bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022–11–20
six papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Whole exome sequencing identified a novel POT1 variant as a candidate pathogenic allele underlying a Li-Fraumeni-like family.
  2. Combined germline pathogenic variants in FLCN and TP53 are associated with early onset renal cell carcinoma and brain tumors.
  3. Germline pathogenic variants associated with ovarian cancer: A historical overview.
  4. Multigene Panel Testing Yields High Rates of Clinically Actionable Variants Among Patients With Colorectal Cancer.
  5. PARP-inhibitors for BRCA1/2-related advanced HER2-negative breast cancer: A meta-analysis and GRADE recommendations by the Italian Association of Medical Oncology.
  6. Association Between Family History and Risk of Pancreatic Cancer in Patients With BRCA1 and BRCA2 Pathogenic Variants.
  1. Front Oncol. 2022 ;12 963364
    Whole exome sequencing identified a novel POT1 variant as a candidate pathogenic allele underlying a Li-Fraumeni-like family.
    Yuping Li, Yupeng Xie, Di Wang, Hanyan Xu, Junru Ye, Jiani C Yin, Junjie Chen, Junrong Yan, Bin Ye, Chengshui Chen.
       Background: Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like (LFL) syndrome are rare hereditary diseases characterized by predisposition to a diverse spectrum of cancer types, primarily sarcoma. The pathogenic variants underlying the majority of LFL cases remain to be explored.
    Methods: We performed whole-exome sequencing (WES) on 13 core members of a large LFL family with highly aggregated incidences of cancers, including cases with sarcoma, non-small cell lung cancer and cardiac angiosarcoma, and conducted a comprehensive literature review of candidate gene associations in LFS/LFL syndromes or sarcoma to identify potential pathogenic germline variants.
    Results: No germline variants in the best-known LFL/LFS-associated gene TP53 were detected. Of all the genes associated with LFS/LFL or sarcoma that we have surveyed, we identified a novel p.P35L germline variant in POT1 (protection of telomeres 1). Germline and somatic alterations in POT1 have been implicated in a series of familial cancers, including angiosarcoma, glioma, melanoma and colorectal cancer. This particular variant is located in the telomere-binding OB1 domain, which is important in maintaining the proper telomere length, and showed high conservation across different POT1 orthologues. No record of the variant was found in any of the 1000 genomes, ExAC, gnomAD, dpSNP and COSMIC databases. Prediction algorithms and in silico structural analysis suggested completely disrupted protein structure and function of POT1 in the presence of this mutation.
    Conclusions: Leveraging WES, we identified a novel germline risk allele, p.P35L in POT1, that likely predisposes to LFL syndrome. Our results support the routine testing of POT1 and other LFL/LFS-associated genes in the risk populations to enable early cancer diagnosis, prevention and intervention.
    Keywords:  Li-Fraumeni-like syndrome; POT1; co-segregation; genetic risk alleles; whole exome sequencing (WES)
    DOI:  https://doi.org/10.3389/fonc.2022.963364
  2. Mol Genet Genomic Med. 2022 Nov 16. e2098
    Combined germline pathogenic variants in FLCN and TP53 are associated with early onset renal cell carcinoma and brain tumors.
    Irma van de Beek, Iris E Glykofridis, Anja Wagner, Dorine T den Toom, Ernie M H F Bongers, Geert J L H van Leenders, Paul C Johannesma, Hanne E J Meijers-Heijboer, Rob M F Wolthuis, Maurice A M van Steensel, Hendrikus J Dubbink, Arjan C Houweling.
       BACKGROUND: We present a family consisting of a father and his two children with an exceptional phenotype of childhood renal cell carcinoma and brain tumors. Extensive genetic testing revealed two inherited tumor predisposition syndromes in all three family members: Birt-Hogg-Dubé syndrome and Li-Fraumeni syndrome. The corresponding genes (FLCN and TP53) are both located on the short arm of chromosome 17.
    METHODS: We describe the phenotype and performed single nucleotide polymorphism (SNP)-based loss of heterozygosity (LOH) analysis of the tumors.
    RESULTS: All examined tumors showed somatic loss of the wild-type alleles of both FLCN and TP53.
    CONCLUSIONS: We hypothesize that a synergistic effect of both mutations caused the unusual phenotype of childhood renal cell carcinoma in this family. This family emphasizes the importance of further genetic testing if a tumor develops at an unexpected young age in an inherited cancer predisposition syndrome.
    Keywords:  Birt-Hogg-Dubé syndrome; Li-Fraumeni syndrome; loss of heterozygosity; renal cell carcinoma
    DOI:  https://doi.org/10.1002/mgg3.2098
  3. Gynecol Oncol Rep. 2022 Dec;44 101105
    Germline pathogenic variants associated with ovarian cancer: A historical overview.
    Emma Lund Johansen, Christine Fribert Thusgaard, Mads Thomassen, Susanne Eriksen Boonen, Kirsten Marie Jochumsen.
      The risk of ovarian, tubal, and peritoneal cancer is related to germline pathogenic variants, and over time, the number of known disease-associated genes has increased significantly. This study reviews the literature regarding the topic from a historical perspective. The aim is to present a timeline of the knowledge gained from the early 1900s until today. The findings are put into perspective by looking at the current gene panel used for screening for suspected hereditary ovarian cancer in Denmark compared to what is known internationally. In 1929, the first familial ovarian cancer incidents were registered, and in 1950, the involvement of a genetic component was suggested for the first time. During the 1970s, several studies reported an accumulation of ovarian cancer in certain families, and during this time, it was discovered that ovarian cancer was linked to both breast cancer and colorectal cancer. The inheritance of cancer disposition has been thoroughly investigated, leading to the discovery of the BRCA genes in the 1990s. Furthermore, new studies based on new genetic technologies have revealed several genes with germline pathogenic variants that increase the risk of ovarian cancer. The identification of these pathogenic variants has led to preventive measures and specific treatment of women with genetic disposition to ovarian cancer. In Denmark, consensus is to include at least ten genes in the screening panel for hereditary ovarian cancer, and in the future additional genes will probably be added.
    Keywords:  Genetic; Germline pathogenic gene variants; Hereditary ovarian cancer; Historical perspective
    DOI:  https://doi.org/10.1016/j.gore.2022.101105
  4. JCO Precis Oncol. 2022 Nov;6 e2200517
    Multigene Panel Testing Yields High Rates of Clinically Actionable Variants Among Patients With Colorectal Cancer.
    Sarah E Coughlin, Brandie Heald, Dana Farengo Clark, Sarah M Nielsen, Kathryn E Hatchell, Edward D Esplin, Bryson W Katona.
       PURPOSE: Whether germline multigene panel testing (MGPT) should be performed in all individuals with colorectal cancer (CRC) remains uncertain. Therefore, we aimed to determine the yield and potential clinical impact of MGPT across a large, diverse CRC cohort.
    METHODS: This was a retrospective cohort study of adults with CRC who underwent MGPT of > 10 genes at a commercial laboratory between March 2015 and May 2021. All data were prospectively collected through a single commercial laboratory and retrospectively analyzed.
    RESULTS: A total of 34,244 individuals with a history of CRC underwent germline MPGT and were included in the analysis. This cohort was predominantly female (60.7%), White (70.6%), and age 50 years or older (68.9%), with 35.5% also reporting a noncolorectal malignancy. At least one pathogenic/likely pathogenic germline variant (PGV) was found in 4,864 (14.2%), with 3,111 (9.1%) having a PGV associated with increased CRC/polyposis risk and 1,048 (3.1%) having an otherwise clinically actionable PGV. Larger gene panels were not clearly associated with higher yield of clinically actionable PGVs. PGVs were more prevalent in individuals of Ashkenazi Jewish descent (P < .001) and Hispanic ethnicity (P < .001). Across all ages, panel sizes, and races/ethnicities, the rate of clinically actionable PGVs on MGPT was 7.9% or greater. A variant of uncertain significance was identified in 13,094 individuals (38.2%). Identification of a variant of uncertain significance associated with panel size (P < .001) and was lower in individuals of Ashkenazi Jewish descent (P < .001), but higher in Black, Asian, and Hispanic individuals (P < .001).
    CONCLUSION: To our knowledge, this is the largest study to date examining MGPT in CRC, demonstrating high rates of clinically actionable variants detected across all age groups, panel sizes, and racial/ethnic groups. This work supports consideration of broadening germline genetic testing criteria for individuals with CRC.
    DOI:  https://doi.org/10.1200/PO.22.00517
  5. Breast. 2022 Oct 29. pii: S0960-9776(22)00179-5. [Epub ahead of print]66 293-304
    PARP-inhibitors for BRCA1/2-related advanced HER2-negative breast cancer: A meta-analysis and GRADE recommendations by the Italian Association of Medical Oncology.
    Federica Miglietta, Michela Cinquini, Maria Vittoria Dieci, Laura Cortesi, Carmen Criscitiello, Filippo Montemurro, Lucia Del Mastro, Alberto Zambelli, Laura Biganzoli, Alessia Levaggi, Chiara Delle Piane, Caterina Marchiò, Massimo Calabrese, Lucio Fortunato, Pierfrancesco Franco, Bruno Meduri, Veronica Andrea Fittipaldo, Stefania Gori.
       BACKGROUND: Approximately 5-10% of unselected breast cancer (BC) patients retain a hereditary predisposition related to a germline mutation in BRCA1/2 genes. The poly-ADP ribose polymerase (PARP)-inhibitors olaparib and talazoparib have been granted marketing authorization by both FDA and EMA for adults with BRCA1/2 germline mutations and HER2-negative (HER2-) advanced BC based on the results from the phase III OlympiAd and EMBRACA trials.
    METHODS: The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer addressed two critical clinical questions, adopting the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach and the Evidence to Decision framework (EtD), to develop recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related triple-negative (clinical question 1) and hormone receptor-positive (HR+)/HER2- (clinical question 2) advanced BC.
    RESULTS: Two studies were eligible (OlympiAd and EMBRACA). For both clinical questions, the Panel judged the benefit/harm balance probably in favor of the intervention, given the favorable impact in terms of PFS, ORR, and QoL at an acceptable cost in terms of toxicity; the overall certainty of the evidence was low. The panel's final recommendations were conditional in favor of PARP-inhibitors over single-agent chemotherapy in both HR+/HER2-and triple-negative BC. Finally, the Panel identified and discussed areas of uncertainty calling for further exploration.
    CONCLUSIONS: The Panel of AIOM BC Clinical Practice Guideline provided clinical recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related HER2-advanced BC by adopting the GRADE methodology.
    Keywords:  BRCA germline mutations; Breast cancer; GRADE methodology; HER2-negative; PARP-Inhibitors
    DOI:  https://doi.org/10.1016/j.breast.2022.10.014
  6. Pancreas. 2022 Aug 01. 51(7): 733-738
    Association Between Family History and Risk of Pancreatic Cancer in Patients With BRCA1 and BRCA2 Pathogenic Variants.
    Ishani Shah, Andy Silva-Santisteban, Katharine A Germansky, Cinthana Kandasamy, Jack Mlabasati, Dora C Huang, Vaibhav Wadhwa, Mohammad Bilal, Mandeep S Sawhney.
       OBJECTIVES: Current guidelines limit pancreatic cancer screening to those BRCA1/2 patients who have a family history of pancreatic cancer. We aimed to assess the association between family history and risk of pancreatic neoplasms in BRCA1/2 patients.
    METHODS: We reviewed medical records of BRCA1/2 patients followed at our institution between 1995 and 2020. Family history was defined as those with a first-degree relative with pancreatic cancer. We compared the incidence and prevalence of pancreatic neoplasms between patients with and without family history of pancreatic cancer.
    RESULTS: We identified 56 BRCA1/2 patients with family history and 238 without family history of pancreatic cancer. No difference between these groups was noted in age, race, or sex. Mean follow-up interval for BRCA1/2 patients was 4.6 years (range, 0-19.7 years). There was no significant difference in prevalence (19.6% vs 12.6; P = 0.3) or incidence (29% vs 14.1%; P = 0.08) of branch-duct intraductal papillary mucinous neoplasm between the 2 groups. No association between family history and pancreatic cancer risk was noted. Only 1 of 10 BRCA1/2 patients with pancreatic cancer had a family history.
    CONCLUSIONS: Our results do not support using family history to determine eligibility for pancreatic cancer screening.
    DOI:  https://doi.org/10.1097/MPA.0000000000002104
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