bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021–12–26
eight papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Melanoma in patients with Li-Fraumeni syndrome (Review).
  2. A decade of RAD51C and RAD51D germline variants in cancer.
  3. Germline Mutation Landscape and Associated Clinical Characteristics in Chinese Patients With Renal Cell Carcinoma.
  4. CDH1 germline mutations in healthy individuals from families with the hereditary diffuse gastric cancer syndrome.
  5. CDH1 germline variants are enriched in patients with colorectal cancer, gastric cancer, and breast cancer.
  6. A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma.
  7. Baseline risk of hematologic malignancy at initiation of frontline PARP inhibitor maintenance for BRCA1/2-associated ovarian cancer.
  8. Prevalence of BRCA1 and BRCA2 pathogenic sequence variants in ovarian cancer patients in the Gulf region: the PREDICT study.
  1. Exp Ther Med. 2022 Jan;23(1): 75
    Melanoma in patients with Li-Fraumeni syndrome (Review).
    Florica Sandru, Mihai Cristian Dumitrascu, Aida Petca, Mara Carsote, Razvan-Cosmin Petca, Adina Ghemigian.
      Li-Fraumeni syndrome (LFS) is a cancer-prone, autosomal dominant syndrome caused by underlying germline gene mutations of TP53, a tumor-suppressor gene encoding the p53 protein with a major role in apoptosis, DNA repair and cell cycle regulation. Cumulative cancer incidence for LFS patients by the age of 70 years is 80-100%, mostly involving adrenocortical carcinoma, brain tumors, bone and soft tissue sarcomas, leukemia and female breast cancer from the age of 20 years. Dominant negative TP53 variant is correlated with an increased tumorigenesis risk in LFS. Sporadic TP53 mutations are related to almost half of global cancers since p53 in addition to p73 protein represent essential players in anticancer cellular protection. Epidemiological aspects concerning skin cancers, especially malignant melanoma (MM), in LFS are less clear. A low level of statistical evidence demonstrates LFS cases with pediatric MM, multiple MM, spitzoid MM, atypical presentations, mucosal and uveal MM. Retrospective cohorts indicate a higher cumulative risk than the general population by the age of 70 years for MM and basal cell carcinoma. Non-syndromic and syndromic TP53 mutations are a major pathway of metastasis, including MM. In LHS, an important level of awareness involves skin cancers despite not being a part of the typical malignancy-containing picture. Additional data are crucially needed. However, at least one dermatologic control is a step in the multidisciplinary panel of surveillance of these patients; but in cases with benign and pre-malign pigmentations, serial dermatoscopy and full body photography are recommended for early melanoma detection in order to improve the prognosis and to reduce the overall malignancy burden.
    Keywords:  Li-Fraumeni syndrome; TP53 gene; adrenocortical carcinoma; breast cancer; melanoma; osteosarcoma; p53 protein; radiotherapy; skin cancer
    DOI:  https://doi.org/10.3892/etm.2021.10998
  2. Hum Mutat. 2021 Dec 19.
    A decade of RAD51C and RAD51D germline variants in cancer.
    Jacopo Boni, Aida Idani, Carla Roca, Lidia Feliubadaló, Eva Tomiak, Evan Weber, William D Foulkes, Alexandre Orthwein, Zaki El Haffaf, Conxi Lazaro, Barbara Rivera.
      Defects in DNA repair genes have been extensively associated to cancer susceptibility. Germline pathogenic variants (GPV) in genes involved in homologous recombination repair pathway predispose to cancers arising mainly in breast and ovary, but also other tissues. The RAD51 paralogs RAD51C and RAD51D were included in this group 10 years ago, when germline variants were associated to non-BRCA1/2 familial ovarian cancer. Here, we have reviewed the landscape of RAD51C and RAD51D germline variants in cancer reported in the literature during the last decade, integrating this list with variants identified by in house patient screening. A comprehensive catalogue of 341 variants that have been classified applying ACMG/AMP criteria has been generated pinpointing to the existence of recurrent variants in both genes. Recurrent variants have been extensively discussed compiling data on population frequencies and functional characterization if available, highlighting variants that have not been fully characterized yet to properly establish their pathogenicity. Finally, we have complemented this data with relevant information regarding conservation of mutated residues among RAD51 paralogs and modeling of hotspot areas, which contributes to generate an exhaustive update on these two cancer predisposition genes. This article is protected by copyright. All rights reserved.
    Keywords:  RAD51C; RAD51D; hereditary cancer; homologous recombination
    DOI:  https://doi.org/10.1002/humu.24319
  3. Front Oncol. 2021 ;11 737547
    Germline Mutation Landscape and Associated Clinical Characteristics in Chinese Patients With Renal Cell Carcinoma.
    Wen Kong, Tongtong Yang, Xiaodong Wen, Zhongyi Mu, Cheng Zhao, Sujun Han, Jing Tian, Xinhao Zhang, Tao Zhou, Yanrui Zhang, Feng Lou, Shanbo Cao, Huina Wang, Jin Zhang.
       Background: Renal cell carcinoma (RCC) is a disease of genomic alterations, of which the complete panorama helps in facilitating molecular-guided therapy. Germline mutation profiles and associated somatic and clinical characteristics remains unexplored in Chinese RCC patients.
    Methods: We retrospectively profiled the germline and somatic mutations of 322 unselected RCC patients using a panel consisting of 808 cancer-related genes. We categorized patients into three groups based on germline mutation status and compared the somatic mutation spectrum among different groups.
    Results: Approximately one out of ten (9.9%) RCC patients were identified to carry pathogenic/likely pathogenic (P/LP) germline variants (PGVs), of which 3.7% were variants in syndromic RCC-associated genes and 6.2% were other cancer-predisposition genes. The most common PGV was found in VHL (2.2%), followed by FH, TSC2, ATM, BRCA1, NBN, and BLM (0.6% each). Young patients (≤46 years) were more likely to harbor PGVs. Variants in syndromic RCC-associated genes were predominant identified in young patients, while variants in other cancer-predisposition genes were found in patients >46 years more frequently. Furthermore, 39.3% (11/28) of patients carrying PGVs were detected to have somatic "second hit" events. Germline and somatic sequencing, including microsatellite instability (MSI) status analysis, provided potentially actionable therapeutic targets in 17.1% of patients in the whole cohort.
    Conclusions: Our results revealed that approximately 10% of RCC patients carried clinically significant germline mutations. Current guidelines recommendation for genetic testing seemed not sensitive enough to identify patients with hereditary RCC susceptibility. It is rational to promote genetic testing in RCC population.
    Keywords:  Chinese population; germline mutations; pathogenic variation; renal cell carcinoma; second hit events
    DOI:  https://doi.org/10.3389/fonc.2021.737547
  4. J Med Genet. 2021 Dec 24. pii: jmedgenet-2021-108226. [Epub ahead of print]
    CDH1 germline mutations in healthy individuals from families with the hereditary diffuse gastric cancer syndrome.
    Giovanni Corso, Francesca Magnoni, Giulia Massari, Cristina Maria Trovato, Alessandra Margherita De Scalzi, Elisa Vicini, Bernardo Bonanni, Paolo Veronesi, Viviana Galimberti, Vincenzo Bagnardi.
      The objective of this study was to determining the frequency of different sub-types of pathogenic CDH1 germline mutations in healthy and asymptomatic individuals from families with the hereditary diffuse gastric cancer (HDGC) syndrome. Relevant literature dating from 1998 to 2019 was systematically searched for data on CDH1 germline mutations. The collected variants were classified according to their subtype into the following classes: missense, non-sense, splicing, insertions and deletions. The χ2 test was used to estimate if the difference observed between patients with gastric cancer (GC) and unaffected individuals was statistically significant. CDH1 genetic screening data were retrieved for 224 patients with GC and 289 healthy individuals. Among the subjects that had tested CDH1 positive, splicing mutations were found in 30.4% of the healthy individuals and in 15.2% of the patients with GC (p=0.0076). Missense mutations were also found to occur in healthy subjects with higher frequency (22.2%) than in GC-affected individuals (18.3%), but the difference was not significant in this case. In families meeting the clinical criteria for the HDGC syndrome, CDH1 splicing and missense germline mutations have been reported to occur with higher frequency in healthy subjects than in patients with cancer. This preliminary observation suggests that not all pathogenic CDH1 germline mutations confer the same risk of developing GC.
    Keywords:  gastroenterology
    DOI:  https://doi.org/10.1136/jmedgenet-2021-108226
  5. Br J Cancer. 2021 Dec 23.
    CDH1 germline variants are enriched in patients with colorectal cancer, gastric cancer, and breast cancer.
    Elio Adib, Talal El Zarif, Amin H Nassar, Elie W Akl, Sarah Abou Alaiwi, Tarek H Mouhieddine, Edward D Esplin, Kathryn Hatchell, Sarah M Nielsen, Huma Q Rana, Toni K Choueiri, David J Kwiatkowski, Guru Sonpavde.
       BACKGROUND AND AIMS: CDH1 germline variants have been linked to heritability in diffuse gastric (DGC) and lobular breast cancer (LBC). Studies have not yet assessed whether CDH1 is a cancer-susceptibility gene in other cancers. Herein, we mapped the landscape of pathogenic and likely pathogenic (P/LP) germline variants in CDH1 across various cancers and ethnicities.
    METHODS: We evaluated CDH1 germline P/LP variants in 212,944 patients at one CLIA-certified laboratory (Invitae) and described their frequency in 7 cancer types. We screened for CDH1 variant enrichment in each cancer relative to a cancer-free population from The Genome Aggregation Database version 3 (gnomADv3).
    RESULTS: CDH1 P/LP variants were identified in 141 patients, most commonly in patients with DGC (27/408, 6.6%) followed by colorectal signet-ring cell cancer (CSRCC; 3/79, 3.8%), gastric cancer (56/2756, 2%), and LBC (22/6809, 0.3%). CDH1 P/LP variants were enriched in specific ethnic populations with breast cancer, gastric cancer, CRC, LBC, DGC, and CSRCC compared to matched ethnicities from gnomADv3.
    CONCLUSION: We report for the first time the prevalence of P/LP CDH1 variants across several cancers and show significant enrichment in CDH1 P/LP variants for patients with CSRCC, DGC, and LBC across various ethnicities. Future prospective studies are warranted to validate these findings.
    DOI:  https://doi.org/10.1038/s41416-021-01673-7
  6. Cells. 2021 Dec 02. pii: 3400. [Epub ahead of print]10(12):
    A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma.
    Megan R Reed, A Geoffrey Lyle, Annick De Loose, Leena Maddukuri, Katrina Learned, Holly C Beale, Ellen T Kephart, Allison Cheney, Anouk van den Bout, Madison P Lee, Kelsey N Hundley, Ashley M Smith, Teresa M DesRochers, Cecile Rose T Vibat, Murat Gokden, Sofie Salama, Christopher P Wardell, Robert L Eoff, Olena M Vaske, Analiz Rodriguez.
      Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30-50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used a comparative transcriptomics approach to identify genes that are uniquely overexpressed in the LFS GBM patient relative to a cancer compendium of 12,747 tumor RNA sequencing data sets, including 200 GBMs. STAT1 and STAT2 were identified as being significantly overexpressed in the LFS patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitors, as a potential therapy. The LFS patient had the highest level of STAT1 and STAT2 expression in an institutional high-grade glioma cohort of 45 patients, further supporting the cancer compendium results. To empirically validate the comparative transcriptomics pipeline, we used a combination of adherent and organoid cell culture techniques, including ex vivo patient-derived organoids (PDOs) from four patient-derived cell lines, including the LFS patient. STAT1 and STAT2 expression levels in the four patient-derived cells correlated with levels identified in the respective parent tumors. In both adherent and organoid cultures, cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. A spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. Two targeted therapies were selected for the patient of interest and resulted in radiographic disease stability. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.
    Keywords:  Li Fraumeni; glioblastoma; organoid; precision medicine; transcriptomics
    DOI:  https://doi.org/10.3390/cells10123400
  7. Gynecol Oncol Rep. 2021 Nov;38 100873
    Baseline risk of hematologic malignancy at initiation of frontline PARP inhibitor maintenance for BRCA1/2-associated ovarian cancer.
    Anastasia Navitski, Duaa H Al-Rawi, Ying Liu, Maria M Rubinstein, Claire F Friedman, Raajit K Rampal, Diana L Mandelker, Karen Cadoo, Roisin E O'Cearbhaill.
      Poly(ADP-ribose) polymerase inhibitors (PARPi) are FDA approved as frontline maintenance for BRCA-associated advanced stage high-grade ovarian cancer (HGOC), having demonstrated an unprecedented improvement in relapse-free survival. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are rare toxicities of PARPi. We describe three patients with germline BRCA-associated (gBRCA+) HGOC and alterations in AML driver genes. Although none evidenced overt hematologic malignancy, PARPi maintenance was cautiously considered given the potential risk of MDS/AML. A better understanding of the role of clonal hematopoiesis in the subsequent development of PARPi-associated MDS/AML will improve management of this patient population.
    Keywords:  Acute myeloid leukemia; BRCA mutation; Myelodysplastic syndrome; Ovarian cancer; PARP inhibitors
    DOI:  https://doi.org/10.1016/j.gore.2021.100873
  8. BMC Cancer. 2021 Dec 20. 21(1): 1350
    Prevalence of BRCA1 and BRCA2 pathogenic sequence variants in ovarian cancer patients in the Gulf region: the PREDICT study.
    Fathi Azribi, Ehab Abdou, Emad Dawoud, Mohamed Ashour, Amgad Kamal, Mohamed Al Sayed, Ikram Burney.
       BACKGROUND: Patients with pathogenic sequence variants (PSVs) in BRCA1/BRCA2 are at high risk of developing ovarian cancer (OC). However, genetic testing for BRCA1/BRCA2 PSVs is still not a routine practice in the Middle East. With the lack of epidemiological studies in the region, we aim to describe the prevalence of BRCA1/BRCA2 PSVs in patients with OC across different countries in the Gulf region.
    METHODS: The PREDICT study was an observational, prospective, epidemiological study, which consecutively recruited women with ovarian, primary peritoneal, and fallopian tube cancers from the following Gulf countries over the period from July 2017 to July 2019; United Arab Emirates (UAE), Kuwait, and Oman. The study was approved by the local ethics committee of participating centers. The BRCA1/BRCA2 PSVs were assessed by tissue genetic testing using next-generation sequencing (NGS).
    RESULTS: A total of 105 women were included with a median age at diagnosis of 52 years (IQR 44.5 - 61.0). Nearly 11.4% of patients reported a family history of ovarian or breast cancer, while 4.7% of patients reported a family history of other cancers. Most of the patients (70.3%) had advanced disease (FIGO stage III/IV) at presentation. Eighty-eight patients (84%) were successfully tested for somatic BRCA1/BRCA2 PSVs. Fifteen patients (17%) were found to have PSVs in either BRCA1, BRCA2, or both genes; of them, 10 patients (11.2%) had BRCA1 somatic PSVs alone, eight patients (9.1%) had BRCA2 somatic PSVs, while three patients (2.9%) had both PSVs. Five patients with BRCA1/BRCA2 somatic PSVs had germline PSVs tests, and three of them tested positive. Concerning treatment, 87.6% of patients received perioperative chemotherapy and 6.6% as first-line palliative chemotherapy. Eighty-seven (82.9%) patients underwent debulking surgery, with no residual disease in 42.5% of patients.
    CONCLUSION: Our study showed that the prevalence of BRCA1/BRCA2 somatic PSVs in patients with OC is higher than the reported global figures (2-8%). However, more studies are warranted to further elucidate the prevalence of BRCA1/BRCA2 somatic and germline PSVs, as well as other relevant genetic alterations, to better understand their impact on OC patient outcomes in Gulf countries.
    TRIAL REGISTRATION: NCT03082976 .
    Keywords:  Cancer genetics; Epidemiology; Gynaecological oncology
    DOI:  https://doi.org/10.1186/s12885-021-09094-8
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