bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2024–05–26
eight papers selected by
Joanna Zawacka, Karolinska Institutet
  1. Germline Pathogenic Variants in Patients With Pancreatic and Periampullary Cancers.
  2. Prevalence and clinical outcomes of germline variants among patients with myeloid neoplasms.
  3. Li-Fraumeni Syndrome With Six Primary Tumors-Case Report.
  4. Germline Predisposition in Hematologic Malignancies: Testing, Management, and Implications.
  5. De novo germline TP53 mutation in a pediatric patient with Li-Fraumeni syndrome and diffuse peritoneal mesothelioma.
  6. Incidental Germline Findings During Comprehensive Genomic Profiling of Pancreatic and Colorectal Cancer: Single-center, Molecular Tumor Board Experience.
  7. A case series of non-small cell lung cancer patients with EGFR or HER2 exon 20 insertion in Li Fraumeni syndrome.
  8. A Novel EGFR Germline Mutation in Lung Adenocarcinoma: Case Report and Literature Review.
  1. JCO Precis Oncol. 2024 May;8 e2400101
    Germline Pathogenic Variants in Patients With Pancreatic and Periampullary Cancers.
    Yohei Ando, Mohamad Dbouk, Takeichi Yoshida, Elizabeth Abou Diwan, Helena Saba, Ali Dbouk, Kanako Yoshida, Nicholas J Roberts, Alison P Klein, Richard Burkhart, Jin He, Ralph H Hruban, Michael Goggins.
       PURPOSE: Inherited cancer susceptibility is often not suspected in the absence of a significant cancer family history. Pathogenic germline variants in pancreatic cancer are well-studied, and routine genetic testing is recommended in the guidelines. However, data on rare periampullary cancers other than pancreatic cancer are insufficient. We compared the prevalence of germline susceptibility variants in patients with pancreatic cancer and nonpancreatic periampullary cancers.
    MATERIALS AND METHODS: Six hundred and eight patients who had undergone pancreaticoduodenal resection at a tertiary referral hospital were studied, including 213 with pancreatic ductal adenocarcinoma, 172 with ampullary cancer, 154 with distal common bile duct cancer, and 69 with duodenal adenocarcinoma. Twenty cancer susceptibility and candidate susceptibility genes were sequenced, and variant interpretation was assessed by interrogating ClinVar and PubMed.
    RESULTS: Pathogenic or likely pathogenic, moderate- to high-penetrant germline variants were identified in 46 patients (7.7%), including a similar percentage of patients with pancreatic (8.5%) and nonpancreatic periampullary cancer (7.1%). Low-penetrant variants were identified in an additional 11 patients (1.8%). Eighty-nine percent of the moderate- to high-penetrant variants involved the major cancer susceptibility genes BRCA2, ATM, BRCA1, CDKN2A, MSH2/MLH1, and PALB2; the remaining 11% involved other cancer susceptibility genes such as BRIP1, BAP1, and MSH6. Almost all pathogenic variant carriers had a family history of cancer.
    CONCLUSION: Patients with pancreatic and nonpancreatic periampullary cancer have a similar prevalence of pathogenic cancer susceptibility variants. Germline susceptibility testing should be considered for patients with any periampullary cancer.
    DOI:  https://doi.org/10.1200/PO.24.00101
  2. J Clin Pathol. 2024 May 22. pii: jcp-2023-209264. [Epub ahead of print]
    Prevalence and clinical outcomes of germline variants among patients with myeloid neoplasms.
    Sunisa Kongkiatkamon, Pimjai Niparuck, Thanawat Rattanathammethee, Sirorat Kobbuaklee, Amornchai Suksusut, Kitsada Wudhikarn, Chupong Ittiwut, Wanna Chetruengchai, Suporn Chuncharunee, Udomsak Bunworasate, Kanya Suphapeetiporn, Ponlapat Rojnuckarin, Chantana Polprasert.
       AIMS: Myeloid neoplasms (MNs) with germline predisposition have been recognised as a distinct entity. Emerging evidence suggests that sporadic myelodysplastic syndromes may also harbour undetected germline predispositions. We investigated germline alterations in a cohort of 122 adult Thai MNs.
    METHODS: MN patients were recruited and tested for germline variants using deep targeted next-generation sequencing. The germline variant was filtered using American College of Medical Genetics classifications and then evaluated for the association with clinical characteristics and outcomes.
    RESULTS: Our findings revealed pathogenic/likely pathogenic germline alterations in 12 (10%) of the patients. These germline lesions were commonly found in the DNA damage response pathway (n=6, 50%). We also identified novel deleterious FANCA A1219GfsTer59 variants in two patients diagnosed with secondary acute myeloid leukaemia (sAML) from aplastic anaemia and AML with myelodysplasia related. Among sAML, individuals with germline mutations had inferior overall survival compared with those with wild-type alleles (2 months vs 12 months) with HR 4.7 (95% CI 1.0 to 20), p=0.037. Therefore, the presence of pathogenic or likely pathogenic mutations may be linked to inferior survival outcomes.
    CONCLUSIONS: Our study highlighted that the prevalence of germline predisposition in Southeast Asian populations is comparable to that in Caucasians. This underscores the importance of germline genetic testing within the Asian population.
    Keywords:  GENETICS; Genes, Neoplasm; Hematologic Diseases; Leukemia, Myeloid
    DOI:  https://doi.org/10.1136/jcp-2023-209264
  3. Case Rep Oncol Med. 2024 ;2024 6699698
    Li-Fraumeni Syndrome With Six Primary Tumors-Case Report.
    Dejan Stojiljković, Ana Cvetković, Andrej Jokić, Dijana Mirčić, Sanja Mihajlović, Ana Krivokuća, Marija Đorđić Crnogorac, Lazar Glisic.
      Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with a high, lifetime risk of a broad spectrum of cancers caused by pathogenic germline TP53 mutations. Numerous different germline TP53 mutations have been associated with LFS, which has an exceptionally diverse clinical spectrum in terms of tumor type and age of onset. Our patient has developed six asynchronous tumors to date: a phyllode tumor of the breast, a pheochromocytoma, a rosette-forming glioneuronal tumor (RGNT), an adrenocortical carcinoma (ACC), a ductal carcinoma of the breast, and a thymoma. The occurrence of such a number of rare tumors is sporadic even among in the population of patients living with cancer predisposition syndromes. In this instance, the omission of pretest genetic counseling and thorough family tree analysis prior to selecting the test led to the oversight of an underlying TP53 likely pathogenic mutation (classified as Class 4). This emphasizes the necessity for such counseling to prevent overlooking crucial genetic information. Neglecting this step could have had profound implications on the patient's treatment, particularly considering the early onset and occurrence of multiple tumors, which typically raise suspicion of a hereditary component. The implications for family members must be considered.
    Keywords:  Li-Fraumeni; case report; mitotane; p53
    DOI:  https://doi.org/10.1155/2024/6699698
  4. Am Soc Clin Oncol Educ Book. 2024 Jun;44(3): e432218
    Germline Predisposition in Hematologic Malignancies: Testing, Management, and Implications.
    Lucy A Godley, Courtney D DiNardo, Kelly Bolton.
      Although numerous barriers for clinical germline cancer predisposition testing exist, the increasing recognition of deleterious germline DNA variants contributing to myeloid malignancy risk is yielding steady improvements in referrals for testing and testing availability. Many germline predisposition alleles are common in populations, and the increasing number of recognized disorders makes inherited myeloid malignancy risk an entity worthy of consideration for all patients regardless of age at diagnosis. Germline testing is facilitated by obtaining DNA from cultured skin fibroblasts or hair bulbs, and cascade testing is easily performed via buccal swab, saliva, or blood. Increasingly as diagnostic criteria and clinical management guidelines include germline myeloid malignancy predisposition, insurance companies recognize the value of testing and provide coverage. Once an individual is recognized to have a deleterious germline variant that confers risk for myeloid malignancies, a personalized cancer surveillance plan can be developed that incorporates screening for other cancer risk outside of the hematopoietic system and/or other organ pathology. The future may also include monitoring the development of clonal hematopoiesis, which is common for many of these cancer risk disorders and/or inclusion of strategies to delay or prevent progression to overt myeloid malignancy. As research continues to identify new myeloid predisposition disorders, we may soon recommend testing for these conditions for all patients diagnosed with a myeloid predisposition condition.
    DOI:  https://doi.org/10.1200/EDBK_432218
  5. Pediatr Blood Cancer. 2024 May 21. e31071
    De novo germline TP53 mutation in a pediatric patient with Li-Fraumeni syndrome and diffuse peritoneal mesothelioma.
    Melek Yaman Ortaköylü, Sonay İncesoy Özdemir, Handan Dinçaslan, Nurdan Taçyıldız, Ufuk Ateş, Ali Ekrem Ünal, Çiğdem Soydal, Ömer Suat Fitoz, Halil Gürhan Karabulut, Hatice Ilgın Ruhi, Emel Cabi Ünal.
      
    DOI:  https://doi.org/10.1002/pbc.31071
  6. Mutagenesis. 2024 May 22. pii: geae014. [Epub ahead of print]
    Incidental Germline Findings During Comprehensive Genomic Profiling of Pancreatic and Colorectal Cancer: Single-center, Molecular Tumor Board Experience.
    Michal Eid, Jakub Trizuljak, Renata Taslerova, Martin Gryc, Jakub Vlazny, Sara Vilmanova, Martina Jelinkova, Alena Homolova, Stepan Tucek, Jan Hlavsa, Tomas Grolich, Zdenek Kala, Zdenek Kral, Ondrej Slaby.
      
    Keywords:  colorectal cancer; germline variants; next-generation sequencing; pancreatic cancer; somatic variants
    DOI:  https://doi.org/10.1093/mutage/geae014
  7. Tumori. 2024 May 23. 3008916241255485
    A case series of non-small cell lung cancer patients with EGFR or HER2 exon 20 insertion in Li Fraumeni syndrome.
    Valeria Cognigni, Enrica Capelletto, Paola Bordi, Valeria Pavese, Federica Maria Carfì, Francesco Gelsomino, Andrea De Giglio, Rita Chiari, Roberta Minari, Enrico Ambrosini, Antonio Percesepe, Daniela Giachino, Paolo Bironzo, Marcello Tiseo.
       INTRODUCTION: Germline pathogenic mutations in TP53 gene are associated with a cancer predisposition syndrome known as Li Fraumeni syndrome. Albeit infrequently, non-small cell lung cancer, especially as oncogene-addicted disease, may be diagnosed in young patients with Li Fraumeni syndrome.
    CASE DESCRIPTION: We report three cases of patients affected by Li Fraumeni syndrome who developed non-small cell lung cancer with EGFR or HER2 exon 20 insertions. The first patient suffered from liposarcoma and, then, brain metastases from HER2-mutated non-small cell lung cancer: after stereotactic radiotherapy, he benefited from enrollment in a clinical trial with a HER2-targeted therapy. The second young patient was a female with personal history of rhabdomyosarcoma, diagnosed with brain metastases from EGFR-mutated non-small cell lung cancer: enrollment in a clinical trial led to a temporary clinical benefit. The last case was a female diagnosed with breast carcinoma, ovarian granulosa cell tumor and advanced EGFR-mutated non-small cell lung cancer at a young age.
    CONCLUSIONS: Young patients affected by oncogene-addicted non-small cell lung cancer and with a positive familial cancer history should be referred for an accurate genetic counselling to look for Li Fraumeni syndrome. The underlying molecular connection between TP53 and HER family receptor tyrosine kinases remains unclear, but an extensive molecular characterization of tumors from patients with Li Fraumeni syndrome should always be performed, to offer patients a personalized therapeutic approach.
    Keywords:  EGFR; HER2; Li Fraumeni syndrome; Non-small cell lung cancer
    DOI:  https://doi.org/10.1177/03008916241255485
  8. Clin Lung Cancer. 2024 Apr 16. pii: S1525-7304(24)00052-4. [Epub ahead of print]
    A Novel EGFR Germline Mutation in Lung Adenocarcinoma: Case Report and Literature Review.
    Parth Sharma, Himil Mahadevia, Sreekanth Donepudi, Lara Kujtan, Beth Gustafson, Ben Ponvilawan, Ammar Al-Obaidi, Janakiraman Subramanian, Dhruv Bansal.
      
    Keywords:  Cancer screening; Genetic susceptibility; Germline testing; Next-generation sequencing; Targeted therapy
    DOI:  https://doi.org/10.1016/j.cllc.2024.04.009
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