bims-lifras Biomed News
on Li-Fraumeni Syndrome
Issue of 2020‒01‒26
nineteen papers selected by
Joanna Zawacka-Pankau



  1. Hered Cancer Clin Pract. 2020 ;18 1
    Omran M, Blomqvist L, Brandberg Y, Pal N, Kogner P, Ståhlbom AK, Tham E, Bajalica-Lagercrantz S.
      Background: The current guidelines in Sweden regarding individuals with a clinically actionable (i.e. pathogenic or likely pathogenic) germline TP53 variant recommend patients to take part of the national Swedish P53 Study (SWEP53).Methods: The study comprises a patient registry (mandatory for all participants) and three optional parts: a biobank, a surveillance program and a psychosocial evaluation of the surveillance. All known adult eligible carriers regardless of age are offered to take part of the surveillance program offering MRI yearly of the whole-body, breast, and brain as well as breast ultrasound. A special surveillance program is offered for individuals 15-18 years old with a 50% risk of being a mutation carrier or with a verified TP53 variation, includes ultrasound of the abdomen and urine corticosteroid profiles. Clinically motivated further examinations are performed upon need. The national inclusion is performed through the six clinical genetic units in Sweden at Umeå, Uppsala, Stockholm, Gothenburg, Linköping and Lund, and the surveillance is mainly performed through the oncology clinics.
    Results: To date, a total of 41 adults and 11 children have been included in the study.
    Conclusions: The SWEP53 is the first structured national surveillance program including radiological and clinical routines for TP53 mutation carriers in the Scandinavian setting. The aim of this publication is to present and describe the ongoing Swedish surveillance study to encourage the initiation of similar studies and to contribute to the knowledge of adequate clinical handling of these cancer prone families.
    Trial registration: Trial registration number: ISRCTN13103571, retrospectively registered on 14/10/2019.
    Keywords:  Germline TP53 mutation; Hereditary breast cancer; LiFraumeni syndrome; Pathological variant; Surveillance program
    DOI:  https://doi.org/10.1186/s13053-020-0133-5
  2. Hemasphere. 2019 Dec;3(6): e321
    Baliakas P, Tesi B, Wartiovaara-Kautto U, Stray-Pedersen AR, Friis LS, Dybedal I, Hovland R, Jahnukainen K, Raaschou-Jensen K, Ljungman P, Rustad CF, Lautrup CK, Kilpivaara O, Kittang AO, Gr Nbæk K, Cammenga J, Hellström-Lindberg E, Andersen MK.
      Myeloid neoplasms (MNs) with germline predisposition have recently been recognized as novel entities in the latest World Health Organization (WHO) classification for MNs. Individuals with MNs due to germline predisposition exhibit increased risk for the development of MNs, mainly acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Setting the diagnosis of MN with germline predisposition is of crucial clinical significance since it may tailor therapy, dictate the selection of donor for allogeneic hematopoietic stem cell transplantation (allo-HSCT), determine the conditioning regimen, enable relevant prophylactic measures and early intervention or contribute to avoid unnecessary or even harmful medication. Finally, it allows for genetic counseling and follow-up of at-risk family members. Identification of these patients in the clinical setting is challenging, as there is no consensus due to lack of evidence regarding the criteria defining the patients who should be tested for these conditions. In addition, even in cases with a strong suspicion of a MN with germline predisposition, no standard diagnostic algorithm is available. We present the first version of the Nordic recommendations for diagnostics, surveillance and management including considerations for allo-HSCT for patients and carriers of a germline mutation predisposing to the development of MNs.
    DOI:  https://doi.org/10.1097/HS9.0000000000000321
  3. Cancers (Basel). 2020 Jan 20. pii: E249. [Epub ahead of print]12(1):
    Fernandez-Moya A, Morales S, Arancibia T, Gonzalez-Hormazabal P, Tapia JC, Godoy-Herrera R, Reyes JM, Gomez F, Waugh E, Jara L.
      The genetic variations responsible for tumorigenesis are called driver mutations. In breast cancer (BC), two studies have demonstrated that germline mutations in driver genes linked to sporadic tumors may also influence BC risk. The present study evaluates the association between SNPs and SNP-SNP interaction in driver genes TTN (rs10497520), TBX3 (rs2242442), KMT2D (rs11168827), and MAP3K1 (rs702688 and rs702689) with BC risk in BRCA1/2-negative Chilean families. The SNPs were genotyped in 489 BC cases and 1078 controls by TaqMan Assay. Our data do not support an association between rs702688: A>G or rs702689: G>A and BC risk. The rs10497520-T allele was associated with a decreased risk in patients with family history of BC or early-onset BC (OR = 0.6, p < 0.0001 and OR = 0.7, p = 0.05, respectively). rs2242442-G was associated with a protective effect and rs11168827-C was associated with increased BC risk in families with a strong history of BC (OR = 0.6, p = 0.02 and OR = 1.4, p = 0.05, respectively). As rs10497520-T and rs2242442-G seemed to protect against BC risk, we then evaluated their combined effect. Familial BC risk decreased in a dose-dependent manner with the protective allele count, reflecting an additive effect (p-trend < 10-4). To our knowledge, this is the first association study of BC driver gene germline variations in a Chilean population.
    Keywords:  breast cancer risk; driver genes; genetic predisposition to breast cancer; germline variants; single nucleotide polymorphisms
    DOI:  https://doi.org/10.3390/cancers12010249
  4. Gynecol Oncol. 2019 Dec 21. pii: S0090-8258(19)31618-X. [Epub ahead of print]
    Connor YD, Miao D, Lin DI, Hayne C, Howitt BE, Dalrymple JL, DeLeonardis KR, Hacker MR, Esselen KM, Shea M.
      OBJECTIVE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and SMARCA4-deficient undifferentiated uterine sarcoma (SMARCA4-DUS) are rare and aggressive tumors, primarily affecting pre- and perimenopausal women. Inactivating SMARCA4 mutations are thought to be the driving molecular events in the majority of these tumors. Here, we report the clinical course of a family with germline SMARCA4 mutation and compare large cohorts of these rare tumor types.METHODS: We extracted clinico-pathological medical record data for the family with germline SMARCA4 mutation. Clinico-genomic data from SCCOHT and SMARCA4-DUS cohorts were retrospectively extracted from the archives of a large CLIA-certified reference molecular laboratory.
    RESULTS: We identified a single family with an inherited germline SMARCA4 mutation, in which two different family members developed either SCCOHT or SMARCA4-DUS, both of whom died within one year of diagnosis, despite aggressive surgical, chemotherapy and immunotherapy treatment. Retrospective comparative analysis of large SCCOHT (n = 48) and SMARCA4-DUS (n = 17) cohorts revealed that SCCOHT patients were younger (median age: 28.5 vs. 49.0) and more likely to have germline SMARCA4 alterations (37.5% vs. 11.8%) than SMARCA4-DUS patients.
    CONCLUSIONS: Growing understanding of the role SMARCA4 plays in the pathogenesis of these rare cancers may inform recommended genetic testing and counseling in families with these tumor types.
    Keywords:  Germline; Hereditary cancer syndromes; Ovarian cancer; SCCOHT; SMARCA4; Uterine sarcomas
    DOI:  https://doi.org/10.1016/j.ygyno.2019.10.031
  5. J Geriatr Oncol. 2020 Jan 21. pii: S1879-4068(19)30420-5. [Epub ahead of print]
    Chavarri-Guerra Y, Slavin TP, Longoria-Lozano O, Weitzel JN.
      Earlier age at onset is one characteristic of hereditary cancer syndromes, so most studies of genetic testing have focused on young patients with cancer. However, recent studies of multigene panel tests in unselected cancer populations have detected a considerable proportion of older patients with germline pathogenic variants (PVs) in cancer susceptibility genes. As the number of older patients with cancer continues to rise, clinicians should be aware of genetic/genomic cancer risk assessment (GCRA) criteria in both young and older adults. Identifying individuals with a germline PV in a cancer susceptibility gene may be important for precision therapy of current cancers and screening and prevention of new primary cancers, as well as cascade testing to identify high cancer risks for family members. Typically, hereditary predisposition germline genetic testing has been recommended for patients with early onset cancers and/or a family history of cancer. However, more recently international guidelines recommend testing for potential therapeutic intervention regardless of age for some tumors frequently seen in older patients, such as epithelial ovarian, pancreatic, and metastatic prostate and breast cancers. GCRA in older patients may present challenges including: clonal hematopoiesis (CH) confounding test interpretation, ethical aspects (autonomy, nonmaleficence, beneficence), patient health status, comorbidities, as well as lack of insurance coverage. These factors should be considered during genetic counseling and when considering cancer screening and risk reduction procedures. This manuscript reviews available data on common hereditary cancer syndromes in older patients and provides tools to help providers perform GCRA in this population.
    Keywords:  Germline pathogenic variants; Hereditary cancer; Older patients
    DOI:  https://doi.org/10.1016/j.jgo.2020.01.001
  6. PLoS One. 2020 ;15(1): e0227260
    Volc SM, Ramos CRN, Galvão HCR, Felicio PS, Coelho AS, Berardineli GN, Campacci N, Sabato CDS, Abrahao-Machado LF, Santana IVV, Campanella N, Lengert AVH, Vidal DO, Reis RM, Dantas CF, Coelho RC, Boldrini E, Serrano SV, Palmero EI.
      Sarcomas represent less than 1% of all solid neoplasms in adults and over 20% in children. Their etiology is unclear, but genetic susceptibility plays an important role in this scenario. Sarcoma is central in Li-Fraumeni Syndrome (LFS), a familial predisposition cancer syndrome. In Brazil, the high prevalence of p.Arg337His mutations in the TP53 gene brings about a unique condition: a cluster of LFS. In the present work, we studied 502 sarcoma patients not selected by age or family history in an attempt to assess the impact of the so-called "Brazilian germline TP53 mutation" (p.Arg337His) on this tumor type. We found that 8% of patients are carriers, with leiomyosarcoma being the main histologic type of sarcoma, corresponding to 52.5% of the patients with the mutated TP53 gene. These findings emphasize the importance of genetic counseling and can better guide the management of sarcoma patients.
    DOI:  https://doi.org/10.1371/journal.pone.0227260
  7. J Surg Case Rep. 2020 Jan;2020(1): rjz386
    Ventura E, Dionísio S, Ferreira Â, Saleiro R, Marques H, Magalhães M, Monteiro C.
      Mesenchymal chondrosarcoma (MCS) is a rare histological variant of chondrosarcoma, with aggressive behaviour. Due to the unique nature of this disease, management strategies are not well established. Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome with a wide tumour spectrum, associated with TP53 germline mutations. We report a case of MCS of the maxilla, treated with surgical excision and adjuvant chemotherapy, in a patient with a past medical history of choroid plexus papilloma and a family history of early age first-degree cervical uterine cancer, that led to the clinical suspicion of a cancer predisposition syndrome and the subsequent diagnosis of LFS. This is the first MCS described in a LFS case. It demonstrates that adjuvant chemotherapy should be considered, in conjunction with surgical excision, in MCS and that cancer predisposition syndromes should be suspected in patients with multiple neoplasms and a strong family history of cancer.
    Keywords:  Li-Fraumeni syndrome; cancer predisposition; maxilla; mesenchymal chondrosarcoma
    DOI:  https://doi.org/10.1093/jscr/rjz386
  8. Target Oncol. 2020 Jan 20.
    Teixeira LA, Candido Dos Reis FJ.
      BACKGROUND: Homologous recombination deficiencies are associated with increased platinum sensitivity and potential response to poly (ADP-ribose) polymerase inhibitors in epithelial ovarian cancer. As an alternative to germline testing or somatic tumor sequencing, BRCA1 deficiency can be detected by immunohistochemistry and might predict homologous recombination deficiencies.OBJECTIVE: This study aimed to assess the association between BRCA1 expression by immunohistochemistry and the prognosis of patients with epithelial ovarian cancer.
    METHODS: We conducted a systematic review and meta-analysis following the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. We searched PubMed, EMBASE, Web of Science, and Scopus databases through July 2019. Reference lists of selected articles were screened for further studies. We conducted qualitative synthesis and meta-analyses of hazard ratios for overall survival and progression-free survival.
    RESULTS: Of 41 studies of BRCA1 expression using immunohistochemistry, 18 evaluated the association of BRCA1 expression with patient survival (2738 cases). The loss of BRCA1 expression was associated with improved overall survival (hazard ratio = 0.67, 95% confidence interval 0.57-0.77) and progression-free survival (hazard ratio = 0.70, 95% confidence interval 0.58-0.84).
    CONCLUSIONS: Negative BRCA1 expression assessed by immunohistochemistry was associated with a better prognosis in epithelial ovarian cancer.
    DOI:  https://doi.org/10.1007/s11523-020-00697-y
  9. Neuro Oncol. 2020 Jan 23. pii: noaa014. [Epub ahead of print]
    Muskens IS, de Smith AJ, Zhang C, Hansen HM, Morimoto L, Metayer C, Ma X, Walsh KM, Wiemels JL.
      BACKGROUND: Pediatric astrocytoma constitutes a majority of malignant pediatric brain tumors. Previous studies that investigated pediatric cancer predisposition have primarily been conducted in tertiary referral centers and focused on cancer predisposition genes. In this study, we investigated the contribution of rare germline variants to risk of malignant pediatric astrocytoma on a population level.METHODS: DNA samples were extracted from neonatal dried bloodspots from 280 pediatric astrocytoma patients (predominantly high grade) born and diagnosed in California and were subjected to whole-exome sequencing. Sequencing data were analyzed using agnostic exome-wide gene-burden testing and variant identification for putatively pathogenic variants in 175 a priori candidate cancer-predisposition genes.
    RESULTS: We identified thirty-three putatively pathogenic germline variants among 31 patients (11.1%) which located in 24 genes largely involved in DNA repair and cell cycle control. Patients with pediatric glioblastoma were most likely to harbor putatively pathogenic germline variants (14.3%, N=9/63). Five variants were located in TP53, of which four were identified among patients with glioblastoma (6.3%, N=4/63). The next most frequently mutated gene was NF1, in which putatively pathogenic variants were identified in four astrocytoma NOS patients. Gene-burden testing also revealed that putatively pathogenic variants in TP53 were significantly associated with pediatric glioblastoma on an exome-wide level (OR:32.8, p=8.04×10-7).
    CONCLUSION: A considerable fraction of pediatric glioma patients, especially those of higher grade, harbor a putatively pathogenic variant in a cancer predisposition gene. Some of these variants may be clinically actionable or may warrant genetic counseling.
    Keywords:  Li-Fraumeni syndrome; Pediatric glioma; exome sequencings; germline variant; glioblastoma
    DOI:  https://doi.org/10.1093/neuonc/noaa014
  10. Curr Oncol Rep. 2020 Jan 23. 22(1): 5
    Sokolova AO, Cheng HH.
      PURPOSE OF REVIEW: This review summarizes recent advances in prostate cancer (PCa) genetics.RECENT FINDINGS: Upwards of 20% of metastatic castration-resistant prostate tumors (mCRPC) carry homologous recombination (HR) repair gene mutations, of which ~ 10% are germline (inherited). Another ~ 5% exhibit microsatellite instability (MSI-H) and/or mismatch repair deficiency (MMRd). Pembrolizumab is approved for tumors with MMRd, thus patients with mCRPC and MMRd are candidates for pembrolizumab. Emerging data indicate that platinum chemotherapy and poly ADP-ribose polymerase inhibitors (PARPi) are effective in PCa exhibiting HR deficiency. NCCN guidelines now recommend germline and somatic tumor testing in specific clinical scenarios due to treatment and family implications. Genetic testing in PCa patients may inform prognosis, treatment options, and have implications for family counseling. PARPi, platinum chemotherapy, and immune checkpoint inhibitors are promising targeted therapies for PCa with specific molecular features. Therapeutic advances, along with importance to relatives, are driving genetic testing in prostate cancer.
    Keywords:  BRCA; Genetics; Germline testing; PARPi; Prostate cancer
    DOI:  https://doi.org/10.1007/s11912-020-0863-6
  11. Gynecol Oncol. 2020 Jan 21. pii: S0090-8258(20)30061-5. [Epub ahead of print]
    Timmerman S, Van Rompuy AS, Van Gorp T, Vanden Bempt I, Brems H, Van Nieuwenhuysen E, Han SN, Neven P, Victoor J, Laenen A, Vergote I.
      OBJECTIVES: To apply the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) to a consecutive series of endometrial cancer (EC) patients diagnosed at a tertiary referral center and assign EC specimens to one of four molecular subgroups using immunohistochemistry (IHC) for p53/mismatch repair protein expression and sequencing for Polymerase Epsilon Exonuclease Domain Mutations (POLE-EDM). Mismatch Repair Deficient (MMR-D) cases were more thoroughly investigated to identify underlying somatic or germline genetic defects.METHODS: Hundred-and eight consecutive endometrial cancer patients, diagnosed between March 2017 and April 2019, were subjected to immunohistochemical and molecular analysis, according to ProMisE. IHC for p53 and the mismatch repair proteins (MLH1, PMS2, MSH6 and PMS2) was performed. All patients were also tested for POLE-EDM by Sanger sequencing. In addition, tumor and corresponding normal tissue of cases with abnormal MMR IHC were tested by PCR for microsatellite instability (MSI) (MSI analysis system, Promega). Hypermethylation of MLH1 promotor was tested with (methylation specific) multiplex ligation dependent probe amplification. MMR-D cases were subjected to germline mutation analysis of the mismatch repair genes, using next generation sequencing on MiSeq (Illumina) with the BRCA Hereditary Cancer MASTR Plus, (Multiplicom/Agilent), RNA mutation analysis and MLPA.
    RESULTS: FIGO classification was stage IA (n = 54), IB (n = 22) II(n = 8), III(n = 18) and IV(n = 6). Of the 33 patients with MMR-D on IHC (31%), 26 showed MLH1 promotor hypermethylation as the probable cause of MMR-D. The remaining 7 patients without MLH1 promotor hypermethylation were referred for germline analysis of Lynch syndrome. Six patients carried a pathogenic germline mutation in one of the mismatch repair genes: MSH6(n = 3), PMS2(n = 1), MLH1(n = 1) and MSH2 (n = 1). Pathogenic POLE-EDM were identified in 7 (6%) patients. Multiple molecular features (POLE-EDM + MMR-D or POLE-EDM + p53 abnormal) were observed in 4 patients (4%). A high concordance between MMR-D and microsatellite instability was observed in our cohort. In cases of a genetic defect in the MMR genes, we do note a large proportion of cases exhibiting microsatellite instability. On the contrary a hypermutation state, as seen in POLE EDM, does not result in accompanied phenotypic changes in MSI status.
    CONCLUSION: The ProMisE classification proved to be an efficient and easily implementable system. Future research should elucidate the precise biological and prognostic meaning of the cases with multiple molecular markers.
    Keywords:  Endometrial cancer; Microsatellite instability; Molecular classification; ProMisE
    DOI:  https://doi.org/10.1016/j.ygyno.2020.01.019
  12. Genet Med. 2020 Jan 22.
    Drost M, Tiersma Y, Glubb D, Kathe S, van Hees S, Calléja F, Zonneveld JBM, Boucher KM, Ramlal RPE, Thompson BA, Rasmussen LJ, Greenblatt MS, Lee A, Spurdle AB, Tavtigian SV, de Wind N.
      PURPOSE: Variants in the DNA mismatch repair (MMR) gene MSH6, identified in individuals suspected of Lynch syndrome, are difficult to classify owing to the low cancer penetrance of defects in that gene. This not only obfuscates personalized health care but also the development of a rapid and reliable classification procedure that does not require clinical data.METHODS: The complete in vitro MMR activity (CIMRA) assay was calibrated against clinically classified MSH6 variants and, employing Bayes' rule, integrated with computational predictions of pathogenicity. To enable the validation of this two-component classification procedure we have employed a genetic screen to generate a large set of inactivating Msh6 variants, as proxies for pathogenic variants.
    RESULTS: The genetic screen-derived variants established that the two-component classification procedure displays high sensitivities and specificities. Moreover, these inactivating variants enabled the direct reclassification of human variants of uncertain significance (VUS) as (likely) pathogenic.
    CONCLUSION: The two-component classification procedure and the genetic screens provide complementary approaches to rapidly and cost-effectively classify the large majority of human MSH6 variants. The approach followed here provides a template for the classification of variants in other disease-predisposing genes, facilitating the translation of personalized genomics into personalized health care.
    Keywords:  DNA mismatch repair; Lynch syndrome; MSH6; functional analysis-based classification; variants of uncertain significance
    DOI:  https://doi.org/10.1038/s41436-019-0736-2
  13. Cell Rep. 2020 Jan 21. pii: S2211-1247(19)31739-5. [Epub ahead of print]30(3): 783-792.e5
    Kang JG, Lago CU, Lee JE, Park JH, Donnelly MP, Starost MF, Liu C, Kwon J, Noguchi AC, Ge K, Wang PY, Hwang PM.
      The physiological effects of the many germline mutations of TP53, encoding the tumor suppressor protein p53, are poorly understood. Here we report generating a p53 R178C knockin mouse modeling the human TP53 R181C mutation, which is notable for its prevalence and prior molecular characterization. Consistent with its weak cancer penetrance in humans, homozygous p53178C/C mice show a modest increase in tumorigenesis but, surprisingly, are lean with decreased body fat content. They display evidence of increased lipolysis and upregulation of fatty acid metabolism in their inguinal white adipose tissue (iWAT). Gene expression and chromatin immunoprecipitation sequencing (ChIP-seq) analyses show that the mutant p53 bound and transactivated Beta-3-Adrenergic Receptor (ADRB3), a gene that is known to promote lipolysis and is associated with obesity. This study reveals that a germline mutation of p53 can affect fat metabolism, which has been implicated in cancer development.
    Keywords:  ADRB3; Li-Fraumeni syndrome; TP53 mutation; cancer; fat; lipolysis; mouse model
    DOI:  https://doi.org/10.1016/j.celrep.2019.12.074
  14. Acta Neuropathol. 2020 Jan 22.
    Kim B, Tabori U, Hawkins C.
      Cancer predisposition syndromes are associated with an increased risk of developing primary malignancies. Here we discuss those which are associated with an increased risk of tumors of the central nervous system (CNS) and gastrointestinal (GI) tract. These can be grouped into those in which the CNS tumors predominate versus those in which the GI cancers predominate. The former include constitutional mismatch repair deficiency (CMMRD) syndrome, Li-Fraumeni syndrome (LFS), and Cowden syndrome (CS) while the latter include familial adenomatosis polyposis 1 (FAP1), Lynch syndrome and polymerase proofreading-associated polyposis syndrome (PPAP). Tumor specificity does exist as medulloblastoma occur in FAP, LFS and CMMRD while glioma are most commonly seen in all replication repair-deficient genes and LFS. Choroid plexus carcinoma is strictly observed in LFS while Cowden syndrome patients develop Lhermitte Duclos disease or meningioma. In each syndrome, specific types of low-grade and high-grade gastrointestinal cancers can occur, but these will be discussed elsewhere. Underlying cancer predisposition syndromes are important to consider when faced with brain tumors, particularly in the pediatric and young adult age groups, as identification of an underlying germ line mutation may change the upfront management of the patient and has implications for future cancer surveillance for both the patient and potentially affected family members. Considerations of family history, presence of skin lesions and consanguinity provide valuable information in identifying patients at potential increased risk.
    Keywords:  Brain tumor; CMMRD; Cancer predisposition syndrome; MMR
    DOI:  https://doi.org/10.1007/s00401-020-02124-y
  15. Int J Cancer. 2020 Jan 20.
    Meng H, Yao L, Yuan H, Xu Y, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xie Y.
      The spectrum and frequency of BRCA1/2 pathogenic variants may be ethnicity-specific. Whether high-frequency founder mutations are present in Chinese women is still largely unknown. In the current study, germline pathogenic variants in the BRCA1/2 genes were determined in 9505 unselected Chinese Han breast cancer patients by next-generation and/ or Sanger sequencing. Four hundred and seventy-one (5.0%) breast cancer patients carried BRCA1/2 pathogenic variants in this cohort. A total of 25 recurrent pathogenic variants (at least found in 4 unrelated patients) were identified in this cohort (8 BRCA1 and 17 BRCA2 recurrent pathogenic variants), 161 patients carried one of these recurrent pathogenic variants in this cohort of 9505 patients. All of these 25 recurrent pathogenic variants were further explored whether they had founder effect through haplotype analysis. The most common pathogenic variant, BRCA1 c.5470_5477del, was found in 30 breast cancer patients from 29 unrelated families. Twenty-seven of these 29 unrelated patients who carried this BRCA1 c.5470_5477del mutation shared an identical haplotype, indicating that BRCA1 c.5470_5477del was a founder mutation in the Chinese Han population. Furthermore, BRCA1 c.5470_5477del mutation carriers had a significantly worse survival than non-carriers (disease-free survival, P = 0.049; overall survival, P = 0.029). Taken together, our data suggested that BRCA1 c.5470_5477del is a founder mutation in the Chinese Han population and BRCA1 c.5470_5477del mutation carriers have a poor survival. This article is protected by copyright. All rights reserved.
    Keywords:  BRCA1; Breast cancer; Chinese; Founder mutation; Haplotype
    DOI:  https://doi.org/10.1002/ijc.32877
  16. Clin Transl Oncol. 2020 Jan 24.
    Rodríguez N, Viñal D, Rodríguez-Cobos J, De Castro J, Domínguez G.
      The development of high-throughput technologies such as next-generation sequencing for DNA sequencing together with the decrease in their cost has led to the progressive introduction of genomic profiling in our daily practice in oncology. Nowadays, genomic profiling is part of genetic counseling, cancer diagnosis, molecular characterization, and as a biomarker of prognosis and response to treatment. Furthermore, germline or somatic genomic characterization of the tumor may provide new treatment opportunities for patients with cancer. In this review, we will summarize the clinical applications and limitations of genomic profiling in oncology clinical practice, focusing on next-generation sequencing.
    Keywords:  Genomic profiling; Hereditary cancer syndromes; Liquid biopsy; Next-generation sequencing; Sanger sequencing
    DOI:  https://doi.org/10.1007/s12094-020-02296-9
  17. Clin Transl Oncol. 2020 Jan 24.
    Guillén-Ponce C, Lastra E, Lorenzo-Lorenzo I, Martín Gómez T, Morales Chamorro R, Sánchez-Heras AB, Serrano R, Soriano Rodríguez MC, Soto JL, Robles L.
      In the last 2 decades, clinical genetics on hereditary colorectal syndromes has shifted from just a molecular characterization of the different syndromes to the estimation of the individual risk of cancer and appropriate risk reduction strategies. In the last years, new specific therapies for some subgroups of patients have emerged as very effective alternatives. At the same time, germline multigene panel testing by next-generation sequencing (NGS) technology has become the new gold standard for molecular genetics.
    Keywords:  Adenomatous polyposis; Colon cancer; Hereditary colorectal cancer; Lynch syndrome
    DOI:  https://doi.org/10.1007/s12094-019-02272-y
  18. Cancer Biomark. 2020 Jan 03.
    Ma H, Song B, Guo S, Li G, Jin G.
      OBJECTIVES: Pancreatic cancer is one of the most lethal malignancies worldwide. Pancreatic adenosquamous carcinoma (PASC) is a rare histological type of pancreatic carcinoma with a poor prognosis. The median survival time after diagnosis is less than one year. It is believed that the pathogenesis of PASC is different from pancreatic adenocarcinoma. In this study, we tried to reveal the intrinsic gene mutations associated with PASC through whole exome sequencing.METHODS: Both cancerous and paracancerous tissues were collected from 12 pathologically diagnosed PASC patients. Their clinical characteristics were collected, and patient survival information was obtained through follow-up. The correlations between the mutations and clinical characteristics were analysed.
    RESULTS: Germline mutations were identified in MAP3K1 (9 cases), PDE4DIP (7), BCR (7), ALK (6), USP6 (5), AR (4), HLA-A (4), SPEN (4), KMT2D (3), NUTM2B (3), ZFHX3 (3), and MN1 (3), while somatic mutations were found in TP53 (5), KRAS (3), HRNR (3), and OBSCN (3). Peripheral tissue invasion was associated with somatic mutations in KRAS (P= 0.0339). Additionally, there were significant correlations between lymphatic metastasis and germline mutations in USP6 (P= 0.0228) and somatic mutations in OBSCN and HRNR (P= 0.0339).
    CONCLUSION: In conclusion, susceptibility genes including MAP3K1, PDE4DIP, and BCR are frequently found to be mutated in the germlines of PASC patients. Somatic mutations in KRAS, OBSCN, and HRNR and germline mutations in USP6 are related to tumour invasion and metastasis, reinforcing the necessity of translating these potential biomarkers into clinical practice.
    Keywords:  Pancreatic adenosquamous carcinoma; germline mutation; somatic mutation; whole exome sequencing
    DOI:  https://doi.org/10.3233/CBM-190236
  19. AACE Clin Case Rep. 2019 May-Jun;5(3):5(3): e222-e225
    Sirbiladze RL, Uyar D, Geurts JL, Shaker JL.
      Objective: To report a patient with the hyperparathyroidism-jaw tumor syndrome (HPT-JT) who was found to have a rare ovarian tumor (granulosa cell tumor [GCT]). HPT-JT is caused by pathogenic variants in the CDC73 gene and results in primary hyperparathyroidism (PHPT), benign fibro-osseous jaw tumors, benign or malignant renal tumors and cysts, and benign or malignant uterine tumors. We believe this is the first reported case of HPT-JT and GCT.Methods: The patient was a 31-year-old woman with abdominal pain who was found to have adult GCT. Her history was significant for a single gland parathyroidectomy at age 23 for PHPT. Her mother also had PHPT with 1-gland removal, as well as a history of renal cysts. Because of the personal and familial history of PHPT, she underwent germline sequencing of genes associated with PHPT including CASR, CDC73, CDKN1B, MEN1 and RET.
    Results: Genetic testing revealed a CDC73 gene pathogenic variant (c.687_688dupAG) which creates a premature translational stop signal causing loss-of-function.
    Conclusion: We report a case of ovarian GCT in a young patient with primary hyperparathyroidism and a CDC73 gene mutation. Ovarian granulosa cell tumor may be another CDC73-related tumor.
    DOI:  https://doi.org/10.4158/ACCR-2018-0555