bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2024–09–15
nine papers selected by
Joanna Zawacka, Karolinska Institutet
  1. Germline p.R181H variant in TP53 in a family exemplifying the genotype-phenotype correlations in Li-Fraumeni syndrome.
  2. Prevalence of Germline Pathogenic Variants in Renal Cancer Predisposition Genes in a Population-Based Study of Renal Cell Carcinoma.
  3. Identification of novel candidate predisposing genes in familial nonmedullary thyroid carcinoma implicating DNA damage repair pathways.
  4. Laparoscopic resection of liver PEComa associated with Li‑Fraumeni syndrome: A case report.
  5. Prevalence of germline variants in Brazilian pancreatic carcinoma patients.
  6. Endoscopic screening for identification of signet ring cell gastric cancer foci in carriers of germline pathogenic variants in CDH1.
  7. Clinical Utility of Molecular Tumor Board Review for Identification of Possible Germline Pathogenic Variants on Tumor Next-Generation Sequencing Reports.
  8. HER2 status and response to neoadjuvant anti-HER2 treatment among patients with breast cancer and Li-Fraumeni syndrome.
  9. Radiation-Associated Secondary Cancer in Patients With Breast Cancer Harboring TP53 Germline Variants.
  1. Fam Cancer. 2024 Sep 11.
    Germline p.R181H variant in TP53 in a family exemplifying the genotype-phenotype correlations in Li-Fraumeni syndrome.
    Claire Freycon, Laura Palma, Crystal Budd, Frederic Coulombe, Leora Witkowski, Pierre Hainaut, William D Foulkes, Catherine Goudie.
      Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline pathogenic/likely pathogenic variants in TP53. Genotype-phenotype correlations are progressively being characterized in LFS with certain TP53 variants associated with attenuated penetrance and phenotypes. We report on a family harboring a TP53 p.R181H variant presenting with a restricted cancer phenotype in adulthood. The proband was a female with breast cancer at the age of 71 years who had three first degree relatives also diagnosed with breast cancer after the age of 40 years (mother, two sisters). Of the nine individuals harboring the variant (6 genetically confirmed, 3 obligate heterozygous), six have not developed malignancies at this time (age range: 36-42). No childhood-onset cancers were reported in this family. A concomitant literature review identified 51 additional individuals harboring the p.R181H variant in TP53, presenting a tumor phenotype dominated by breast cancer. Rare occurrences of other adult-onset cancers (prostate, colorectal and thyroid) and only few childhood onset cancer were documented. These observations are consistent with functional analysis showing that p.R181H retains partial p53 function and suggesting possible reduced cancer penetrance, particularly in the pediatric setting.
    Keywords:   TP53 gene; Genotype-phenotype correlations; Li-Fraumeni syndrome; p.R181H variant
    DOI:  https://doi.org/10.1007/s10689-024-00419-7
  2. Cancers (Basel). 2024 Aug 27. pii: 2985. [Epub ahead of print]16(17):
    Prevalence of Germline Pathogenic Variants in Renal Cancer Predisposition Genes in a Population-Based Study of Renal Cell Carcinoma.
    Fiona Bruinsma, Philip Harraka, Susan Jordan, Daniel J Park, Bernard Pope, Jason Steen, Roger L Milne, Graham G Giles, Ingrid Winship, Katherine M Tucker, Melissa C Southey, Tu Nguyen-Dumont.
      Renal cell carcinoma (RCC) has been associated with germline pathogenic or likely pathogenic (PLP) variants in recognised cancer susceptibility genes. Studies of RCC using gene panel sequencing have been highly variable in terms of study design, genes included, and reported prevalence of PLP variant carriers (4-26%). Studies that restricted their analysis to established RCC predisposition genes identified variants in 1-6% of cases. This work assessed the prevalence of clinically actionable PLP variants in renal cancer predisposition genes in an Australian population-based sample of RCC cases. Germline DNA from 1029 individuals diagnosed with RCC who were recruited through the Victoria and Queensland cancer registries were screened using a custom amplicon-based panel of 21 genes. Mean age at cancer diagnosis was 60 ± 10 years, and two-thirds (690, 67%) of the participants were men. Eighteen participants (1.7%) were found to carry a PLP variant. Genes with PLP variants included BAP1, FH, FLCN, MITF, MSH6, SDHB, TSC1, and VHL. Most carriers of PLP variants did not report a family history of the disease. Further exploration of the clinical utility of gene panel susceptibility testing for all RCCs is warranted.
    Keywords:  cancer predisposition; family history; gene panel testing; population-based; renal cell carcinoma
    DOI:  https://doi.org/10.3390/cancers16172985
  3. Int J Cancer. 2024 Sep 09.
    Identification of novel candidate predisposing genes in familial nonmedullary thyroid carcinoma implicating DNA damage repair pathways.
    Carolina Pires, Inês J Marques, Ana Saramago, Margarida M Moura, Marta Pojo, Rafael Cabrera, Catarina Santos, Francisco Rosário, Diana Lousa, João B Vicente, Tiago M Bandeiras, Manuel R Teixeira, Valeriano Leite, Branca M Cavaco.
      The genetic basis of nonsyndromic familial nonmedullary thyroid carcinoma (FNMTC) is still poorly understood, as the susceptibility genes identified so far only account for a small percentage of the genetic burden. Recently, germline mutations in DNA repair-related genes have been reported in cases with thyroid cancer. In order to clarify the genetic basis of FNMTC, 94 genes involved in hereditary cancer predisposition, including DNA repair genes, were analyzed in 48 probands from FNMTC families, through targeted next-generation sequencing (NGS). Genetic variants were selected upon bioinformatics analysis and in silico studies. Structural modeling and network analysis were also performed. In silico results of NGS data unveiled likely pathogenic germline variants in 15 families with FNMTC, in genes encoding proteins involved in DNA repair (ATM, CHEK2, ERCC2, BRCA2, ERCC4, FANCA, FANCD2, FANCF, and PALB2) and in the DICER1, FLCN, PTCH1, BUB1B, and RHBDF2 genes. Structural modeling predicted that most missense variants resulted in the disruption of networks of interactions between residues, with implications for local secondary and tertiary structure elements. Functional annotation and network analyses showed that the involved DNA repair proteins functionally interact with each other, within the same DNA repair pathway and across different pathways. MAPK activation was a common event in tumor progression. This study supports that rare germline variants in DNA repair genes may be accountable for FNMTC susceptibility, with potential future utility in patients' clinical management, and reinforces the relevance of DICER1 in disease etiology.
    Keywords:  DNA repair; cancer predisposition; familial nonmedullary thyroid cancer (FNMTC); molecular genetics; next‐generation sequencing (NGS)
    DOI:  https://doi.org/10.1002/ijc.35159
  4. Biomed Rep. 2024 Nov;21(5): 154
    Laparoscopic resection of liver PEComa associated with Li‑Fraumeni syndrome: A case report.
    Ryuji Takada, Makoto Takahashi, Tatsuya Hayashi, Taku Higashihara, Yasuhiro Morita, Dai Inoue, Haruka Okada, Junko Araki.
      Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline mutations in tumor suppressor gene TP53. Perivascular epithelioid cell tumors (PEComas) are a group of tumors by the World Health Organization Classification as mesenchymal tumors composed of histologically and immunohistochemically distinctive PECs. The present study reports a rare case of PEComa associated with LFS. A 32-year-old female patient was referred to Tokyo Metropolitan Tama Medical Center (Tokyo, Japan) in March 2022 for a detailed examination of a liver mass. The patient had received a diagnosis of LFS based on a history of sarcoma and germline variants of TP53 7 years previously. Magnetic resonance imaging revealed a ring-enhanced mass in the liver segment 8 (S8). This was observed in the arterial phase, followed by washout of contrast media in the venous phase. Owing to the possibility of malignancy (such as metastatic liver tumor or hepatocellular carcinoma), the patient was referred for diagnostic surgery. In August 2022, a laparoscopic partial hepatectomy of S8 was performed without complications and she was discharged on postoperative day 7. The pathological findings led to the diagnosis of PEComa. The patient is currently under follow-up at 1 year and 4 months postoperative. Laparoscopic hepatectomy was useful as a diagnostic treatment because it was relatively non-invasive. Mutations in TP53 are involved in the development of PEComa. Further cases and studies are required to clarify the relationship between LFS and PEComa.
    Keywords:  Li-Fraumeni syndrome; PEComa; TP53; laparoscopic liver resection; surgery
    DOI:  https://doi.org/10.3892/br.2024.1842
  5. Sci Rep. 2024 09 10. 14(1): 21083
    Prevalence of germline variants in Brazilian pancreatic carcinoma patients.
    Lívia Munhoz Rodrigues, Simone Maistro, Maria Lucia Hirata Katayama, Vinícius Marques Rocha, Rossana Veronica Mendoza Lopez, Edia Filomena di Tullio Lopes, Fernanda Toledo Gonçalves, Cintia Fridman, Pedro Adolpho de Menezes Pacheco Serio, Luciana Rodrigues Carvalho Barros, Luiz Antonio Senna Leite, Vanderlei Segatelli, Maria Del Pilar Estevez-Diz, Rodrigo Santa Cruz Guindalini, Ulysses Ribeiro Junior, Maria Aparecida Azevedo Koike Folgueira.
      We evaluated the prevalence of pathogenic/likely pathogenic germline variants (PGV) in Brazilian pancreatic adenocarcinoma (PC) patients, that represent a multiethnic population, in a cross-sectional study. We included 192 PC patients unselected for family history of cancer. We evaluated a panel of 113 cancer genes, through genomic DNA sequencing and 46 ancestry-informative markers, through multiplex PCR. The median age was 61 years; 63.5% of the patients presented disease clinical stages III or IV; 8.3% reported personal history of cancer; 4.7% and 16.1% reported first-degree relatives with PC or breast and/or prostate cancer, respectively. Although the main ancestry was European, there was considerable genetic composition admixture. Twelve patients (6.25%) were PGV carriers in PC predisposition genes (ATM, BRCA1, BRCA2, CDKN2A, MSH2, PALB2) and another 25 (13.0%) were PGV carriers in genes with a limited association or not previously associated with PC (ACD, BLM, BRIP1, CHEK2, ERCC4, FANCA, FANCE, FANCM, GALNT12, MITF, MRE11, MUTYH, POLE, RAD51B, RAD51C, RECQL4, SDHA, TERF2IP). The most frequently affected genes were CHEK2, ATM and FANC. In tumor samples from PGV carriers in ACD, BRIP1, MRE11, POLE, SDHA, TERF2IP, which were examined through exome sequencing, the main single base substitutions (SBS) mutational signature was SBS1+5+18, probably associated with age, tobacco smoking and reactive oxygen species. SBS3 associated with homologous repair deficiency was also represented, but on a lower scale. There was no difference in the frequency of PGV carriers between: (a) patients with or without first-degree relatives with cancer; and (b) patients with admixed ancestry versus those with predominantly European ancestry. Furthermore, there was no difference in overall survival between PGV carriers and non-carriers. Therefore, genetic testing should be offered to all Brazilian pancreatic cancer patients, regardless of their ancestry. Genes with limited or previously unrecognized associations with pancreatic cancer should be further investigated to clarify their role in cancer risk.
    Keywords:  Genetic ancestry; Germline variants; Pancreatic cancer
    DOI:  https://doi.org/10.1038/s41598-024-71884-4
  6. Fam Cancer. 2024 Sep 11.
    Endoscopic screening for identification of signet ring cell gastric cancer foci in carriers of germline pathogenic variants in CDH1.
    Lady Katherine Mejia Perez, Margaret O'Malley, Arjun Chatterjee, Ruishen Lyu, Qijun Yang, Michael W Cruise, Lisa LaGuardia, David Liska, Carole Macaron, R Matthew Walsh, Carol A Burke.
      To determine the preoperative detection of signet ring cancer cells (SRC) on upper endoscopy (EGD) in patients with CDH1 pathogenic variant (PV) undergoing gastrectomy. To evaluate the development of advanced diffuse gastric cancer (DGC) in patients choosing surveillance. Guidelines recommend prophylactic total gastrectomy (pTG) in CDH1 PV carriers with family history of DGC between 18 and 40 years. Annual EGD with biopsies according to established protocols is recommended in carriers with no SRC and no family history of DGC, with consideration of pTG. Retrospective analysis of asymptomatic patients with CDH1 PVs with ≥ 1 surveillance EGD. Outcomes included pre-operative EGD detection of SRC, surgical stage, and progression to advanced DGC in those electing surveillance with EGD. 48 patients with CDH1 PVs who had ≥ 1 EGD were included. 24/ 48 (50%) underwent gastrectomy, including pTG in 7 patients. SRCC were detected on gastrectomy specimen in 21/24 (87.5%). SRCs were identified by EGD in 17/21 patients who had SRCC on gastrectomy specimens (sensitivity 81%, 17/21). All cancers were stage pT1a. The remaining 17 patients (50% with a family history of gastric cancer) continue in annual EGD surveillance with a median follow-up of 34.6 months. No SRCC or advanced DGC have been diagnosed. No CDH1 PV carriers without SRCC on random biopsies followed in an endoscopic program developed advanced DGC over a median follow up of 3 years. In the short term, EGD surveillance might be a safe alternative to immediate pTG in experienced hands in referral centers.
    Keywords:   CDH1 ; Endoscopy; Gastrectomy; Hereditary diffuse gastric cancer; Surveillance
    DOI:  https://doi.org/10.1007/s10689-024-00421-z
  7. JCO Precis Oncol. 2024 Sep;8 e2400301
    Clinical Utility of Molecular Tumor Board Review for Identification of Possible Germline Pathogenic Variants on Tumor Next-Generation Sequencing Reports.
    Taylor A Rives, James Collard, Ning Li, Donglin Yan, Charles S Dietrich, Rachel W Miller, Frederick R Ueland, Justine Pickarski, Jill M Kolesar.
       PURPOSE: Tumor next-generation sequencing (NGS) testing identifies possible germline pathogenic variants (PGPVs), creating a dilemma for appropriate recognition, triage, and management. The objective of this study was to determine the clinical utility of an institutional molecular tumor board (MTB) in assessing tumor NGS reports for PGPVs.
    METHODS: Our institutional MTB reviews all NGS reports to provide treatment and further testing recommendations, including genetic counseling referral and consideration of genetic testing (GC/GT). We studied the patients reviewed by the MTB who were recommended for GC/GT to determine the frequency of referral to a GC, germline test completion, rate of pathogenic germline variants (PGVs), factors related to PGVs, and germline conversion rate (GCR).
    RESULTS: Of the 2,355 patients reviewed by the MTB during the study period, 609 (25.9%) had a recommendation for GC/GT. Of the 609 with a GC/GT recommendation, only 181 (29.7%) were referred for GC/GT by their treating physicians, and only 107 (17.6%) completed GT. Of the 107 patients completing GT, 29 (26%) had a confirmed PGV. The only factors significantly associated with PGVs were testing due to a PGPV and higher mean variant allele fraction on the tumor NGS. Only 40 patients with a GC/GT recommendation (14.3%) due to a PGPV completed GT; however, the GCR was 42.5% (n = 17/40).
    CONCLUSION: The MTB review of PGPV is clinically valuable, identifying PGPV in 12% of patients undergoing tumor NGS and a GCR of 42.5%. Rates of GC/GT completion were relatively low due to under-referral by treating physicians. Given the high GCR, the authors encourage institutional algorithms to help increase GC/GT rates for patients found to have PGPV following tumor NGS testing.
    DOI:  https://doi.org/10.1200/PO.24.00301
  8. Eur J Cancer. 2024 Sep 05. pii: S0959-8049(24)00963-8. [Epub ahead of print]211 114307
    HER2 status and response to neoadjuvant anti-HER2 treatment among patients with breast cancer and Li-Fraumeni syndrome.
    Michele Bottosso, Renata L Sandoval, Benjamin Verret, Natalia Polidorio, Olivier Caron, Alessandra Gennari, Brittany L Bychkovsky, Sophie H Cahill, Maria I Achatz, Valentina Guarneri, Fabrice André, Judy E Garber.
       BACKGROUND: Breast cancer (BC) is the most common cancer among females with Li-Fraumeni syndrome (LFS), but available data on LFS-related BC characteristics are derived from small retrospective cohorts. Prior work has demonstrated a high proportion of HER2-positive BCs, but our understanding of how HER2-positive LFS BCs respond to anti-HER2 treatments is limited.
    METHODS: BCs diagnosed in patients with germline TP53 variants between 2002-2022 were assembled from three institutions. Hormone receptor (HR) and HER2 expression were retrieved from pathology records. Pathologic complete response (pCR) was defined as ypT0/is ypN0.
    RESULTS: A total of 264 BCs were identified among 232 patients with LFS: 211 (79.9 %) were invasive carcinomas, of which 106 were HER2-positive. Among HER2-positive BCs, most tumors co-expressed HRs (72.6 %) and were more frequent among those diagnosed at younger age (p < 0.001). Mastectomy was the preferred surgical approach among women with nonmetastatic cancers (77.8 %) and most received anti-HER2 targeted therapy (74.7 %). Among 38 patients receiving neoadjuvant therapy with available post-treatment pathology reports, 27 (71.1 %) achieved pCR: 18/26 (69.2 %) among HR-positive and 7/10 (70.0 %) HR-negative. The rate of pCR was 84.6 % among patients treated with an anthracycline-free regimen (all received trastuzumab). Among classifiable HER2-negative BCs (n = 77), 31 (40.3 %) were HER2-low and 46 (59.7 %) HER2-zero.
    CONCLUSIONS: Among females with LFS and BC, HER2-positive subtype was associated with younger age at diagnosis and a predominant HR-positivity. Favorable pCR rates were observed among those receiving neoadjuvant HER2-directed therapies, for both HR-positive and negative tumors. These data may inform the counseling and care of patients with LFS.
    Keywords:  Breast cancer; HER2; HER2-low; Li-Fraumeni syndrome; Neoadjuvant treatment
    DOI:  https://doi.org/10.1016/j.ejca.2024.114307
  9. JAMA Oncol. 2024 Sep 12.
    Radiation-Associated Secondary Cancer in Patients With Breast Cancer Harboring TP53 Germline Variants.
    Gustav Y Cederquist, Lillian A Boe, Michael Walsh, Gary M Freedman, Kara N Maxwell, Neil Taunk, Lior Z Braunstein.
      
    DOI:  https://doi.org/10.1001/jamaoncol.2024.3683
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