bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022–07–17
seven papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Inherited Germline Cancer Susceptibility Gene Variants in Individuals with Non-Muscle-Invasive Bladder Cancer.
  2. Gastrointestinal stromal tumors caused by novel germline variants in SDHB and KIT: a report of two cases and literature review.
  3. Fumarate hydratase gene germline variants and mosaicism associated with pheochromocytoma and paraganglioma.
  4. Two Clinical Cases of Li-Fraumeni Syndrome and Prostate Cancer: Genetic Counseling and Clinical-Surgical Management.
  5. Decision-making and regret in patients with germline CDH1 variants undergoing prophylactic total gastrectomy.
  6. Pancreatic mixed acinar-neuroendocrine carcinoma in a patient with a germline BRCA2 mutation: a case report.
  7. Molecular testing of rhabdomyosarcoma in clinical trials to improve risk stratification and outcome: A consensus view from European paediatric Soft tissue sarcoma Study Group, Children's Oncology Group and Cooperative Weichteilsarkom-Studiengruppe.
  1. Clin Cancer Res. 2022 Jul 14. pii: ccr.22.1006. [Epub ahead of print]
    Inherited Germline Cancer Susceptibility Gene Variants in Individuals with Non-Muscle-Invasive Bladder Cancer.
    Eugene J Pietzak, Karissa Whiting, Preethi Srinivasan, Chaitanya Bandlamudi, Aliya Khurram, Vijai Joseph, Aleksandra Walasek, Emily Bochner, Timothy Clinton, Nima Almassi, Hong Truong, Manuel R de Jesus Escano, Michal Wiseman, Diana Mandelker, Yelena Kemel, Liying Zhang, Michael F Walsh, Karen A Cadoo, Jonathan A Coleman, Hikmat Al-Ahmadie, Jonathan E Rosenberg, Gopakumar V Iyer, David B Solit, Irina Ostrovnaya, Kenneth Offit, Mark E Robson, Zsofia K Stadler, Michael F Berger, Dean F Bajorin, Maria Carlo, Bernard H Bochner.
       PURPOSE: Identification of inherited germline variants can guide personalized cancer screening, prevention, and treatment. Pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes are frequent among patients with locally advanced or metastatic urothelial carcinoma, but their prevalence and significance in patients with non-muscle invasive bladder cancer (NMIBC), the most common form of urothelial carcinoma, is understudied.
    EXPERIMENTAL DESIGN: Germline analysis was conducted on paired tumor/normal sequencing results from two distinct cohorts of patients initially diagnosed with NMIBC. Associations between clinicopathologic features and clinical outcomes with the presence of P/LP germline variants in ≥76 hereditary cancer predisposition genes were analyzed.
    RESULTS: A similar frequency of P/LP germline variants were seen in our two NMIBC cohorts (12% [12/99] vs. 8.7% [10/115], p=0.4). In the combined analysis, P/LP germline variants were found only in patients with high-grade NMIBC (22/163), but none of the 46 patients with low-grade NMIBC (13.5% vs. 0%, p=0.005). Fifteen (9.2%) patients with high-grade NMIBC had P/LP variants in DNA damage response (DDR) genes, most within the nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways. Contrary to prior reports in NMIBC patients not receiving BCG, P/LP germline variants were not associated with worse recurrence-free or progression-free survival in patients treated with BCG.
    CONCLUSIONS: Our results support offering germline counseling and testing for all patients with high-grade bladder cancer, regardless of the initial tumor stage. Therapeutic strategies that target impaired DNA repair may benefit patients with high-grade NMIBC.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-1006
  2. Clin J Gastroenterol. 2022 Jul 11.
    Gastrointestinal stromal tumors caused by novel germline variants in SDHB and KIT: a report of two cases and literature review.
    Sean Rasmussen, Ashley Stueck, Bruce Colwell, Daniel Gaston, Michael Carter.
      Gastrointestinal stromal tumors (GISTs) are usually caused by somatic mutations, but there are rare germline variants that predispose patients to the development of one or, more commonly, multiple GISTs. We present 2 cases of multifocal GISTs related to previously unreported germline variants. The first case is a 28-year-old female who developed multiple gastric GISTs with widespread abdominal metastases that were resistant to imatinib. Assessment by Medical Genetics identified a germline SDHB splice site mutation (NM_003000.3, c.286 + 2T > G, p.?). The second case is a 64-year-old male who presented with multiple gastric tumors that were resistant to imatinib. Next-generation sequencing revealed a germline KIT exon 17 mutation (NM_000222.3, c.2459A > T, p.D820V). These cases highlight the diverse clinical presentations of patients with germline variants and raise several important points about the diagnosis and management of these patients, in particular: mutation in the SDH family of genes (somatic or germline) should be suspected in KIT and PDGFRA wild-type tumors; germline testing should be considered in patients with multiple GISTs or those who present with disease at a young age; and somatic next-generation sequencing cannot only help identify optimal therapy in all patients with GISTs but also help guide referral to Medical Genetics for appropriate patients.
    Keywords:  Gastric cancer; Gastrointestinal stromal tumors; Hereditary cancer syndromes; Next-generation sequencing
    DOI:  https://doi.org/10.1007/s12328-022-01672-y
  3. Ann N Y Acad Sci. 2022 Jul 12.
    Fumarate hydratase gene germline variants and mosaicism associated with pheochromocytoma and paraganglioma.
    Xiaosen Ma, Yunying Cui, Yinjie Gao, Xuebin Zhang, Min Nie, Anli Tong.
      Fumarate hydratase (FH) catalyzes the conversion of fumaric acid to L-malic acid. Heterozygous variants of the human fumarate hydratase gene (FH) predispose to hereditary leiomyomatosis and renal cell cancer and, rarely, pheochromocytoma/paraganglioma (PPGL). No mosaic variant in FH has been reported yet. Using next-generation sequencing, five individuals with FH variants were found in 319 PPGL patients. Immunohistochemistry staining and loss of heterozygosity analysis in tumor tissues were performed to determine the pathogenicity of the variants. Deep targeted sequencing was performed on the peripheral blood DNA of a pheochromocytoma (PCC) patient with uterine leiomyomas. Finally, two of the five variants were found to be pathogenic. A germline variant (c.817G>A, p.Ala273Thr) was found in a patient with a PPGL family history. A mosaic variant (c.206G>A, p.Gly69Asp) with an allelic ratio of 5% in blood DNA was confirmed in the PCC patient with uterine leiomyomas. No metastatic PPGL was observed in the two PPGL patients with FH pathogenic variants. In summary, we report mosaicism in FH and the first PPGL pedigree with an FH pathogenic germline variant. Both germline variants and mosaicism should be taken into account during genetic testing.
    Keywords:  FH; genetics; mosaicism; paraganglioma; pheochromocytoma
    DOI:  https://doi.org/10.1111/nyas.14866
  4. Clin Genitourin Cancer. 2022 Jun 09. pii: S1558-7673(22)00129-X. [Epub ahead of print]
    Two Clinical Cases of Li-Fraumeni Syndrome and Prostate Cancer: Genetic Counseling and Clinical-Surgical Management.
    Guillem Abad-Carratalà, Marc Blanco-Silvestre, Anna Sánchez-Llopis, Rosa Monsonís-Usó, Conrado Martínez-Cadenas, Pedro Martínez-Meneu, Bárbara Amaya-Barroso, Elia Muñoz-Vicente, Carmen Garau-Perelló, Paula Ponce-Blasco, Laura Barrios-Arnau, Manuel Bosquet-Sanz, Miguel Rodrigo-Aliaga.
      
    Keywords:  TP53 mutation; treatment
    DOI:  https://doi.org/10.1016/j.clgc.2022.06.002
  5. J Med Genet. 2022 Jul 11. pii: jmedgenet-2022-108733. [Epub ahead of print]
    Decision-making and regret in patients with germline CDH1 variants undergoing prophylactic total gastrectomy.
    Lauren A Gamble, Robert R C Grant, Sarah G Samaranayake, Grace-Ann Fasaye, Christopher Koh, Louis Korman, Bilal Asif, Theo Heller, Jonathan M Hernandez, Andrew M Blakely, Jeremy L Davis.
       INTRODUCTION: Prophylactic total gastrectomy (PTG) can eliminate gastric cancer risk and is recommended in carriers of a germline CDH1 pathogenic variant. PTG has established risks and potential life-long morbidity. Decision-making regarding PTG is complex and not well-understood.
    METHODS: Individuals with germline CDH1 pathogenic or likely pathogenic variants who underwent surveillance endoscopy and recommended for PTG were evaluated. Factors associated with decision to pursue PTG (PTGpos) or not (PTGneg) were queried. A decision-regret survey was administered to patients who elected PTG.
    RESULTS: Decision-making was assessed in 120 patients. PTGpos patients (63%, 76/120) were younger than PTGneg (median 45 vs 58 years) and more often had a strong family history of gastric cancer (80.3% vs 34.1%). PTGpos patients reported decision-making based on family history more often and decided soon after diagnosis (8 vs 27 months) compared with PTGneg. Negative endoscopic surveillance results were more common among PTGneg patients. Age >60 years, male sex and longer time to decision were associated with deferring PTG. Strong family history, a family member who died of gastric cancer and carcinoma on endoscopic biopsies were associated with decision to pursue PTG. In the PTGpos group, 30 patients (43%) reported regret which was associated with occurrence of a postoperative complication and no carcinoma detected on final pathology.
    CONCLUSION: The decision to undergo PTG is influenced by family cancer history and surveillance endoscopy results. Regret is associated with surgical complications and pathological absence of cancer. Individual cancer-risk assessment is necessary to improve pre-operative counselling and inform the decision-making process.
    TRIAL REGISTRATION NUMBER: NCT03030404.
    Keywords:  clinical decision-making; digestive system neoplasms; genetic predisposition to disease; surgical oncology; surgical procedures, operative
    DOI:  https://doi.org/10.1136/jmg-2022-108733
  6. Clin J Gastroenterol. 2022 Jul 12.
    Pancreatic mixed acinar-neuroendocrine carcinoma in a patient with a germline BRCA2 mutation: a case report.
    Mio Ikeda, Shin Miura, Kiyoshi Kume, Kazuhiro Kikuta, Shin Hamada, Tetsuya Takikawa, Kei Nakagawa, Michiaki Unno, Toru Furukawa, Atsushi Masamune.
      Loss of function in the BRCA2 gene exacerbates ovarian, breast, and pancreatic ductal cancer risk. Despite being implicated in the pancreatic ductal epithelium carcinogenesis, the involvement of a germline BRCA2 mutation in acinar and endocrine cells is less reported. A 45-year-old woman with a history of breast cancer was referred to our hospital for a detailed examination of epigastric pain. Her father had pancreatic cancer, and her paternal aunt had a history of breast cancer. Contrast-enhanced computed tomography revealed a round tumor with a contrast effect in the pancreatic head. The patient underwent pancreaticoduodenectomy, and postoperative pathology and genetic testing revealed amphicrine-type mixed acinar-neuroendocrine carcinoma with a germline BRCA2 mutation. Recent studies have reported the BRCA2 mutation in genome sequencing of pancreatic acinar cell carcinoma and neuroendocrine tumor; perhaps, genetic testing for the BRCA2 mutation is feasible for patients with mixed neuroendocrine-non-neuroendocrine neoplasm.
    Keywords:  BRCA1; BRCA2; MiNEN; Pancreatic cancer; Pancreatic tumor
    DOI:  https://doi.org/10.1007/s12328-022-01668-8
  7. Eur J Cancer. 2022 Jul 11. pii: S0959-8049(22)00324-0. [Epub ahead of print]172 367-386
    Molecular testing of rhabdomyosarcoma in clinical trials to improve risk stratification and outcome: A consensus view from European paediatric Soft tissue sarcoma Study Group, Children's Oncology Group and Cooperative Weichteilsarkom-Studiengruppe.
    Simone Hettmer, Corinne M Linardic, Anna Kelsey, Erin R Rudzinski, Christian Vokuhl, Joanna Selfe, Olivia Ruhen, Jack F Shern, Javed Khan, Alexander R Kovach, Philip J Lupo, Susanne A Gatz, Beat W Schäfer, Samuel Volchenboum, Véronique Minard-Colin, Ewa Koscielniak, Douglas S Hawkins, Gianni Bisogno, Monika Sparber-Sauer, Rajkumar Venkatramani, Johannes H M Merks, Janet Shipley.
      Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas in children/adolescents less than 18 years of age with an annual incidence of 1-2/million. Inter/intra-tumour heterogeneity raise challenges in clinical, pathological and biological research studies. Risk stratification in European and North American clinical trials previously relied on clinico-pathological features, but now, incorporates PAX3/7-FOXO1-fusion gene status in the place of alveolar histology. International working groups propose a coordinated approach through the INternational Soft Tissue SaRcoma ConsorTium to evaluate the specific genetic abnormalities and generate and integrate molecular and clinical data related to patients with RMS across different trial settings. We review relevant data and present a consensus view on what molecular features should be assessed. In particular, we recommend the assessment of the MYOD1-LR122R mutation for risk escalation, as it has been associated with poor outcomes in spindle/sclerosing RMS and rare RMS with classic embryonal histopathology. The prospective analyses of rare fusion genes beyond PAX3/7-FOXO1 will generate new data linked to outcomes and assessment of TP53 mutations and CDK4 amplification may confirm their prognostic value. Pathogenic/likely pathogenic germline variants in TP53 and other cancer predisposition genes should also be assessed. DNA/RNA profiling of tumours at diagnosis/relapse and serial analyses of plasma samples is recommended where possible to validate potential molecular biomarkers, identify new biomarkers and assess how liquid biopsy analyses can have the greatest benefit. Together with the development of new molecularly-derived therapeutic strategies that we review, a synchronised international approach is expected to enhance progress towards improved treatment assignment, management and outcomes for patients with RMS.
    Keywords:  Rhabdomyosarcoma; adolescent; gene signatures; germ line and somatic genetics; molecular biomarkers; molecular targets; paediatric; young adults
    DOI:  https://doi.org/10.1016/j.ejca.2022.05.036
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