bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒07‒19
twelve papers selected by
Joanna Zawacka-Pankau
University of Warsaw


  1. Cancer Res. 2020 Jul 16. pii: canres.1390.2020. [Epub ahead of print]
    Powers J, Pinto EM, Barnoud T, Leung JC, Martynyuk T, Kossenkov AV, Phillips AH, Desai H, Hausler R, Kelly G, Le AN, Li MM, MacFarland SP, Pyle LC, Zelley K, Nathanson KL, Domchek SM, Slavin TP, Weitzel JN, Stopfer JE, Garber JE, Joseph V, Offit K, Dolinsky JS, Gutierrez S, McGoldrick K, Couch FJ, Levin B, Edelman MC, Fein Levy C, Spunt SL, Kriwacki RW, Zambetti GP, Ribeiro RC, Murphy ME, Maxwell KN.
      Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li Fraumeni Syndrome (LFS). Here we identified a rare TP53 tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited Chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison to TP53 normal lines showed that while classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3 and LCN15) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R mutant tetramer, and the G334R mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison to classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance Li Fraumeni Syndrome.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1390
  2. Pediatr Blood Cancer. 2020 Jul 13. e28486
    Pondrom M, Bougeard G, Karanian M, Bonneau-Lagacherie J, Boulanger C, Boutroux H, Briandet C, Chevreau C, Corradini N, Coze C, Defachelles AS, Galmiche-Roland L, Orbach D, Piguet C, Scoazec JY, Vérité C, Willems M, Frebourg T, Minard V, Brugières L.
      OBJECTIVE: To describe the clinical characteristics and outcome of patients with Li-Fraumeni-associated rhabdomyosarcoma (RMS).METHOD: Retrospective analysis of data from 31 French patients with RMS diagnosed before the age of 20 years associated with a TP53 pathogenic germline variant. Cases were identified through the French Li-Fraumeni database. Central histologic review was performed in 16 cases.
    RESULTS: The median age at diagnosis was 2.3 years, and the median follow-up was 9.1 years (0.3-34.8). The main tumor sites were head and neck (n = 13), extremities (n = 8), and trunk (n = 8). The local pathology report classified the 31 tumors in embryonal (n = 26), alveolar (n = 1), pleomorphic (n = 1), and spindle-cell (n = 1) RMS (missing = 2). After histological review, anaplasia (diffuse or focal) was reported in 12/16 patients. Twenty-five patients had localized disease, three had lymph node involvement, and three distant metastases. First-line therapy combined surgery (n = 27), chemotherapy (n = 30), and radiotherapy (n = 14) and led to RMS control in all, but one patient. Eleven patients relapsed, and 18 patients had second malignancies. The 10-year event-free, progression-free, and overall survival rates were 36% (95% CI: 20-56), 62% (95% CI: 43-77) and 76% (95% CI: 56-88), respectively. The 10-year cumulative risk of second malignancies was 40% (95% CI: 22-60).
    CONCLUSION: The high incidence of multiple primary tumors strongly influences the long-term prognosis of RMS associated with TP53 pathogenic germline variants. Anaplastic RMS in childhood, independently of the familial history, should lead to TP53 analysis at treatment initiation to reduce, whenever possible, the burden of genotoxic drugs and radiotherapy in carriers and to ensure the early detection of second malignancies.
    Keywords:   TP53 ; Fraumeni; Li-Fraumeni syndrome; anaplastic rhabdomyosarcoma; chemotherapy; early detection; rhabdomyosarcoma; second malignancy
    DOI:  https://doi.org/10.1002/pbc.28486
  3. Mol Biol Rep. 2020 Jul 15.
    Feitosa JADS, das Chagas PF, de Sousa GR, Queiroz RGP, Cruzeiro GAV, Tone LG, Borges KS, Valera ET.
      TP53 p.R337H germline mutation is highly prevalent in the Southern region of Brazil. We sought to investigate TP53 p.R337H mutation in pediatric tumor samples from a population settled in a geographic area of high prevalence for this variant. Mutation assessment and genetic counseling for carriers/relatives were provided. 6/57 tumor samples were heterozygous for TP53 p.R337H. As expected, a high frequency was observed within adrenocortical tumors (3/3) and choroid plexus carcinomas (2/2). Interestingly, the TP53 R337H mutation was found in one case of pediatric rhabdomyosarcoma with Li-Fraumeni pedigree. Our finding expands the spectrum of childhood cancer associated with this germline mutation.
    Keywords:  Li–Fraumeni syndrome; Pediatric cancer; Rhabdomyosarcoma; Tumor genetics
    DOI:  https://doi.org/10.1007/s11033-020-05655-5
  4. Transl Lung Cancer Res. 2020 Jun;9(3): 646-658
    Liu M, Liu X, Suo P, Gong Y, Qu B, Peng X, Xiao W, Li Y, Chen Y, Zeng Z, Lu Y, Huang T, Zhao Y, Liu M, Li L, Chen Y, Zhou Y, Liu G, Yao J, Chen S, Song L.
      Background: Germline variations may contribute to lung cancer susceptibility besides environmental factors. The influence of germline mutations on lung cancer susceptibility and their correlation with somatic mutations has not been systematically investigated.Methods: In this study, germline mutations from 1,026 non-small cell lung cancer (NSCLC) patients were analyzed with a 58-gene next-generation sequencing (NGS) panel containing known hereditary cancer-related genes, and were categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines in pathogenicity, and the corresponding somatic mutations were analyzed using a 605-gene NGS panel containing known cancer-related genes.
    Results: Plausible genetic susceptibility was found in 4.7% of lung cancer patients, in which 14 patients with pathogenic mutations (P group) and 34 patients with likely-pathogenic mutations (LP group) were identified. The ratio of the first degree relatives with lung cancer history of the P groups was significantly higher than the Non-P group (P=0.009). The ratio of lung cancer patients with history of other cancers was higher in P (P=0.0007) or LP (P=0.017) group than the Non-P group. Pathogenic mutations fell most commonly in BRCA2, followed by CHEK2 and ATM. Likely-pathogenic mutations fell most commonly in NTRK1 and EXT2, followed by BRIP1 and PALB2. These genes are involved in DNA repair, cell cycle regulation and tumor suppression. By comparing the germline mutation frequency from this study with that from the whole population or East Asian population (gnomAD database), we found that the overall odds ratio (OR) for P or LP group was 17.93 and 15.86, respectively, when compared with the whole population, and was 2.88 and 3.80, respectively, when compared with the East Asian population, suggesting the germline mutations of the P and LP groups were risk factors for lung cancer. Somatic mutation analysis revealed no significant difference in tumor mutation burden (TMB) among the groups, although a trend of lower TMB in the pathogenic group was found. The SNV/INDEL mutation frequency of TP53 in the P group was significantly lower than the other two groups, and the copy number variation (CNV) mutation frequency of PIK3CA and MET was significantly higher than the Non-P group. Pathway enrichment analysis found no significant difference in aberrant pathways among the three groups.
    Conclusions: A proportion of 4.7% of patients carrying germline variants may be potentially linked to increased susceptibility to lung cancer. Patients with pathogenic germline mutations exhibited stronger family history and higher lung cancer risk.
    Keywords:  BRCA2; EGFR; Lung cancer; germline; pathogenic; susceptibility
    DOI:  https://doi.org/10.21037/tlcr-19-403
  5. Cancers (Basel). 2020 Jul 09. pii: E1848. [Epub ahead of print]12(7):
    de Angelis de Carvalho N, Niitsuma BN, Kozak VN, Costa FD, de Macedo MP, Kupper BEC, Silva MLG, Formiga MN, Volc SM, Aguiar Junior S, Palmero EI, Casali-da-Rocha JC, Carraro DM, Torrezan GT.
      Lynch syndrome (LS) is a hereditary cancer-predisposing syndrome associated most frequently with epithelial tumors, particularly colorectal (CRC) and endometrial carcinomas (EC). The aim of this study was to investigate the relationship between sarcomas and LS by performing clinical and molecular characterization of patients presenting co-occurrence of sarcomas and tumors from the LS spectrum. We identified 27 patients diagnosed with CRC, EC, and other LS-associated tumors who had sarcomas in the same individuals or families. Germline genetic testing, mismatch repair (MMR) protein immunohistochemistry, microsatellite instability (MSI), and other molecular analyses were performed. Five LS patients presenting personal or family history of sarcomas were identified (3 MSH2 carriers and 2 MLH1), with 2 having Muir-Torre phenotypes. For two MSH2 carriers we confirmed the etiology of the sarcomas (one liposarcoma and two osteosarcomas) as LS-related, since the tumors were MSH2/MSH6-deficient, MSI-high, or presented a truncated MSH2 transcript. Additionally, we reviewed 43 previous reports of sarcomas in patients with LS, which revealed a high frequency (58%) of MSH2 alterations. In summary, sarcomas represent a rare clinical manifestation in patients with LS, especially in MSH2 carriers, and the analysis of tumor biological characteristics can be useful for definition of tumor etiology and novel therapeutic options.
    Keywords:  Lynch syndrome; MSH2 germline variant; hereditary cancer; mismatch repair deficiency; sarcoma
    DOI:  https://doi.org/10.3390/cancers12071848
  6. Eur J Hum Genet. 2020 Jul 16.
    Guillerm E, Svrcek M, Bardier-Dupas A, Basset N, Coulet F, Colas C.
      In Lynch-like syndrome, patients have tumors with microsatellite instability but no germline pathogenic variant in mismatch repair genes or somatic methylation of the MLH1 promoter. Identification of the mechanism that causes these tumors is crucial for guiding screening of the patients and their relatives. Double somatic hits are the usual explanation for these cases; however, we have previously reported a de novo mosaic pathogenic variant in a patient with Lynch-like syndrome. Using tumoral NGS analysis of a series of 16 patients with Lynch-like syndrome, we found six patients with double somatic hits, including one patient with mosaicism of a de novo pathogenic variant in MSH2. This variant was transmitted to the patient's offspring, which has significant implications for genetic counseling.
    DOI:  https://doi.org/10.1038/s41431-020-0689-6
  7. Cancers (Basel). 2020 Jul 09. pii: E1853. [Epub ahead of print]12(7):
    Olkinuora A, Gylling A, Almusa H, Eldfors S, Lepistö A, Mecklin JP, Nieminen TT, Peltomäki P.
      Some 10-50% of Lynch-suspected cases with abnormal immunohistochemical (IHC) staining remain without any identifiable germline mutation of DNA mismatch repair (MMR) genes. MMR proteins form heterodimeric complexes, giving rise to distinct IHC patterns when mutant. Potential reasons for not finding a germline mutation include involvement of an MMR gene not predicted by the IHC pattern, epigenetic mechanism of predisposition, primary mutation in another DNA repair or replication-associated gene, and double somatic MMR gene mutations. We addressed these possibilities by germline and tumor studies in 60 Lynch-suspected cases ascertained through diagnostics (n = 55) or research (n = 5). All cases had abnormal MMR protein staining in tumors but no point mutation or large rearrangement of the suspected MMR genes in the germline. In diagnostic practice, MSH2/MSH6 (MutS Homolog 2/MutS Homolog 6) deficiency prompts MSH2 mutation screening; in our study, 3/11 index individuals (27%) with this IHC pattern revealed pathogenic germline mutations in MSH6. Individuals with isolated absence of MSH6 are routinely screened for MSH6 mutations alone; we found a predisposing mutation in MSH2 in 1/7 such cases (14%). Somatic deletion of the MSH2-MSH6 region, joint loss of MSH6 and MSH3 (MutS Homolog 3) proteins, and hindered MSH2/MSH6 dimerization offered explanations to misleading IHC patterns. Constitutional epimutation hypothesis was pursued in the MSH2 and/or MSH6-deficient cases plus 38 cases with MLH1 (MutL Homolog 1)-deficient tumors; a primary MLH1 epimutation was identified in one case with an MLH1-deficient tumor. We conclude that both MSH2 and MSH6 should be screened in MSH2/6- and MSH6-deficient cases. In MLH1-deficient cases, constitutional epimutations of MLH1 warrant consideration.
    Keywords:  DNA mismatch repair; Lynch syndrome; colorectal cancer; deep sequencing
    DOI:  https://doi.org/10.3390/cancers12071853
  8. J Am Coll Surg. 2020 Jul 11. pii: S1072-7515(20)30536-6. [Epub ahead of print]
    Hu H, Zhu Y, Pu N, Burkhart RA, Burns W, Laheru D, Zheng L, He J, Goggins MG, Yu J.
      BACKGROUD: The frequency and significance of the germline variants in DNA damage repair genes still need to be elucidated in patients with sporadic pancreatic ductal adenocarcinoma (PDAC). Our purpose was to determine whether germline variants in DNA damage repair genes were associated with survival of patients with sporadic PDAC.STUDY DESIGN: We retrospectively identified 854 patients with sporadic PDAC with germline DNA sequenced in targeted 22 DNA damage repair genes by next-generation sequencing. Outcomes were compared in terms of clinicopathologic features, disease-free survival (DFS) and overall survival (OS).
    RESULTS: Nineteen patients had deleterious mutations; 103 had variant(s) of unknown significance (VUS). Germline DNA damage repair deleterious variant carriers had superior DFS (median, 19.1 months vs. 11.9 months, p=0.012) and OS (median, 29.7 months vs. 20.2 months, p=0.034) as compared with wild-type patients. Germline DNA damage repair VUS variant carriers also had superior DFS when compared with wild-type patients. In subgroup analysis, this improved survival was limited to patients receiving adjuvant chemotherapy, deleterious variant carriers vs. wild-type patients DFS (median, 36.3 months vs. 13.1 months, p=0.006) and OS (median, 43.7 months vs. 24.3 months, p=0.045), VUS variant carriers vs. wild-type patients DFS (16.5 months vs. 13.1 months, p=0.007).
    CONCLUSION: Having a deleterious variant in a DNA damage repair gene is associated with improved survival after resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma.
    Keywords:  DNA damage repair; Pancreatic ductal adenocarcinoma; chemotherapy
    DOI:  https://doi.org/10.1016/j.jamcollsurg.2020.06.019
  9. J Gastrointest Oncol. 2020 Jun;11(3): 559-566
    Geurts JL.
      Inherited syndromes are important to recognize in the setting of a pancreatic neuroendocrine tumor (PNET) as there are significant implications for the patient's medical management and opportunity for early detection of subsequent manifestations. Although most PNETs are sporadic, approximately 10% are due to an inherited syndrome, which include multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4 (MEN4), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). The general hallmarks of a hereditary endocrine neoplasia predisposition syndrome include any one of the following: multiple primary tumors (in the same or different organs), rare tumors (prevalence of less than 1 in 1,000 people in the general population), earlier age of diagnosis (usually under the age of 40), characteristic pattern of disease in the individual or family (phenotype and inheritance pattern). These syndromes are monogenic (due to a single gene disorder), highly penetrant (with all carriers of the disease exhibiting at least part of the phenotype) and can display variable expressivity (where affected individuals may have different presentations and features of the disease). A thoughtful approach to management is required, even if the presenting symptom is resolved, as these syndromes often involve multi-organ disease with a lifelong risk for tumor development. Additionally, the natural history of tumors in the setting of a hereditary condition may be different than would be expected in a sporadic form of the disease. For example, in some circumstances the risk of metastatic disease is lower, and therefor longer observation is the preferred approach over early surgical intervention. The unique aspects to management, challenges in hereditary disease recognition and accurate diagnosis, and rarity of these syndromes are all reasons to support referral to high-volume centers with the experience and knowledge to treat patients with hereditary endocrine neoplasia syndromes.
    Keywords:  Multiple endocrine neoplasia type 1 (MEN1); genetic counseling; neuroendocrine tumor; pancreatic neoplasms; von Hippel-Lindau disease (VHL)
    DOI:  https://doi.org/10.21037/jgo.2020.03.09
  10. J Clin Oncol. 2020 Jul 16. JCO1902399
    Lambertini M, Ameye L, Hamy AS, Zingarello A, Poorvu PD, Carrasco E, Grinshpun A, Han S, Rousset-Jablonski C, Ferrari A, Paluch-Shimon S, Cortesi L, Senechal C, Miolo G, Pogoda K, Pérez-Fidalgo JA, De Marchis L, Ponzone R, Livraghi L, Estevez-Diz MDP, Villarreal-Garza C, Dieci MV, Clatot F, Berlière M, Graffeo R, Teixeira L, Córdoba O, Sonnenblick A, Luna Pais H, Ignatiadis M, Paesmans M, Partridge AH, Caron O, Saule C, Del Mastro L, Peccatori FA, Azim HA.
      PURPOSE: Young women with germline BRCA mutations have unique reproductive challenges. Pregnancy after breast cancer does not increase the risk of recurrence; however, very limited data are available in patients with BRCA mutations. This study investigated the impact of pregnancy on breast cancer outcomes in patients with germline BRCA mutations.PATIENTS AND METHODS: This is an international, multicenter, hospital-based, retrospective cohort study. Eligible patients were diagnosed between January 2000 and December 2012 with invasive early breast cancer at age ≤ 40 years and harbored deleterious germline BRCA mutations. Primary end points were pregnancy rate, and disease-free survival (DFS) between patients with and without a pregnancy after breast cancer. Pregnancy outcomes and overall survival (OS) were secondary end points. Survival analyses were adjusted for guarantee-time bias controlling for known prognostic factors.
    RESULTS: Of 1,252 patients with germline BRCA mutations (BRCA1, 811 patients; BRCA2, 430 patients; BRCA1/2, 11 patients) included, 195 had at least 1 pregnancy after breast cancer (pregnancy rate at 10 years, 19%; 95% CI, 17% to 22%). Induced abortions and miscarriages occurred in 16 (8.2%) and 20 (10.3%) patients, respectively. Among the 150 patients who gave birth (76.9%; 170 babies), pregnancy complications and congenital anomalies occurred in 13 (11.6%) and 2 (1.8%) cases, respectively. Median follow-up from breast cancer diagnosis was 8.3 years. No differences in DFS (adjusted hazard ratio [HR], 0.87; 95% CI, 0.61 to 1.23; P = .41) or OS (adjusted HR, 0.88; 95% CI, 0.50 to 1.56; P = .66) were observed between the pregnancy and nonpregnancy cohorts.
    CONCLUSION: Pregnancy after breast cancer in patients with germline BRCA mutations is safe without apparent worsening of maternal prognosis and is associated with favorable fetal outcomes. These results provide reassurance to patients with BRCA-mutated breast cancer interested in future fertility.
    DOI:  https://doi.org/10.1200/JCO.19.02399
  11. Cancer Res. 2020 Jul 15. 80(14): 2977-2978
    Cai C.
      Cancer cells with germline deleterious mutations of BRCA1 or BRCA2 are deficient in homologous recombination repair and therefore sensitive to PARP inhibitor treatment. However, wild-type BRCA1/2-expressing cells with defects in other DNA damage repair pathway components may also exhibit "BRCAness," which in combination with PARP inhibition can similarly induce synthetic lethality. In this issue of Cancer Research, Luo and colleagues report a novel mechanism by which BRCA1 protein degradation in response to DNA double-strand breaks is regulated by prolyl isomerase Pin1. Inactivation of Pin1 can establish BRCAness in cancer cells and thus sensitize cells to PARP inhibitor treatment.See related articles by Luo et al., p. 3033.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1451
  12. Oral Oncol. 2020 Jul 09. pii: S1368-8375(20)30332-8. [Epub ahead of print] 104896
    Dartaha R, Benmelouka AY, Jobran AWM.
      Xeroderma pigmentosum is an orphan hereditary photosensitive human disorder that is recognized by the development of skin lesions in sun-exposed regions of the body due to severe photosensitivity. Patients with this condition have an abnormal DNA repair process due to a genetic mutation. Xeroderma pigmentosum is considered as a risk factor of cancer since the affected population may develop various cutaneous cancers including both melanoma and non-melanoma cutaneous malignancies even at a younger age than the general population. This risk concerns also asymptomatic heterozygote individuals. Here, we present a case of 46 years old man with a familial history of Xeroderma pigmentosum who developed a microscopically confirmed squamous cell carcinoma of the lip.
    Keywords:  Familial history; Lip squamous cell carcinoma; Microscopic surgery; Reconstruction; Xeroderma pigmentosum
    DOI:  https://doi.org/10.1016/j.oraloncology.2020.104896