bims-lifras Biomed News
on Li-Fraumeni Syndrome
Issue of 2019‒12‒29
ten papers selected by
Joanna Zawacka-Pankau



  1. J Mol Diagn. 2019 Dec 24. pii: S1525-1578(19)30459-3. [Epub ahead of print]
    Mester JL, Jackson SA, Postula K, Stettner A, Solomon S, Bissonnette J, Murphy PD, Klein RT, Hruska KS.
      Heterozygous (HET) TP53 pathogenic variants (PV) are associated with Li-Fraumeni syndrome (LFS), a dominantly inherited condition causing high risk for sarcoma, breast, and other cancers. Recent reports have described patients without features of LFS and apparently HET TP53 PV in blood cells but not fibroblasts (FB), suggesting the variant occurred sporadically during hematopoiesis and rose to high allele fraction through clonal expansion. To explore possible clonal hematopoiesis in patients undergoing hereditary cancer testing, FB testing was performed for patients with apparently HET or mosaic TP53 PV identified in blood, oral rinse, or buccal specimens via next-generation sequencing panels. Among 291 individuals with TP53 PV, 146 (50.2%) appeared HET and 145 (49.8%) were mosaic. Twenty-nine HET cases were proven constitutional through familial testing. FB testing was completed for 17 apparently HET and 36 mosaic patients. FB testing was positive in 11/17 (64.7%) apparently HET patients, only one of whom met Chompret criteria. Five of 36 (13.9%) mosaic patients were also mosaic in FB, indicating constitutional mosaicism. Breast cancers in patients with constitutional TP53 PV were diagnosed at younger ages (P < 0.0001) and were more likely to demonstrate HER2 overexpression (P = 0.0003). These results demonstrate the utility of cultured FB testing to clarify constitutional status for TP53 PVs identified on next-generation sequencing panel testing, particularly for patients not meeting LFS or Chompret criteria.
    DOI:  https://doi.org/10.1016/j.jmoldx.2019.12.003
  2. J Genet Couns. 2019 Dec 23.
    Forbes Shepherd R, Keogh LA, Werner-Lin A, Delatycki MB, Forrest LE.
      Li-Fraumeni syndrome (LFS), a rare cancer syndrome caused by pathogenic germline variants in TP53, has serious implications for adolescents and young adults (AYAs; aged 15-39 years). The early-onset and multi-organ cancer risk associated with LFS means health professionals must concurrently contend with the developmental needs of individuals who are diagnosed from a young age, and recent changes in practice due to advances in whole-body cancer surveillance. To help understand how current practice meets the developmental needs of AYAs with, or at risk of, LFS, we conducted a national online survey to explore the experiences of health professionals who care for this population in Australia and New Zealand. Forty-three respondents completed the survey (56% genetic counselors), one-third of whom had facilitated predictive TP53 testing for minors (n = 14/43, 33%). In hypothetical scenarios describing 15-year-olds eligible for predictive TP53 testing, respondents were more supportive of testing for emotionally mature compared to immature minors (p = .009); and more supportive of adolescent wishes compared to parental wishes for testing (p = .020) when families held discordant views on testing. Genetic health professionals were more likely than oncology health professionals to address psychological (p = .017) and information needs about reproductive options for LFS during consultations than to refer them on (p = .004). All respondents supported comprehensive risk management for LFS, but noted important medical, logistical, and psychosocial limitations for AYAs. This study offers valuable insight into developmentally appropriate practices of Australasian health professionals who care for AYAs with, or at risk of, LFS. These findings suggest they may foster the autonomy of minors undergoing predictive TP53 genetic testing and be supportive of new whole-body risk management guidelines.
    Keywords:  Li-Fraumeni syndrome; adolescent and young adult; counseling techniques; health professionals; practice; predictive genetic testing; psychosocial; referral practices; risk management; survey; workforce
    DOI:  https://doi.org/10.1002/jgc4.1199
  3. Am J Clin Oncol. 2019 Dec 23.
    Lehrer S, Rheinstein PH.
      BACKGROUND: Early onset colorectal cancer in persons younger than 50 years is increasingly common. Clinical and molecular characterizations reveal a distinctive disease. Thirty percent of patients have mutations of hereditary cancer syndromes, especially Lynch syndrome. A recent analysis, testing germline DNA for mutations in 25 cancer susceptibility genes, showed that some patients younger than 50 years had mutations of high-penetrance colorectal cancer genes such as APC (adenopolyposis coli). Others had mutations in high-penetrance or moderate-penetrance genes not traditionally associated with colorectal cancer, such as ATM (ataxia telangiectasia mutated), whereas still others had low penetrance colorectal cancer genes. In the current study, we examined the incidence of second cancers following early onset (age less than 50 y) colorectal cancer.METHODS: The initial study population was assembled using records from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. The SEER*Stat MP-SIR (multiple primary-standardized incidence ratio) tool was used to calculate SIRs and excess risk for second primary malignancies. The SIR is expressed as the ratio of observed-to-expected (O/E) cases. We used The Cancer Genome Atlas (TCGA) and AACR Project Genie for genetic analysis. The data were accessed with the online Xena Browser and cBioportal.
    RESULTS: Acute myelogenous leukemia (AML) O/E ratios were significantly >1 in patients aged less than 50 years, at 12 to 59 months after colorectal cancer. In patients aged 50 years and older, O/E ratios were equal to 1 or quite close at 12 to 59 months after colorectal cancer. Alterations in 3 AML genes, CEBPA-AS1, MLLT1, and MLLT6, affected the prognosis of colorectal cancer patients less than 50 years but not older than 50 years. One AML gene, FLT3, had the highest copy number alteration frequency of any gene in 1438 colorectal patients 18 to 48 years of age. Genetic alterations of FLT3/TP53 were mutually exclusive. Genetic alterations of FLT3/JAK2 and JAK2/CTNNB1 were co-occurrent.
    CONCLUSION: These observations suggest that early onset colorectal cancer and AML may be related diseases.
    DOI:  https://doi.org/10.1097/COC.0000000000000658
  4. Clin Cancer Res. 2019 Dec 23. pii: clincanres.0224.2019. [Epub ahead of print]
    Goldstein JB, Zhao L, Wang X, Ghelman Y, Overman MJ, Javle M, Shroff RT, Varadhachary GR, Wolf RA, McAllister F, Futreal PA, Fogelman DR.
      Background and Aims Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival (OS) in pancreatic cancer. The frequency of germline mutations has been reported in patients predominantly under the age of 60 or with strong family history. We examine the incidence of deleterious germline mutations and compare the chemotherapy responses and OS in an unselected group of metastatic pancreatic cancer patients. Methods Metastatic pancreatic cancer patients, who were seen at a single cancer center between 2010 and 2016, were included. Germline DNA was sequenced using a 263-gene panel to identify novel mutations (N = 133 MD Anderson cohort, N = 127 TCGA cohort). Chemotherapy response and OS were determined by review of medical records. Results Deleterious germline mutations were identified in 26 of 133 patients (19.5%). Patients with DNA damage repair (DDR) gene mutations (ATM, BRCA1/2, CDKN2A, CHEK2, ERCC4, PALB2, n = 15) had an improved OS as compared to patients without (16.8 versus 9.1 months, P = 0.03). Conversely, patients with other deleterious mutations had a trend towards worse OS. Although, survival in the later group was longer (P= NS) in those mutants initially treated with gemcitabine/nab-paclitaxel. A family history of multiple breast, ovarian, and pancreatic cancers was associated with DDR gene mutations and better survival. Conclusion We have identified novel germline mutations that are prognostic for survival in pancreatic cancer patients. We observe improved survival in patients with DDR gene mutations and worsened survival in patients with deleterious mutations in non-DDR genes.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-19-0224
  5. Transl Oncol. 2019 Dec 20. pii: S1936-5233(19)30504-2. [Epub ahead of print]13(2): 212-220
    Gallardo-Rincón D, Álvarez-Gómez RM, Montes-Servín E, Toledo-Leyva A, Montes-Servín E, Michel-Tello D, Alamilla-García G, Bahena-González A, Hernández-Nava E, Fragoso-Ontiveros V, Espinosa-Romero R, Cetina-Pérez L.
      Ovarian cancer (OC) is an important cause of gynecologic cancer-related deaths. In Mexico, around 4700 new cases of OC are diagnosed per year and it represents the second cause of gynecological cancer mortality with more than 2700 deaths. Germline mutations in BRCA1/2 genes are present in 13-18% of OC cases. Few studies have evaluated the presence of mutations in BRCA genes in a population of OC Mexican patients and their relationship with clinical response and survival rates. A total of 179 OC patients were studied by molecular testing for BRCA1/2 through next-generation sequencing and multiplex ligation-dependent probe amplification. Recurrence-free survival (RFS) was estimated by the Kaplan-Meier method. BRCA mutation was detected in 33% of patients. A percentage of 66.1% were BRCA1 mutated and 33.9% were BRCA2 mutated. BRCA1 mutation carriers had a worst RFS compared with BRCA2 mutation carriers (37.6 [29-46.2] vs 72.7 [38.4-107.2]; P = 0.030). The most common mutation for BRCA1 was ex9-12del (28.2%) (Mexican founder mutation). The Mexican founder mutation had a better RFS than other BRCA1 mutations (86.1 [37.2-135.1] vs 34.5 [20.7-48.2]; P = 0.033). The presence of BRCA2 mutations in the ovarian cancer cluster region (OCCR) had a significantly better RFS than mutations in breast cancer cluster regions (BCCR) and not-related risk region (NRR) (NR vs 72.8 [39-106.6] vs 25.8 [8.3-43.2]; P = 0.013). These results demonstrate that the prevalence of BRCA1/2 positive patients in OC Mexican patients are the highest reported. Patients with mutations in BRCA2 have a better prognosis than those mutated in BRCA1. The Mexican founder mutation has an important role in clinical outcomes. These results highlight the importance to test all the HGSP (high-grade serous papillary) OC patients with or without cancer family history (CFH) in Mexican population.
    DOI:  https://doi.org/10.1016/j.tranon.2019.11.003
  6. Sci Rep. 2019 Dec 27. 9(1): 19986
    Jarhelle E, Riise Stensland HMF, Hansen GÅM, Skarsfjord S, Jonsrud C, Ingebrigtsen M, Strømsvik N, Van Ghelue M.
      Families with breast and ovarian cancer are often tested for disease associated sequence variants in BRCA1 and BRCA2. Pathogenic sequence variants (PVs) in these two genes are known to increase breast and ovarian cancer risks in females. However, in most families no PVs are detected in these two genes. Currently, several studies have identified other genes involved in hereditary breast and ovarian cancer (HBOC). To identify genetic risk factors for breast and ovarian cancer in a Norwegian HBOC cohort, 101 breast and/or ovarian cancer patients negative for PVs and variants of unknown clinical significance (VUS) in BRCA1/2 were screened for PVs in 94 genes using next-generation sequencing. Sixteen genes were closely scrutinized. Nine different deleterious germline PVs/likely pathogenic variants (LPVs) were identified in seven genes in 12 patients: three in ATM, and one in CHEK2, ERCC5, FANCM, RAD51C, TP53 and WRN. Additionally, 32 different VUSs were identified and these require further characterization. For carriers of PV/LPV in many of these genes, there are no national clinical management programs in Norway. The diversity of genetic risk factors possibly involved in cancer development show the necessity for more knowledge to improve the clinical follow-up of this genetically diverse patient group.
    DOI:  https://doi.org/10.1038/s41598-019-55515-x
  7. Cancer Cell Int. 2019 ;19 334
    Siraj AK, Parvathareddy SK, Bu R, Iqbal K, Siraj S, Masoodi T, Concepcion RM, Ghazwani LO, AlBadawi I, Al-Dayel F, Al-Kuraya KS.
      Background: Endometrial carcinoma (EC) accounts for 5.8% of all cancers in Saudi females. Although most ECs are sporadic, 2-5% tend to be familial, being associated with Lynch syndrome and Cowden syndrome. In this study, we attempted to uncover the frequency, spectrum and phenotype of germline mutations in the proofreading domain of POLE and POLD1 genes in a large cohort of ECs from Middle Eastern region.Methods: We performed Capture sequencing and Sanger sequencing to screen for proofreading domains of POLE and POLD1 genes in 432 EC cases, followed by evaluation of protein expression using immunohistochemistry. Variant interpretation was performed using PolyPhen-2, MutationAssessor, SIFT, CADD and Mutation Taster.
    Results: In our cohort, four mutations (0.93%) were identified in 432 EC cases, two each in POLE and POLD1 proofreading domains. Furthermore, low expression of POLE and POLD1 was noted in 41.1% (170/1414) and 59.9% (251/419) of cases, respectively. Both the cases harboring POLE mutation showed high nuclear expression of POLE protein, whereas, of the two POLD1 mutant cases, one case showed high expression and another case showed low expression of POLD1 protein.
    Conclusions: Our study shows that germline mutations in POLE and POLD1 proofreading region are a rare cause of EC in Middle Eastern population. However, it is still feasible to screen multiple cancer related genes in EC patients from Middle Eastern region using multigene panels including POLE and POLD1.
    Keywords:  Endometrial carcinoma; POLD1; POLE; Proofreading domains
    DOI:  https://doi.org/10.1186/s12935-019-1058-9
  8. J Clin Med. 2019 Dec 21. pii: E30. [Epub ahead of print]9(1):
    Tatsi C, Stratakis CA.
      The genetic landscape of pituitary adenomas (PAs) is diverse and many of the identified cases remain of unclear pathogenetic mechanism. Germline genetic defects account for a small percentage of all patients and may present in the context of relevant family history. Defects in AIP (mutated in Familial Isolated Pituitary Adenoma syndrome or FIPA), MEN1 (coding for menin, mutated in Multiple Endocrine Neoplasia type 1 or MEN 1), PRKAR1A (mutated in Carney complex), GPR101 (involved in X-Linked Acrogigantism or X-LAG), and SDHx (mutated in the so called "3 P association" of PAs with pheochromocytomas and paragangliomas or 3PAs) account for the most common familial syndromes associated with PAs. Tumor genetic defects in USP8, GNAS, USP48 and BRAF are some of the commonly encountered tissue-specific changes and may explain a larger percentage of the developed tumors. Somatic (at the tumor level) genomic changes, copy number variations (CNVs), epigenetic modifications, and differential expression of miRNAs, add to the variable genetic background of PAs.
    Keywords:  gene; pituitary; tumor
    DOI:  https://doi.org/10.3390/jcm9010030
  9. Breast J. 2019 Dec 22.
    Wood ME, Rehman HT, Bedrosian I.
      Family history is an important cancer risk assessment tool, and it is easy to use. The family history is integral in identifying an individual's risk for primary cancer and assists in the assessment of risk for a second primary cancer. For oncology providers, the critical family history is defined as including first- and second-degree family history, maternal and paternal history, type of primary cancer, and age at diagnosis and ethnicity. Family history should be taken at diagnosis and updated periodically. Despite the importance of family history to patient care, there are significant barriers to taking a family history. We review the impact of collecting complete family history data with respect to calculation of cancer risk, recommendations for screening, and prevention strategies and referral for genetic testing.
    Keywords:  cancer family history; genetics; prevention; screening
    DOI:  https://doi.org/10.1111/tbj.13722
  10. J Assist Reprod Genet. 2019 Dec 24.
    Porcu E, Cillo GM, Cipriani L, Sacilotto F, Notarangelo L, Damiano G, Dirodi M, Roncarati I.
      PURPOSE: To determine the impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcome. The main purpose and research question of the study is to determine the impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcomes.METHODS: Prospective study: 67 breast cancer patients between 18 and 40 years old, undergoing a fertility preservation by means of oocyte storage were considered. Inclusions criteria for the study were age between 18 and 40 years old, BMI between 18 and 28, breast cancer neoplasm stage I and II according to American Joint Committee on Cancer classification (2017) and no metastasis.
    EXCLUSION CRITERIA: age over 40 years old, BMI < 18 and > 28, breast cancer neoplasm stage III and IV and do not performed the BRCA test. A total of 21 patients had not performed the test and were excluded. Patients were divided into four groups: Group A was composed by 11 breast cancer patients with BRCA 1 mutations, Group B was composed by 11 breast cancer patients with BRCA 2 mutations, Group C was composed by 24 women with breast cancer without BRCA mutations, and Group D (control) was composed by 181 normal women.
    RESULTS: Group A showed significant lower AMH levels compared to Group C and D (1.2 ± 1.1 vs 4.5 ± 4.1 p < 0.05 and 1.2 ± 1.1 vs 3.8 ± 2.5 p < 0.05). BRCA1 mutated patients showed a significant lower rate of mature oocytes (MII) compared to Group C (3.1 ± 2.3 vs 7.2 ± 4.4 p < 0,05) and Group D (3.1 ± 2.3 vs 7.3 ± 3.4; p < 0,05). Breast cancer patients needed a higher dose of gonadotropins compared to controls (Group A 2206 ± 1392 Group B2047.5 ± 829.9 Group C 2106 ± 1336 Group D 1597 ± 709 p < 0,05). No significant differences were found among the groups considering basal FSH levels, duration of stimulation, number of developed follicles, and number of total retrieved oocytes. Regarding BRCA2 mutation, no effect on fertility was shown in this study.
    CONCLUSIONS: The study showed that BRCA1 patients had a higher risk of premature ovarian insufficiency (POI) confirmed by a diminished ovarian reserve and a lower number of mature oocytes suitable for cryopreservation.
    Keywords:  BRCA; Breast cancer; Fertility preservation; Oocyte cryopreservation
    DOI:  https://doi.org/10.1007/s10815-019-01658-9