bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒01‒31
sixteen papers selected by
Joanna Zawacka-Pankau
University of Warsaw


  1. Int Cancer Conf J. 2021 Jan;10(1): 6-10
    Yoshihama T, Hirasawa A, Sugano K, Yoshida T, Ushiama M, Ueki A, Akahane T, Nanki Y, Sakai K, Makabe T, Yamagami W, Susumu N, Kameyama K, Kosaki K, Aoki D.
      There has been a rapid advance in germline multigene panel testing by next-generation sequencing, and it is being widely used in clinical settings. A 56-year-old woman suspected of having Lynch syndrome was identified as a BRCA2 pathogenic variant carrier by multigene panel testing. The patient was diagnosed with endometrial cancer at the age of 39 years, and total laparoscopic hysterectomy and bilateral salpingectomy were performed at the age of 49 years; however, bilateral oophorectomy was not performed at that time. As she had a family history of colorectal cancer and a history of endometrial cancer, Lynch syndrome was suspected. However, germline multigene panel testing revealed a pathogenic BRCA2 variant rather than pathogenic variants in mismatch repair genes. In this case, with conventional genetic risk assessment, we were unable to determine whether the patient had a high risk of hereditary breast and ovarian cancer; thus, germline multigene panel testing may provide valuable information to improve disease management strategies for patients in clinical settings. Particularly, germline multigene panel testing may be useful for detecting hereditary tumor syndromes if a patient does not present with a typical family history of cancer.
    Keywords:  BRCA2; Genetic counseling; Hereditary breast and ovarian cancer; Lynch syndrome; Multigene panel testing
    DOI:  https://doi.org/10.1007/s13691-020-00449-9
  2. Genes (Basel). 2021 Jan 23. pii: 150. [Epub ahead of print]12(2):
    Rofes P, Del Valle J, Torres-Esquius S, Feliubadaló L, Stradella A, Moreno-Cabrera JM, López-Doriga A, Munté E, De Cid R, Campos O, Cuesta R, Teulé Á, Grau È, Sanz J, Capellá G, Díez O, Brunet J, Balmaña J, Lázaro C.
      Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (BRCA1 and BRCA2). BRCA1-associated ring domain 1 (BARD1), nuclear partner of BRCA1, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of BARD1 truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive BARD1 screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous BARD1 truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating BARD1 variants with overall risk (odds ratio (OR) = 3.78; CI = 2.10-6.48; p = 1.16 × 10-5). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18; CI = 2.10-7.70; p = 5.45 × 10-5). Furthermore, deleterious BARD1 variants were enriched among triple-negative BC patients (OR = 5.40; CI = 1.77-18.15; p = 0.001) compared to other BC subtypes. Our results support the role of BARD1 as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors.
    Keywords:  BARD1; breast cancer; hereditary breast and ovarian cancer; moderate cancer risk; ovarian cancer; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/genes12020150
  3. Clin Transl Gastroenterol. 2020 Dec;11(12): e00280
    Carreño M, Pena-Couso L, Mercadillo F, Perea J, Urioste M.
      INTRODUCTION: Not all patients with hereditary diffuse gastric cancer (HDGC) are found to carry germline pathogenic variants in the associated gene CDH1, which translates into a challenging clinical management and poor cancer prevention. Thus, several studies have searched for other candidate genes, among which stands PALB2. Our work explores the implication of this known cancer gene in HDGC.METHODS: We searched for germline PALB2 variants by Sanger sequencing in a series of 58 patients with HDGC who tested negative for CDH1 alterations.
    RESULTS: No clearly pathogenic variants in PALB2 were found in these patients. Only 5 rare genetic variants were identified, 3 of which were classified as variants of uncertain significance.
    DISCUSSION: Despite the promising association between PALB2 and HDGC suggested by certain works in the literature, our findings do not support PALB2 as a high predisposition gene for HDGC. Larger studies are needed to define its role in this disease and therefore improve cancer prevention.
    DOI:  https://doi.org/10.14309/ctg.0000000000000280
  4. Genes (Basel). 2021 Jan 22. pii: 142. [Epub ahead of print]12(2):
    Dobbin EAF, Medeiros JAG, Costa MSCR, Rodrigues JCG, Guerreiro JF, Kroll JE, Souza SJ, de Assumpção PP, Ribeiro-Dos-Santos Â, Santos SEBD, Burbano RMR, Fernandes MR, Santos NPCD.
      Estimates show that 5-10% of breast cancer cases are hereditary, caused by genetic variants in autosomal dominant genes; of these, 16% are due to germline mutations in the BRCA1 and BRCA2 genes. The comprehension of the mutation profile of these genes in the Brazilian population, particularly in Amazonian Amerindian groups, is scarce. We investigated fifteen polymorphisms in the BRCA1 and BRCA2 genes in Amazonian Amerindians and compared the results with the findings of global populations publicly available in the 1000 Genomes Project database. Our study shows that three variants (rs11571769, rs144848, and rs11571707) of the BRCA2 gene, commonly associated with hereditary breast cancer, had a significantly higher allele frequency in the Amazonian Amerindian individuals in comparison with the African, American, European, and Asian groups analyzed. These data outline the singular genetic profiles of the indigenous population from the Brazilian Amazon region. The knowledge about BRCA1 and BRCA2 variants is critical to establish public policies for hereditary breast cancer screening in Amerindian groups and populations admixed with them, such as the Brazilian population.
    Keywords:  BRCA1; BRCA2; Brazil; Native Americans; hereditary breast cancer; indigenous populations
    DOI:  https://doi.org/10.3390/genes12020142
  5. Ann Transl Med. 2020 Dec;8(24): 1704
    Bonadio RC, Crespo JR, Estevez-Diz MDP.
      Ovarian cancer is one of the cancers most influenced by hereditary factors. Testing for hereditary susceptibility genes is recommended for every woman with epithelial ovarian cancer (EOC). Pathogenic germline variants in BRCA1 and BRCA2 genes are responsible for a substantial fraction of hereditary ovarian cancer. However, alterations in other genes, such as BRIP1, RAD51C, RAD51D, and mismatch repair genes, also enhance ovarian cancer risk. Other genes may also participate in ovarian carcinogenesis, but their role as ovarian cancer susceptibility genes still needs to be clarified. With several genes involved, the complexity of genetic testing increases. In this context, next-generation sequencing (NGS) allows testing for multiple genes simultaneously, with rapid turn-around time. However, the incorporation of this technology into clinical practice faces some challenges. In this review, we will discuss the ovarian cancer risk assessment in the era of NGS.
    Keywords:  Ovarian cancer; cancer risk; hereditary; next-generation sequencing (NGS)
    DOI:  https://doi.org/10.21037/atm-20-1582
  6. Fam Cancer. 2021 Jan 24.
    Ni Raghallaigh H, Eeles R.
      Improvements in DNA sequencing technology and discoveries made by large scale genome-wide association studies have led to enormous insight into the role of genetic variation in prostate cancer risk. High-risk prostate cancer risk predisposition genes exist in addition to common germline variants conferring low-moderate risk, which together account for over a third of familial prostate cancer risk. Identifying men with additional risk factors such as genetic variants or a positive family history is of clinical importance, as men with such risk factors have a higher incidence of prostate cancer with some evidence to suggest diagnosis at a younger age and poorer outcomes. The medical community remains in disagreement on the benefits of a population prostate cancer screening programme reliant on PSA testing. A reduction in mortality has been demonstrated in many studies, but at the cost of significant amounts of overdiagnosis and overtreatment. Developing targeted screening strategies for high-risk men is currently the subject of investigation in a number of prospective studies. At present, approximately 38% of the familial risk of PrCa can be explained based on published SNPs, with men in the top 1% of the risk profile having a 5.71-fold increase in risk of developing cancer compared with controls. With approximately 170 prostate cancer susceptibility loci now identified in European populations, there is scope to explore the clinical utility of genetic testing and genetic-risk scores in prostate cancer screening and risk stratification, with such data in non-European populations eagerly awaited. This review will focus on both the rare and common germline genetic variation involved in hereditary and familial prostate cancer, and discuss ongoing research in exploring the role of targeted screening in this high-risk group of men.
    Keywords:  Familial prostate cancer; Germline genetics; Hereditary prostate cancer; Prostate cancer; Prostate cancer risk
    DOI:  https://doi.org/10.1007/s10689-021-00227-3
  7. Front Oncol. 2020 ;10 574813
    Ye F, He M, Huang L, Lang G, Hu X, Shao Z, Di G, Cao A.
      Background: Little is known regarding the clinicopathologic characteristics, oncologic outcomes, and treatment strategies that could be ascribed to BRCA mutation in early-onset triple-negative breast cancer (eTNBC).Methods: eTNBC patients who underwent BRCA genetic testing were derived from our clinical database between 2012 and 2018. Differences in clinical features and pathologic characteristics were examined in groups divided by BRCA mutation status, and the contribution of germline mutations in conjunction with treatment modalities to survival outcomes was determined.
    Results: Of the 355 qualifying eTNBC patients, 67 (18.87%) were BRCA mutated and 288 (81.13%) were BRCA wild. Overall, median age at diagnosis was 34 years (range, 24-40 years) in the BRCA mutated subgroup and 35 years (range, 21-40 years) in BRCA wild. The majority of clinicopathologic parameters were parallel; however, tumor size (P = 0.07) and nuclear grade (P =0.08) tend to be more aggressive in the BRCA mutated subgroup. Compared with BRCA wild patients, BRCA mutated patients had a higher likelihood of receiving anthracyclines and taxane-based combination chemotherapy (P = 0.04) and tend to be lower tumor burden (P =0.01). After approximately 5-year median follow-up, the overall survival (OS) (P = 0.021) and breast cancer-specific survival (BCSS) (P = 0.004) in BRCA mutated patients were superior to those in their BRCA wild counterparts. Intriguingly, the clinical outcomes were comparable in patients with breast conserving surgery (BCS) regardless of BRCA mutations and in patients with BRCA mutations in spite of surgical schedules.
    Conclusions: These results suggest that eTNBC patients with BRCA mutations are prone to better OS and BCSS, which might be largely attributed to more benefit from anthracyclines and taxane-based chemotherapy. The BCS procedure could be a safe alternative surgical option for eTNBC patients with BRCA mutations. Future studies with substantial numbers of participants are urgently needed to validate whether BRCA mutation eTNBC patients are more sensitive to chemotherapy.
    Keywords:  breast cancer; breast cancer type 1 susceptibility protein; early-onset; mutation; triple-negative
    DOI:  https://doi.org/10.3389/fonc.2020.574813
  8. Case Rep Pediatr. 2021 ;2021 6612802
    Martínez-Beckerat R, Alas-Pineda C, Melgar-Gonzales M, Mejía-Raudales B, Andino-Paz N, Bejarano-Cáceres S, Chiang J.
      Li-Fraumeni syndrome is an inherited, autosomal dominant disease. It is categorized as a rare disease caused by mutations of the TP53 gene, which causes increased susceptibility of the patients and their children to many types of cancer. Choroid plexus tumor is rare, which occurs in 0.3 cases per 1,000,000 people, of which 40% turn out to be carcinomas. We present a 12-year-old boy with a history of worsening headaches of more than one month, gait disturbance, projectile vomiting, and right hemiparesis. An intraventricular tumor was identified in the occipital of the left lateral ventricle, which turned out to be a TP53-mutant choroidal plexus carcinoma.
    DOI:  https://doi.org/10.1155/2021/6612802
  9. Ann Transl Med. 2020 Dec;8(24): 1703
    Fostira F, Papadimitriou M, Papadimitriou C.
      Epithelial ovarian cancer (EOC) is probably the tumor type with the highest percentage of hereditary cases observed, irrespectively of selection criteria. A fourth to a fifth of unselected epithelial EOC patients carry pathogenic variants (PVs) in a number of genes, the majority of which encode for proteins involved in DNA repair pathways. BRCA1 and BRCA2 predisposing PVs were the first to be associated to ovarian cancer, with the advent in DNA sequencing technologies leading to the discovery and association of additional genes which compromise the homologous recombination (HR) pathway. In addition, PVs genes involved in mismatch repair (MMR) pathway, account for 10-15% of hereditary EOC. The identification of women with HR deficient ovarian cancers has significant clinical implications concerning chemotherapy regimen planning and development and use of targeted therapies as well. More specifically, in patients with BRCA1/2 PVs or HR deficiency maintenance treatment with poly(ADP-ribose) polymerase (PARP) inhibitors, either in the first line setting or in recurrent disease, improves the progression-free survival. But also patients with HR proficient tumors show a benefit. Therefore, genetic testing in ovarian cancer has a prognostic and predictive value. In this review, we discuss which ovarian cancer patients should be referred for genetic counseling and how to perform genetic testing. We also discuss the timing of genetic testing and its clinical relevance to BRCA status.
    Keywords:  BRCA mutations; Genetic testing; homologous recombination hereditary ovarian cancer; poly(ADP-ribose) polymerase inhibitors (PARP inhibitors)
    DOI:  https://doi.org/10.21037/atm-20-1422
  10. Appl Clin Genet. 2021 ;14 1-9
    McAlarnen L, Stearns K, Uyar D.
      Completion of genetic testing is increasingly important for the complex care of patients with suspected hereditary breast and ovarian cancers (HBOC) and their at-risk family members. Identification of individuals with pathogenic variants has implications for targeted treatment recommendations, risk reduction strategies, increased surveillance recommendations, as well as the genetic testing of family members, known as cascade testing or screening. Due to advances in technology and decreasing costs, what was once single-gene genetic testing has evolved into large-scale multi-gene panel genomic testing. As germline genomic testing for HBOC becomes more and more available, it is important to identify the challenges that are associated with its use. In this manuscript, we review the current issues faced by germline genomic testing for HBOC which include effectively managing the marked increases in genetic referrals, interpreting the vast amount of information yielded by newer testing methods such as next generation sequencing (NGS), recognizing the need for better cascade screening strategies, potential exacerbation of health disparities and improving support for patients navigating the emotional impact related to positive, negative and indeterminate testing results.
    Keywords:  BRCA; cascade testing; genetic testing; genomic testing; hereditary breast and ovarian cancer syndrome; next-generation sequencing
    DOI:  https://doi.org/10.2147/TACG.S245021
  11. Cancers (Basel). 2021 Jan 22. pii: 406. [Epub ahead of print]13(3):
    Gallon R, Gawthorpe P, Phelps RL, Hayes C, Borthwick GM, Santibanez-Koref M, Jackson MS, Burn J.
      International guidelines for the diagnosis of Lynch syndrome (LS) recommend molecular screening of colorectal cancers (CRCs) to identify patients for germline mismatch repair (MMR) gene testing. As our understanding of the LS phenotype and diagnostic technologies have advanced, there is a need to review these guidelines and new screening opportunities. We discuss the barriers to implementation of current guidelines, as well as guideline limitations, and highlight new technologies and knowledge that may address these. We also discuss alternative screening strategies to increase the rate of LS diagnoses. In particular, the focus of current guidance on CRCs means that approximately half of Lynch-spectrum tumours occurring in unknown male LS carriers, and only one-third in female LS carriers, will trigger testing for LS. There is increasing pressure to expand guidelines to include molecular screening of endometrial cancers, the most frequent cancer in female LS carriers. Furthermore, we collate the evidence to support MMR deficiency testing of other Lynch-spectrum tumours to screen for LS. However, a reliance on tumour tissue limits preoperative testing and, therefore, diagnosis prior to malignancy. The recent successes of functional assays to detect microsatellite instability or MMR deficiency in non-neoplastic tissues suggest that future diagnostic pipelines could become independent of tumour tissue.
    Keywords:  Lynch syndrome; mismatch repair deficiency; screening
    DOI:  https://doi.org/10.3390/cancers13030406
  12. Genes (Basel). 2021 Jan 21. pii: 136. [Epub ahead of print]12(2):
    Parenti S, Rabacchi C, Marino M, Tenedini E, Artuso L, Castellano S, Carretta C, Mallia S, Cortesi L, Toss A, Barbieri E, Manfredini R, Luppi M, Trenti T, Tagliafico E.
      Next-generation sequencing (NGS)-based cancer risk screening with multigene panels has become the most successful method for programming cancer prevention strategies. ATM germ-line heterozygosity has been described to increase tumor susceptibility. In particular, families carrying heterozygous germ-line variants of ATM gene have a 5- to 9-fold risk of developing breast cancer. Recent studies identified ATM as the second most mutated gene after CHEK2 in BRCA-negative patients. Nowadays, more than 170 missense variants and several truncating mutations have been identified in ATM gene. Here, we present the molecular characterization of a new ATM deletion, identified thanks to the CNV algorithm implemented in the NGS analysis pipeline. An automated workflow implementing the SOPHiA Genetics' Hereditary Cancer Solution (HCS) protocol was used to generate NGS libraries that were sequenced on Illumina MiSeq Platform. NGS data analysis allowed us to identify a new inactivating deletion of exons 19-27 of ATM gene. The deletion was characterized both at the DNA and RNA level.
    Keywords:  ATM; breast cancer; clinical genomics; hereditary cancer syndromes; homologous recombination repair; molecular diagnostics; next-generation sequencing
    DOI:  https://doi.org/10.3390/genes12020136
  13. Exp Eye Res. 2021 Jan 22. pii: S0014-4835(21)00021-X. [Epub ahead of print] 108456
    Chai P, Luo Y, Yu J, Li Y, Yang J, Zhuang A, Fan J, Han M, Jia R.
      Retinoblastoma (Rb) is the most common primary intraocular childhood malignancy and one of the main causes of blindness in children. In China, most tumors are diagnosed at an advanced stage and have relatively poor outcomes compared to developed countries. Here, we aimed to update the clinical manifestations and RB transcriptional corepressor 1 (RB1) mutation spectrum in Chinese Rb patients. Medical charts of 184 eyes in 145 Chinese Rb patients belonging to unrelated families were reviewed. Genomic DNA was isolated from peripheral blood of the patients and their parents. Mutation analysis of whole coding regions, promoter regions and flanking splice sites in the RB1 gene was performed. In addition, multiplex ligation-dependent probe amplification (MLPA) was done to detect gross aberrations. Germline RB1 mutations were observed in 37.2% (54/145) of Rb patients. RB1-mutated patients presented with earlier age of diagnosis (p = 0.019), with a significantly larger proportion of bilateral cases (p = <0.001) and secondary malignancies (p = 0.027) relative to those without RB1 mutations. For ocular clinical presentations, RB1-mutated retinoblastomas presented with a larger proportion of ectropion uveae (p = 0.017) and iris neovascularization (p = 0.001). These RB1 mutations comprised of 13 (24.1%) nonsense mutation, 13 (24.1%) splicing mutations, 11 (20.4%) frameshift deletions, 11 (20.4%) gross mutations, 3 (5.6%) missense mutations, 2 (3.7%) promoter mutations and 1 (1.9%) non-frameshift deletion. In addition, 8 novel RB1 mutations were identified. These germline RB1 mutations were not related to age at diagnosis or laterality. Here, we provide a comprehensive spectrum of RB1 germline mutations in Chinese Rb patients and describe correlations between RB1 mutations and clinical presentations. Our study also provides new evidence that will inform management and genetic counselling of Rb patients and families.
    Keywords:  Clinical presentations; Mutations; RB1; Retinoblastoma
    DOI:  https://doi.org/10.1016/j.exer.2021.108456
  14. NPJ Genom Med. 2020 Jan 31. 5(1): 8
    Ndiaye R, Diop JPD, Bourdon-Huguenin V, Dem A, Diouf D, Dieng MM, Diop PS, Kane Gueye SM, Ba SA, Dia Y, Ka S, Mbengue B, Thiam A, Sylla Niang M, Gueye PM, Faye O, Lopez Sall P, Cisse A, Diop PA, Sobol H, Dieye A.
      BRCA1 and BRCA2 are the most incriminated genes in inherited breast/ovarian cancers. Several pathogenic variants of these genes conferring genetic predisposition have been described in different populations but rarely in sub-Saharan Africa. The objectives of this study were to identify pathogenic variants of the BRCA genes involved in hereditary breast cancer in Senegal and to search for a founder effect. We recruited after free informed consent, 27 unrelated index cases diagnosed with breast cancer and each having a family history. Mutation screening of the genes identified a duplication of ten nucleotides c.815_824dupAGCCATGTGG, (p.Thr276Alafs) (NM_007294.3) located in exon 11 of BRCA1 gene, in 15 index cases (allelic frequency 27.7%). The pathogenic variant has been previously reported in African Americans as a founder mutation of West African origin. Haplotypes analysis of seven microsatellites surrounding the BRCA1 gene highlights a shared haplotype encompassing ~400 kb between D17S855 and D17S1325. This haplotype was not detected in none of 15 healthy controls. Estimation of the age of the pathogenic variant suggested that it occurred ~1400 years ago. Our study identified a founder pathogenic variant of BRCA1 predisposing to breast cancer and enabled the establishment of an affordable genetic test as a mean of prevention for Senegalese women at risk.
    DOI:  https://doi.org/10.1038/s41525-020-0114-7
  15. JNCI Cancer Spectr. 2020 Dec;4(6): pkaa063
    Walcott FL, Wang PY, Bryla CM, Huffstutler RD, Singh N, Pollak MN, Khincha PP, Savage SA, Mai PL, Dodd KW, Hwang PM, Fojo AT, Annunziata CM.
      Background: Li-Fraumeni syndrome (LFS) is a highly penetrant autosomal dominant cancer predisposition disorder caused by germline TP53 pathogenic variants. Patients with LFS have increased oxidative phosphorylation capacity in skeletal muscle and oxidative stress in blood. Metformin inhibits oxidative phosphorylation, reducing available energy for cancer cell proliferation and decreasing production of reactive oxygen species that cause DNA damage. Thus, metformin may provide pharmacologic risk reduction for cancer in patients with LFS, but its safety in nondiabetic patients with germline TP53 pathogenic variants has not been documented.Methods: This study assessed safety and tolerability of metformin in nondiabetic LFS patients and measured changes in metabolic profiles. Adult patients with LFS and germline TP53 variant received 14 weeks of metformin. Blood samples were obtained for measurement of serum insulin-like growth factor-1, insulin, and insulin-like growth factor binding protein 3. Hepatic mitochondrial function was assessed with fasting exhaled CO2 after ingestion of 13C-labeled methionine. Changes in serum metabolome were measured. All statistical tests were 2-sided.
    Results: We enrolled 26 participants: 20 females and 6 males. The most common adverse events were diarrhea (50.0%) and nausea (46.2%). Lactic acidosis did not occur, and there were no changes in fasting glucose. Cumulative mean 13C exhalation was statistically significantly suppressed by metformin (P = .001). Mean levels of insulin-like growth factor binding protein 3 and insulin-like growth factor-1 were statistically significantly lowered (P = .02). Lipid metabolites and branched-chain amino acids accumulated.
    Conclusions: Metformin was safe and tolerable in patients with LFS. It suppressed hepatic mitochondrial function as expected in these individuals. This study adds to the rationale for development of a pharmacologic risk-reduction clinical trial of metformin in LFS.
    DOI:  https://doi.org/10.1093/jncics/pkaa063