA1 and 7 in BRCA1-2) and 12 with uncertain variants (7 in BRCA1 and 5 in BRCA2). Only one case was found with a large BRCA1 deletion. Whole exome analysis allowed to characterize pathogenic variants in 21 additional genes: 10 genes more traditionally associated to breast and ovarian cancer (ATM, BRIP1, CDH1, PALB2, PTEN, RAD51C, and TP53) (5% diagnostic yield) and 11 in candidate cancer susceptibility genes (DPYD, ERBB3, ERCC2, MUTYH, NQO2, NTHL1, PARK2, RAD54L, and RNASEL). In conclusion, this study allowed a personalized risk assessment and clinical surveillance in an increased number of HBOC families and to broaden the spectrum of causative variants also to candidate non-canonical genes.
    Keywords:  BRCA1; BRCA2; HBOC; WES (Whole Exome Sequencing); cancer susceptibility genes
    DOI:  https://doi.org/10.3389/fonc.2021.649435
  11. Cancer Sci. 2021 May 25.
    Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population.
    Senda N, Kawaguchi-Sakita N, Kawashima M, Inagaki-Kawata Y, Yoshida K, Takada M, Kataoka M, Torii M, Nishimura T, Kawaguchi K, Suzuki E, Kataoka Y, Matsumoto Y, Yoshibayashi H, Yamagami K, Tsuyuki S, Takahara S, Yamauchi A, Shinkura N, Kato H, Moriguchi Y, Okamura R, Kan N, Suwa H, Sakata S, Mashima S, Yotsumoto F, Tachibana T, Tanaka M, Togashi K, Haga H, Yamada T, Kosugi S, Inamoto T, Sugimoto M, Ogawa S, Toi M.
      Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all p < 0.0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multi-gene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from non-carriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cut-off of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction.
    Keywords:   BRCA ; Tyrer-Cuzick model; breast cancer; pathogenic germline variant; risk factor
    DOI:  https://doi.org/10.1111/cas.14986
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