bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2024–02–04
seven papers selected by
Joanna Zawacka, Karolinska Institutet
  1. Feasibility and Clinical Utility of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified in Research Germline Sequencing: A Prospective Interventional Study.
  2. Deficiencies in germline genetic testing in young-onset colorectal cancer patients.
  3. Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol.
  4. BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer.
  5. Myelodysplastic neoplasms evolving from inherited bone marrow failure syndromes / germline predisposition syndromes: Back under the microscope.
  6. High amount of fertility reducing tumors and procedures, but no evidence for premature ovarian failure in female Lynch syndrome patients.
  7. Rare germline mutation and MSH2-&MSH6 + expression in a double primary carcinoma of colorectal carcinoma and endometrial carcinoma: a case report.
  1. JCO Precis Oncol. 2024 Jan;8 e2300266
    Feasibility and Clinical Utility of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified in Research Germline Sequencing: A Prospective Interventional Study.
    Megan L Hutchcraft, Shulin Zhang, Nan Lin, Justine C Pickarski, Elizabeth A Belcher, Sainan Wei, Thèrése Bocklage, Rachel W Miller, John L Villano, Michael J Cavnar, Joseph Kim, Susanne M Arnold, Frederick R Ueland, Jill M Kolesar.
       PURPOSE: Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant secondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician.
    METHODS: This prospective, interventional cohort study enrolled Total Cancer Care participants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic analysis in a Clinical Laboratory Improvement Amendments-certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College of Medical Genomics and Genetics SF v2.0 genes. After a protocol modification in consenting patients, the MTB reported PGVs to treating oncology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing.
    RESULTS: Of the 781 enrolled participants, 32 (4.1%) harbored cancer predisposition PGVs, 24 (3.1%) were heterozygous carriers of an autosomal recessive cancer predisposition syndrome, and 14 (1.8%) had other hereditary disease PGVs. Guideline-directed testing would have missed 37.5% (12/32) of the inherited cancer predisposition PGVs, which included BRCA1, BRCA2, MSH6, SDHAF2, SDHB, and TP53 variants. Three hundred fifteen participants consented to reporting results; results for all living patients were reported to the clinical team with half referred to a licensed genetic counselor. There was concordance between all research variants identified in patients (n = 9) who underwent clinical confirmatory sequencing.
    CONCLUSION: MTB reporting of research-grade germline sequencing to the clinical oncology team is feasible. Over a third of PGVs identified using a universal testing strategy would have been missed by guideline-based approach, suggesting a role for expanding germline testing.
    DOI:  https://doi.org/10.1200/PO.23.00266
  2. Am J Surg. 2024 Jan 26. pii: S0002-9610(24)00025-4. [Epub ahead of print]
    Deficiencies in germline genetic testing in young-onset colorectal cancer patients.
    Hannah Ficarino, Ben Cage, Jean Paul Osula, Alexis Heatherly, Daniel Chu, Sushanth Reddy, Smita Bhatia, Robert Hollis.
       BACKGROUND: Young-onset colorectal cancer (YO-CRC) patients have high rates of pathologic genetic variants on germline testing, however it is unclear what factors are associated with genetic testing completion.
    METHODS: We performed a retrospective review of YO-CRC patients aged ≤50 years between 2014 and 2021 who received the entirety of their cancer care at a single institution. The primary outcome was completion of germline multigene panel testing. Variables were examined for association with germline multigene panel testing.
    RESULTS: Among 100 YO-CRC patients, only 31 ​% (n ​= ​31) completed genetic testing. Testing rates did not differ by colorectal cancer stage but were significantly higher among patients who received chemotherapy (39.8 ​% vs 5.9 ​%; p ​= ​0.01) and in patients with increasing number of relatives with a family history of cancer (p ​< ​0.01).
    CONCLUSIONS: Only one-third of YO-CRC patients completed genetic testing. Patients seen by oncology or with increasingly strong family cancer history were more likely to complete genetic testing.
    Keywords:  Colorectal cancer; Genetic counseling; Genetic testing; Young-onset
    DOI:  https://doi.org/10.1016/j.amjsurg.2024.01.022
  3. Trials. 2024 Feb 03. 25(1): 103
    Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol.
    Miriam Dixon-Zegeye, Rachel Shaw, Linda Collins, Kendra Perez-Smith, Alexander Ooms, Maggie Qiao, Pan Pantziarka, Louise Izatt, Marc Tischkowitz, Rachel E Harrison, Angela George, Emma R Woodward, Simon Lord, Lara Hawkes, D Gareth Evans, James Franklin, Helen Hanson, Sarah P Blagden.
       BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70-100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin's mechanism of anticancer activity in this context is unclear.
    METHODS: Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI.
    DISCUSSION: Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis.
    TRIAL REGISTRATION: ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.
    Keywords:  Cancer; Chemoprevention; LFS; Li-Fraumeni syndrome; Metformin; Precision-Prevention; TP53; p53
    DOI:  https://doi.org/10.1186/s13063-024-07929-w
  4. Cancer Med. 2024 Feb 02.
    BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer.
    Caroline Stahnke Richau, Nicole de Miranda Scherer, Bruna Palma Matta, Elvismary Molina de Armas, Fábio Carvalho de Barros Moreira, Anke Bergmann, Claudia Bessa Pereira Chaves, Mariana Boroni, Anna Claudia Evangelista Dos Santos, Miguel Angelo Martins Moreira.
       BACKGROUND: Approximately 3/4 of ovarian cancers are diagnosed in advanced stages, with the high-grade epithelial ovarian carcinoma (EOC) accounting for 90% of the cases. EOC present high genomic instability and somatic loss-of-function variants in genes associated with homologous recombination mutational repair pathway (HR), such as BRCA1 and BRCA2, and in TP53. The identification of germline variants in HR genes in EOC is relevant for treatment of platinum resistant tumors and relapsed tumors with therapies based in synthetic lethality such as PARP inhibitors. Patients with somatic variants in HR genes may also benefit from these therapies. In this work was analyzed the frequency of somatic variants in BRCA1, BRCA2, and TP53 in an EOC cohort of Brazilian patients, estimating the proportion of variants in tumoral tissue and their association with progression-free survival and overall survival.
    METHODS: The study was conducted with paired blood/tumor samples from 56 patients. Germline and tumoral sequences of BRCA1, BRCA2, and TP53 were obtained by massive parallel sequencing. The HaplotypeCaller method was used for calling germline variants, and somatic variants were called with Mutect2.
    RESULTS: A total of 26 germline variants were found, and seven patients presented germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2. The analysis of tumoral tissue identified 52 somatic variants in 41 patients, being 43 somatic variants affecting or likely affecting protein functionality. Survival analyses showed that tumor staging was associated with overall survival (OS), while the presence of somatic mutation in TP53 was not associated with OS or progression-free survival.
    CONCLUSION: Frequency of pathogenic or likely pathogenic germline variants in BRCA1 and BRCA2 (12.5%) was lower in comparison with other studies. TP53 was the most altered gene in tumors, with 62.5% presenting likely non-functional or non-functional somatic variants, while eight 14.2% presented likely non-functional or non-functional somatic variants in BRCA1 or BRCA2.
    Keywords:   BRCA1 ; BRCA2 ; TP53 ; homologous recombination repair pathway; ovarian cancer; somatic mutation
    DOI:  https://doi.org/10.1002/cam4.6729
  5. Leuk Res. 2024 Jan 23. pii: S0145-2126(24)00007-9. [Epub ahead of print]137 107441
    Myelodysplastic neoplasms evolving from inherited bone marrow failure syndromes / germline predisposition syndromes: Back under the microscope.
    M Tarek Elghetany, Mrinal M Patnaik, Joseph D Khoury.
      Inherited bone marrow failure syndromes and germline predisposition syndromes (IBMFS/GPS) are associated with increased risk for hematologic malignancies, particularly myeloid neoplasms, such as myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). The diagnosis of MDS in these syndromes poses difficulty due to frequent bone marrow hypocellularity and the presence of some degree of dysplastic features related to the underlying germline defect causing abnormal maturation of one or more cell lines. Yet, the diagnosis of MDS is usually associated with a worse outcome in several IBMFS/GPS. Criteria for the diagnosis of MDS in IBMFS/GPS have not been standardized with some authors suggesting a mixture of morphologic, cytogenetic, and genetic criteria. This review highlights these challenges and suggests a more standardized approach to nomenclature and diagnostic criteria.
    Keywords:  Bone marrow; Cytogenetics; Germline predisposition; Inherited bone marrow failure; Myelodysplastic syndrome clonal evolution
    DOI:  https://doi.org/10.1016/j.leukres.2024.107441
  6. Fam Cancer. 2024 Jan 27.
    High amount of fertility reducing tumors and procedures, but no evidence for premature ovarian failure in female Lynch syndrome patients.
    Sabine Biermann, Michael Knapp, Peter Wieacker, Stefan Aretz, Verena Steinke-Lange.
      Lynch syndrome (LS; HNPCC) patients carry heterozygous pathogenic germline variants in mismatch repair (MMR) genes, which have also been shown to play an important role in meiosis. Therefore, it was hypothesized, that LS might be associated with a higher risk for premature ovarian failure (POF) or earlier menopause. Data on medical gynaecological history, cancer diagnoses and therapy were collected from 167 female LS patients and compared to a population-based control cohort. There was no difference between the age of menopause in patients compared to controls and no evidence for a higher risk of POF in LS patients. However, around one third (35%) of the probands have already had premenopausal cancer and mostly cancer-related treatment affecting fertility before the age of 45 years. Therefore, childbearing time might still be limited in these patients, especially due to the premenopausal cancer risk. LS patients should be informed in time about the elevated premenopausal cancer risks and the possible impact on family planning. This is particularly relevant since the average childbearing age has increased during the last decades.
    Keywords:  Cancer predisposition; Hereditary CRC; Lynch syndrome; Menopause; Mismatch-repair genes
    DOI:  https://doi.org/10.1007/s10689-024-00357-4
  7. Diagn Pathol. 2024 Jan 31. 19(1): 25
    Rare germline mutation and MSH2-&MSH6 + expression in a double primary carcinoma of colorectal carcinoma and endometrial carcinoma: a case report.
    Tiansong Zhang, Xiaoqiang Huang, Wenjie Liu, Xiulan Ling, Zhenping Su, Mengwei Huang, Shuanlong Che.
       BACKGROUND: Multiple primary malignancies are rare in cancer patients, and risk factors may include genetics, viral infection, smoking, radiation, and other environmental factors. Lynch syndrome (LS) is the most prevalent form of hereditary predisposition to double primary colorectal and endometrial cancer in females. LS, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a common autosomal dominant condition. Pathogenic germline variants in the DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2, and less frequently, deletions in the 3' end of EPCAM cause LS. It manifested itself as loss of MMR nuclear tumor staining (MMR protein deficient, dMMR).
    CASE PRESENTATION: This case study describes a double primary carcinoma in a 49-year-old female. In June 2022, the patient was diagnosed with highly to moderately differentiated endometrioid adenocarcinoma. The patient's mother died of esophageal cancer at age 50, and the father died of undefined reasons at age 70. Immunohistochemical stainings found ER (++), PR (++), P53 (+), MSH2 (-), MSH6 (+), MLH1 (+), and PMS2 (+). MMR gene sequencing was performed on endometrial tumor and peripheral blood samples from this patient. The patient carried two pathogenic somatic mutations in the endometrial tumor, MSH6 c.3261dupC (p.Phe1088LeufsTer5) and MSH2 c.445_448dup (p.Val150fs), in addition to a rare germline mutation MSH6 c.133G > C (p.Gly45Arg). Two years ago, the patient was diagnosed with moderately differentiated adenocarcinoma in the left-half colon. Immunohistochemical stainings found MSH2(-), MSH6(+), MLH1(+), and PMS2(+) (data not shown).
    CONCLUSIONS: In the case of a patient with double primary EC and CRC, a careful evaluation of the IHC and the genetic data was presented. The patient carried rare compound heterozygous variants, a germline missense mutation, and a somatic frameshift mutation of MSH6, combined with a novel somatic null variant of MSH2. Our study broadened the variant spectrum of double primary cancer and provided insight into the molecular basis for abnormal MSH2 protein loss and double primary carcinoma.
    Keywords:  Deficient mismatch repair gene; Double primary carcinoma; Lynch-Like syndrome; Novel mutation
    DOI:  https://doi.org/10.1186/s13000-024-01447-8
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