bims-lifras Biomed News
on Li-Fraumeni Syndrome
Issue of 2019‒09‒08
eight papers selected by
Joanna Zawacka-Pankau



  1. Hum Mutat. 2019 Sep 06.
    Coffee B, Cox HC, Bernhisel R, Manley S, Bowles K, Roa BB, Mancini-DiNardo D.
      Previous analysis of Next-Generation Sequencing (NGS) hereditary pan-cancer panel testing demonstrated that approximately 40% of TP53 pathogenic and likely pathogenic variants (PVs) detected have NGS allele frequencies between 10-30%, indicating that they likely are acquired somatically. These are seen more frequently in older adults, suggesting that most result from normal aging-related clonal hematopoiesis. For this analysis, apparent heterozygous germline TP53 PV carriers (NGS allele frequency 30-70%) were offered follow-up testing to confirm variant origin. Ninety-eight probands had samples submitted for follow-up family member testing, fibroblast testing, or both. The apparent heterozygous germline TP53 PV was not detected in 32.6% (15/46) of submitted fibroblast samples, indicating that it was acquired somatically, either through clonal hematopoiesis or via constitutional mosaicism. Notably, no individuals with confirmed germline or likely germline TP53 PVs met classic Li-Fraumeni syndrome (LFS) criteria, only 41% met Chompret LFS criteria, and 59% met neither criteria, based upon provider-reported personal and family cancer history. Comprehensive reporting of TP53 PVs detected using NGS, combined with follow-up analysis to confirm variant origin, is advised for clinical testing laboratories. These findings underscore the investment required to provide individuals and family members with clinically accurate genetic test results pertaining to their LFS risk. This article is protected by copyright. All rights reserved.
    Keywords:  Li-Fraumeni syndrome; Next-Generation Sequencing; TP53; acquired somatically; hereditary pan-cancer gene panel; pathogenic variant
    DOI:  https://doi.org/10.1002/humu.23910
  2. J Am Stat Assoc. 2019 ;114(526): 541-552
    Shin SJ, Yuan Y, Strong LC, Bojadzieva J, Wang W.
      Penetrance, which plays a key role in genetic research, is defined as the proportion of individuals with the genetic variants (i.e., genotype) that cause a particular trait and who have clinical symptoms of the trait (i.e., phenotype). We propose a Bayesian semiparametric approach to estimate the cancer-specific age-at-onset penetrance in the presence of the competing risk of multiple cancers. We employ a Bayesian semiparametric competing risk model to model the duration until individuals in a high-risk group develop different cancers, and accommodate family data using family-wise likelihoods. We tackle the ascertainment bias arising when family data are collected through probands in a high-risk population in which disease cases are more likely to be observed. We apply the proposed method to a cohort of 186 families with Li-Fraumeni syndrome identified through probands with sarcoma treated at MD Anderson Cancer Center from 1944 to 1982.
    Keywords:  Li-Fraumeni syndrome; cancer specific age-at-onset penetrance; competing risk; family-wise likelihood; gamma frailty model
    DOI:  https://doi.org/10.1080/01621459.2018.1482749
  3. Am J Hum Genet. 2019 Sep 05. pii: S0002-9297(19)30303-9. [Epub ahead of print]105(3): 658-668
    Egolf LE, Vaksman Z, Lopez G, Rokita JL, Modi A, Basta PV, Hakonarson H, Olshan AF, Diskin SJ.
      Neuroblastoma is a cancer of the developing sympathetic nervous system. It is diagnosed in 600-700 children per year in the United States and accounts for 12% of pediatric cancer deaths. Despite recent advances in our understanding of this malignancy's complex genetic architecture, the contribution of rare germline variants remains undefined. Here, we conducted a genome-wide analysis of large (>500 kb), rare (<1%) germline copy number variants (CNVs) in two independent, multi-ethnic cohorts totaling 5,585 children with neuroblastoma and 23,505 cancer-free control children. We identified a 550-kb deletion on chromosome 16p11.2 significantly enriched in neuroblastoma cases (0.39% of cases and 0.03% of controls; p = 3.34 × 10-9). Notably, this CNV corresponds to a known microdeletion syndrome that affects approximately one in 3,000 children and confers risk for diverse developmental phenotypes including autism spectrum disorder and other neurodevelopmental disorders. The CNV had a substantial impact on neuroblastoma risk, with an odds ratio of 13.9 (95% confidence interval = 5.8-33.4). The association remained significant when we restricted our analysis to individuals of European ancestry in order to mitigate potential confounding by population stratification (0.42% of cases and 0.03% of controls; p = 4.10 × 10-8). We used whole-genome sequencing (WGS) to validate the deletion in paired germline and tumor DNA from 12 cases. Finally, WGS of four parent-child trios revealed that the deletion primarily arose de novo without maternal or paternal bias. This finding expands the clinical phenotypes associated with 16p11.2 microdeletion syndrome to include cancer, and it suggests that disruption of the 16p11.2 region may dysregulate neurodevelopmental pathways that influence both neurological phenotypes and neuroblastoma.
    Keywords:  16p11.2 microdeletion; chromosomal abnormalities; copy number variation; de novo; genetic predisposition; genome-wide association study; germline; neuroblastoma; pediatric cancer; rare variant
    DOI:  https://doi.org/10.1016/j.ajhg.2019.07.020
  4. Nat Commun. 2019 Sep 06. 10(1): 4053
    Lindsay SJ, Rahbari R, Kaplanis J, Keane T, Hurles ME.
      Whole genome sequencing (WGS) studies have estimated the human germline mutation rate per basepair per generation (~1.2 × 10-8) to be higher than in mice (3.5-5.4 × 10-9). In humans, most germline mutations are paternal in origin and numbers of mutations per offspring increase with paternal and maternal age. Here we estimate germline mutation rates and spectra in six multi-sibling mouse pedigrees and compare to three multi-sibling human pedigrees. In both species we observe a paternal mutation bias, a parental age effect, and a highly mutagenic first cell division contributing to the embryo. We also observe differences between species in mutation spectra, in mutation rates per cell division, and in the parental bias of mutations in early embryogenesis. These differences between species likely result from both species-specific differences in cellular genealogies of the germline, as well as biological differences within the same stage of embryogenesis or gametogenesis.
    DOI:  https://doi.org/10.1038/s41467-019-12023-w
  5. J Ovarian Res. 2019 Aug 31. 12(1): 80
    Li W, Shao D, Li L, Wu M, Ma S, Tan X, Zhong S, Guo F, Wang Z, Ye M.
      BACKGROUND: Multiple targeted gene sequencing is seldom performed in both germline and somatic testing for ovarian cancer. This study is to evaluate the specific genetic alterations, including both somatic and germline mutations, in Chinese patients with epithelial ovarian cancer (EOC) in a prospective cohort study.MATERIALS AND METHODS: Mutations in a customed 21-gene panel that included BRCA1, BRCA2, and 19 other tumor suppressor genes related to homologous recombination (HR) deficiency or non-HR deficiency were detected by targeted exon capture and next-generation sequencing (NGS) technology across all coding exons and exon-intron (±20 base pairs) boundaries. Patients were enrolled consecutively and unselectively without age or family history consideration. Sixty-two unselected patients with epithelial ovarian cancer were enrolled in our study to be tested for paired somatic and germline mutations. All patients were tested using a 21-gene panel that included BRCA1, BRCA2, CHEK2, PALB2, BRIP1, TP53, PTEN, STK11, CDH1, ATM, BARD1, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PMS1, PMS2, RAD50, and RAD51C.
    RESULTS: Mutation analysis revealed that 77.4% (48/62) of patients carried one or more of 64 identified genetic alterations, including 19 germline and 45 somatic deleterious mutations. Twelve individuals shared both germline and somatic mutations. BRCA mutants existed in 17 of 62 (27.4%) patients. Of the 64 mutations detected, 46 (74.2%) were in 7 other HR or non-HR genes, including TP53, PTEN, ATM, CHEK2, PALB2, RAD51C, and STK11. In somatic mutation analysis, TP53 showed frequent pathogenic or likely pathogenic mutations in 56.5% (35/62) of enrolled cases, among which six cases harbored a loss of heterozygosity.
    CONCLUSIONS: This is the first report of multi-gene panel testing for germline and somatic mutations among Chinese EOC patients, which revealed a broader deleterious variants than only BRCA testing.
    REGISTRATION: Registration No. NCT03015376, clinicaltrials.gov , registered on January 10, 2017.
    Keywords:  Epithelial ovarian cancer; Germline mutation; Homologous recombination deficiency; Next-generation sequencing; Somatic mutation
    DOI:  https://doi.org/10.1186/s13048-019-0560-y
  6. Gynecol Oncol. 2019 Aug 31. pii: S0090-8258(19)31479-9. [Epub ahead of print]
    Ong PY, Poon SL, Tan KT, Putti TC, Ow SGW, Chen SJ, Chen CH, Lee SC.
      OBJECTIVE: Clinical genetic testing to diagnose germline mutations often requires blood sample or saliva smear from a cancer-affected individual. This rules out testing in families when cancer-affected individuals are deceased. We explored the use of a next-generation sequencing (NGS) platform to diagnose germline pathogenic mutations from tumors.METHODS: Archival tumors (ovarian = 26, breast = 25, others = 9) were retrieved from 60 cancer patients who have undergone multi-gene panel blood testing. Genomic DNA was extracted and sequenced for BRCA1/2 using a NGS platform. 41/60 specimens were sequenced for 5 other genes (APC, ATM, PALB2, PTEN, TP53). Tumor testing and results interpretation were performed blinded to the blood test result.
    RESULTS: All 38 patients with no BRCA1/2 mutations on blood testing were correctly tested negative on tumor. Tumor testing correctly diagnosed BRCA1/2 pathogenic mutations in 15/22 (68%) patients while in 7/22 (32%) patients, the mutation was either detected but incorrectly classified as VUS (n = 3) or not detected at all (n = 4). Overall concordance rate for tumor and blood testing for BRCA1/2 mutations was 88%, with 0% false positive and 32% false negative rate for pathogenic mutations. Tumor testing correctly diagnosed 1/2 pathogenic germline ATM mutation, 1/1 pathogenic germline PALB2 mutation and 2/2 pathogenic germline TP53 mutations. False positive germline mutations were diagnosed in 4 genes at a rate of 2.4%-10.3% (APC = 2.4%, PALB2 = 2.4%, PTEN = 4.9%, TP53 = 10.3%).
    CONCLUSION: Tumor testing for BRCA1/2 germline mutations using an NGS platform is fairly reliable with no false positive findings, and correctly diagnosed more than two-thirds of pathogenic germline BRCA1/2 mutations. However, it is not reliable to diagnose pathogenic germline mutations in genes frequently mutated in sporadic cancers, such as PTEN and TP53.
    Keywords:  Archival tumor; BRCA1/2; Genetic testing; Germline mutations; Next-generation sequencing
    DOI:  https://doi.org/10.1016/j.ygyno.2019.08.027
  7. Eur J Med Genet. 2019 Sep 03. pii: S1769-7212(19)30330-1. [Epub ahead of print] 103753
    Yanus GA, Akhapkina TA, Iyevleva AG, Kornilov AV, Suspitsin EN, Kuligina ES, Ivantsov AO, Aleksakhina SN, Sokolova TN, Sokolenko AP, Togo AV, Imyanitov EN.
      Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome (LS), is a common cancer-predisposing syndrome. This study aimed to investigate the spectrum of germ-line mutations in Russian LS patients. LS-related mismatch repair (MMR) genes were analyzed in 16 patients, who were forwarded to genetic testing due to strong clinical features of LS and had high-level microsatellite instability (MSI-H) in the tumor (n = 14) or unknown MSI status (n = 2). In addition, 672 consecutive colorectal cancer (CRC) cases were screened for family history; 15 patients were younger than 50 years and reported 2 or more instances of LS-related cancers in 1st- or 2nd-degree relatives. Seven of these cases demonstrated MSI-H and therefore were subjected to DNA germ-line testing. Overall, 17/23 (74%) subjects carried LS-associated gene variants (MLH1: 10; MSH2: 4; MSH6: 2; PMS2: 1), with 2 alleles (MLH1 c.677G > T and MSH2 с.1906G > C) detected twice. Testing for recurrent mutations of 30 consecutive MSI-H CRCs led to the identification of 2 additional subjects with LS. The analysis of all relevant publications identified 28 unrelated LS patients presented in Russian medical literature and 3 unrelated Russian LS subjects described in international journals. Overall, 15/49 (31%) genetic defects revealed in Russian LS patients were represented by six recurrent alleles (MLH1: c.350C > T, c.677G > T, c.1852_1854del; MSH2: c.942+3A > T, c.1861C > T, с.1906G > C). We conclude that the founder effect for LS in Russia is seemingly less pronounced than the one for hereditary breast-ovarian cancer syndrome, however testing for recurrent LS mutations may be considered feasible in some circumstances.
    Keywords:  Colorectal cancer; DNA mismatch repair; Founder effect; Hereditary cancer syndromes; Lynch syndrome
    DOI:  https://doi.org/10.1016/j.ejmg.2019.103753
  8. Clin Cancer Res. 2019 Sep 06. pii: clincanres.0848.2019. [Epub ahead of print]
    de Jonge MM, Ritterhouse LL, de Kroon CD, Vreeswijk MPG, Segal JP, Puranik R, Study H, Hollema H, Rookus MA, van Asperen CJ, Van Leeuwen FE, Smit VTHBM, Howitt BE, Bosse T.
      PURPOSE: Whether endometrial cancer (EC) should be considered part of the gBRCA1/2-associated Hereditary Breast and Ovarian Cancer (HBOC)-syndrome is topic of debate. We sought to assess whether ECs occurring in gBRCA carriers are enriched for clinicopathologic and molecular characteristics, thereby supporting a causal relationship.EXPERIMENTAL DESIGN: Thirty-eight gBRCA carriers that developed EC were selected from the nationwide cohort study on Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON), and these were supplemented with four institutional cases. Tumor tissue was retrieved via PALGA (Dutch Pathology Registry). Nineteen morphologic features were scored and histotype was determined by three expert gynecologic pathologists, blinded for molecular analyses (UCM-OncoPlus Assay including 1213 genes). ECs with LOH of the gBRCA- wildtype allele (gBRCA/LOHpos) were defined "gBRCA -associated", those without LOH (gBRCA/LOHneg) were defined 'sporadic'.
    RESULTS: LOH could be assessed for 40 ECs (30 gBRCA1, 10 gBRCA2 ), of which 60% were gBRCA/LOHpos. gBRCA/LOHpos ECs were more frequently of non-endometrioid (58%, P=0.001) and grade 3 histology (79%, P<0.001). All but two were in the TP53-mutated TCGA-subgroup (91.7%, P<0.001). In contrast, gBRCA/LOHneg ECs were mainly grade 1 endometrioid EC (94%) and showed a more heterogeneous distribution of TCGA-molecular subgroups: POLE-mutated (6.3%), MSI-high (25%), NSMP (62.5%) and TP53-mutated (6.3%).
    CONCLUSIONS: We provide novel evidence in favour of EC being part of the gBRCA-associated HBOC-syndrome. gBRCA-associated ECs are enriched for EC subtypes associated with unfavourable clinical outcome. These findings have profound therapeutic consequences as these patients may benefit from treatment strategies such as PARP-inhibitors. Additionally, it should influence counselling and surveillance of gBRCA carriers.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-19-0848