bims-lifras Biomed News
on Li-Fraumeni Syndrome
Issue of 2020‒01‒12
ten papers selected by
Joanna Zawacka-Pankau



  1. Pediatr Blood Cancer. 2020 Jan 06. e28158
    Jiménez I, Laé M, Tanguy ML, Savignoni A, Gauthier-Villars M, Desjardins L, Cassoux N, Dendale R, Rodriguez J, Doz F, Brisse HJ, Aerts I.
      BACKGROUND: The long-term survival of germline retinoblastoma patients is decreased due to the risk of second primary tumors (SPTs) that occur years after the diagnosis of retinoblastoma. This risk is related to genetic predisposition and other factors, such as the treatment of retinoblastoma by external beam radiotherapy (EBRT).PROCEDURE: We studied the incidence, risk factors, and prognosis of specific craniofacial SPTs developed within the margins of radiation field in a cohort of 209 patients with germline retinoblastoma treated with EBRT at our institution between 1977 and 2010. Clinical characteristics, survival, incidence, and histology of craniofacial SPTs were recorded.
    RESULTS: Fifty-three of the 209 patients developed 60 distinct craniofacial SPTs in irradiated field with a median time from EBRT of 16.9 years (4-35) and a median follow-up of 24.8 years (5.3-40). Osteosarcoma (33.3%) and undifferentiated sarcoma (23.3%) were the more prevalent histological entities. Benign tumors (16.7%) also occurred. The cumulative incidence of craniofacial SPTs reached 32.6% at 35 years after EBRT, and the median survival after diagnosis was five years. In our series, irradiation under 12 months of age, bilateral EBRT, or previous treatment of retinoblastoma with chemotherapy did not significantly increase the risk of craniofacial SPTs.
    CONCLUSIONS: This work presents a strong argument to avoid EBRT in the management of retinoblastoma and emphasizes the high risk and poor prognosis of specific craniofacial SPTs. This study also points to the question of the need and benefits of special programs for early detection of craniofacial SPTs in survivors of irradiated germline retinoblastoma.
    Keywords:  external beam radiotherapy; germline retinoblastoma; hereditary retinoblastoma; second malignant neoplasms; second primary tumors
    DOI:  https://doi.org/10.1002/pbc.28158
  2. Biochim Biophys Acta Rev Cancer. 2020 Jan 06. pii: S0304-419X(19)30205-7. [Epub ahead of print] 188339
    Raimundo L, Ramos H, Loureiro JB, Calheiros J, Saraiva L.
      Increasing emphasis has been given to prevention as a feasible approach to reduce the cancer burden. However, for its clinical success, further advances are required to identify effective chemopreventive agents. This review affords a critical and up-to-date discussion of issues related to cancer prevention, including an in-depth knowledge on BRCA1 and p53 tumor suppressor proteins as key molecular players. Indeed, it compiles the most recent advances on the topic, highlighting the unique potential of BRCA1 and p53 germline mutations as molecular biomarkers for risk assessment and targets for chemoprevention. Relevant evidences are herein provided supporting the effectiveness of distinct pharmacological agents in cancer prevention, by targeting BRCA1 and p53. Moreover, the rationale for using germline mutant BRCA1- or p53-related cancer syndromes as model systems to investigate effective chemopreventive agents is also addressed. Altogether, this work provides an innovative conception about the dependence on p53 and BRCA1 co-inactivation in tumor formation and development, emphasizing the relationship between these two proteins as an encouraging direction for future personalized pharmacological interventions in cancer prevention.
    Keywords:  BRCA1; Cancer risk; Chemopreventive agents; Hereditary breast and ovarian cancer syndrome; Li-Fraumeni syndrome; p53
    DOI:  https://doi.org/10.1016/j.bbcan.2020.188339
  3. Hereditas. 2020 ;157 1
    Wu Y, Zhang H, Weng X, Wang H, Zhou Q, Wu Y, Shen Y, Hu Z.
      Background: Breast cancer is a one of the malignant carcinomas partially caused by genetic risk factors. Germline BRCA1 gene mutations are reportedly associated with breast cancers. Identification of BRCA1 mutations greatly improves the preventive strategies and management of breast cancer. The aim of our study was to investigate the frequency of the deleterious BRCA1: p.Ile1845fs variant in breast carcinomas, as well as the correlation between p.Ile1845fs variant with clinicopathological parameters and clinical outcomes.Results: A total of 23,481 clinically high-risk patients with breast cancer and 6489 healthy controls were recruited for p.Ile1845fs variant sequencing (either sanger or next generation sequencing). We identified 94 breast cancer patients (0.40%, 94/23481) as well as 11 healthy controls (0.17%, 11/6489) carried p.Ile1845fs variant. BRCA1: p.Ile1845fs variant showed a higher frequency in patients with TNBC molecular typing (20.21%, 19/94) and family history (37.23%, 35/94) compared with non-carriers (P = 3.62E-6 and 0.034, respectively). According to our data, we advanced the frequency of p.Ile1845fs variant and we confirmed that BRCA1: p.Ile1845fs variant was associated with increased risk of breast cancer (OR = 2.36, 95%CI = 1.26-4.89, P = 0.004).
    Conclusions: BRCA1: p.Ile1845fs variant was a frequently pathogenic mutation in breast cancer in Han Chinese women and our data may be helpful for diagnosis and therapy of breast cancer.
    Keywords:  BRCA1; Breast cancer; Clinicopathological; P.Ile1845fs
    DOI:  https://doi.org/10.1186/s41065-019-0115-7
  4. J Hum Genet. 2020 Jan 06.
    Kim HK, Lee EJ, Lee YJ, Kim J, Kim Y, Kim K, Lee SW, Chang S, Lee YJ, Lee JW, Lee W, Chun S, Son BH, Jung KH, Kim YM, Min WK, Ahn SH.
      The clinical utility of BRCA1/2 genotyping was recently extended from the selection of subjects at high risk for hereditary breast and ovary cancer to the identification of candidates for poly (ADP-ribose) polymerase (PARP) inhibitor treatment. This underscores the importance of accurate interpretation of BRCA1/2 genetic variants and of reducing the number of variants of uncertain significance (VUSs). Two recent studies by Findlay et al. and Starita et al. introduced high-throughput functional assays, and proactively analyzed variants in specific regions regardless of whether they had been previously observed. We retrospectively reviewed all BRCA1 and BRCA2 germline genetic test reports from patients with breast or ovarian cancer examined at Asan Medical Center (Seoul, Korea) between September 2011 and December 2018. Variants were assigned pathogenic or benign strong evidence codes according to the functional classification and were reclassified according to the ACMG/AMP 2015 guidelines. Among 3684 patients with available BRCA1 and BRCA2 germline genetic test reports, 429 unique variants (181 from BRCA1) were identified. Of 34 BRCA1 variants intersecting with the data reported by Findlay et al., three missense single-nucleotide variants from four patients (0.11%, 4/3684) were reclassified from VUSs to likely pathogenic variants. Four variants scored as functional were reclassified into benign or likely benign variants. Three variants that overlapped with the data reported by Starita et al. could not be reclassified. In conclusion, proactive high-throughput functional study data are useful for the reclassification of clinically observed VUSs. Integrating additional evidence, including functional assay results, may help reduce the number of VUSs.
    DOI:  https://doi.org/10.1038/s10038-019-0713-2
  5. Cancer Med. 2020 Jan 07.
    Ye F, Huang L, Lang G, Hu X, Di G, Shao Z, Cao A.
      PURPOSE: Previous studies provide inconsistent interpretations of the effect of inherited genetic factors on the survival and prognosis of patients with breast cancer. The aim of this study was to examine the effect of germline BRCA1 and BRCA2 mutation on survival and subsequent breast events in Chinese women who underwent breast-conserving surgery.METHODS: A retrospective review of the clinical and pathological records was performed in patients diagnosed with primary invasive breast cancer between 2005 and 2018 in the cancer registry database. Clinicopathological data and data regarding treatment and outcomes, including date and site of disease progression, were collected. The survival outcomes and independent risk factors were conducted using SPSS.
    RESULTS: Overall, a total of 501 patients who underwent breast-conserving surgery were identified and subjected to analyses, of which 63 cases with BRCA1 or BRCA2 mutation. The median age at diagnosis was 41 (range, 24-74) for carriers and 37 (range, 17-84) for noncarriers. After a median follow-up time of 61 months (range, 8-161) and 70 months (range, 0-153), respectively, in carriers and noncarriers, the overall survival (P = .173) and disease-free survival (P = .424) were not significantly different. Analogously, there was no significant difference between the two groups about the outcomes of ipsilateral breast tumor recurrence (P = .348), yet the contralateral breast cancer (CBC) was overt worse than noncarriers (P < .001). When adjusted to confounding factors, BRCA mutation was the only independent risk factors to CBC (HR = 7.89, P = .01).
    CONCLUSION: In this study, BRCA mutation carriers have higher risk of CBC. And, BRCA mutation is the only independent risk factor to CBC. Therefore, intensive surveillance and follow-up as well as more effective individual prevention are urgent. Decisions on alternatively effective prevention, especially the prevention of CBC, are urgent and should take into account patient prognosis and preferences.
    Keywords:  BRCA1/2 mutation; breast cancer; breast-conserving surgery; outcomes; subsequent breast events
    DOI:  https://doi.org/10.1002/cam4.2836
  6. Asian J Surg. 2020 Jan 07. pii: S1015-9584(19)30880-2. [Epub ahead of print]
    Park CS, Park HY, Jung JH, Kim WW, Chae YS, Lee SJ, Park JY, Park JY, Lee J.
      BACKGROUND: The authors compared the clinical features between familial (non-hereditary) and hereditary breast cancer. And we also analyzed their oncologic outcomes to establish appropriate surveillance protocol for familial (non-hereditary) and hereditary breast cancer.METHODS: Among 232 patients with breast cancer who were performed BRCA gene evaluation, twenty-eight patients were diagnosed as hereditary breast cancer with BRCA gene mutation and one-hundred and seventy-six patients were familial (non-hereditary) breast cancer. The clinical characteristics and oncologic outcomes were compared between two groups.
    RESULTS: While the incidence of multifocality was higher in familial (non-hereditary) breast cancer group (p < 0.001), the bilaterality was higher in hereditary breast cancer group (p < 0.001). And the rate of pathologic complete remission was also significantly higher in hereditary breast cancer group (p = 0.030). The characteristics of tumor were different between familial (non-hereditary) breast cancer and hereditary breast cancer. The oncologic outcome was better in familial (non-hereditary) breast cancer group than hereditary breast cancer group except death.
    CONCLUSION: The clinical characteristics of familial (non-hereditary) breast cancer were different from those of hereditary breast cancer but similar to those of sporadic breast cancer. The prognosis of the familial (non-hereditary) breast cancer was significantly better than hereditary breast cancer.
    Keywords:  BRCA; Breast; Carcinoma; Familial; Hereditary
    DOI:  https://doi.org/10.1016/j.asjsur.2019.12.001
  7. Genet Med. 2020 Jan 08.
    Dines JN, Shirts BH, Slavin TP, Walsh T, King MC, Fowler DM, Pritchard CC.
      PURPOSE: Guidelines for variant interpretation incorporate variant hotspots in critical functional domains as evidence for pathogenicity (e.g., PM1 and PP2), but do not use "coldspots," that is, regions without essential functions that tolerate variation, as evidence a variant is benign. To improve variant classification we evaluated BRCA1 and BRCA2 missense variants reported in ClinVar to identify regions where pathogenic missenses are extremely infrequent, defined as coldspots.METHODS: We used Bayesian approaches to model variant classification in these regions.
    RESULTS: BRCA1 exon 11 (~60% of the coding sequence), and BRCA2 exons 10 and 11 (~65% of the coding sequence), are coldspots. Of 89 pathogenic (P) or likely pathogenic (LP) missense variants in BRCA1, none are in exon 11 (odds <0.01, 95% confidence interval [CI] 0.0-0.01). Of 34 P or LP missense variants in BRCA2, none are in exons 10-11 (odds <0.01, 95% CI 0.0-0.01). More than half of reported missense variants of uncertain significance (VUS) in BRCA1 and BRCA2 are in coldspots (3115/5301 = 58.8%). Reclassifying these 3115 VUS as likely benign would substantially improve variant classification.
    CONCLUSION: In BRCA1 and BRCA2 coldspots, missense variants are very unlikely to be pathogenic. Classification schemes that incorporate coldspots can reduce the number of VUS and mitigate risks from reporting benign variation as VUS.
    Keywords:  ACMG; BRCA1; VUS; coldspot; variant classification
    DOI:  https://doi.org/10.1038/s41436-019-0740-6
  8. Saudi Med J. 2020 Jan;41(1): 9-17
    Junejo NN, AlKhateeb SS.
      The second most common type of tumor worldwide is prostate cancer (PCa). Certain genetic factors contribute to a risk of developing PCa of as much as 40%. BRCA1 and BRCA2 mutations have linked with an increased risk for breast, ovarian, and PCa. However, BRCA2 is the most common gene found altered in early-onset of PCa in males younger than 65. BRCA2 mutation has a higher chance of developing an advanced stage of the disease, resulting in short survival time. This review aimed to describe the genetic changes in BRCA2 that contribute to the risk of PCa, to define its role in the early diagnosis in a man with a strong family history, and to outline the purpose of genetic testing and counseling. Also, the review summarizes the impact of BRCA2 gene mutation in localized PCa, and the treatment strategies have used for PCa patients with a BRCA2 modification.
    DOI:  https://doi.org/10.15537/smj.2020.1.24759