bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020–12–06
fiveteen papers selected by
Joanna Zawacka-Pankau, University of Warsaw
  1. Pathogenic Germline Mutations of DNA Repair Pathway Components in Early-Onset Sporadic Colorectal Polyp and Cancer Patients.
  2. Identifying potential germline variants from sequencing hematopoietic malignancies.
  3. Locoregional treatments and ipsilateral breast cancer recurrence rates in BRCA1/2 mutation carriers.
  4. Case series of three patients with hereditary diffuse gastric cancer in a single family: Three case reports and review of literature.
  5. Sensitivity and specificity of loss of heterozygosity analysis for the classification of rare germline variants in BRCA1/2: results of the observational AGO-TR1 study (NCT02222883).
  6. Endometrial cancer in germline BRCA mutation carriers: a systematic review and meta-analysis.
  7. Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology.
  8. BRCA1/2 Variants and Metabolic Factors: Results From a Cohort of Italian Female Carriers.
  9. Breast cancer associated pathogenic variants among women 61 years and older with triple negative breast cancer.
  10. Clinical interpretation of PRSS1 gene variants in patients with pancreatitis.
  11. Clinical and genetic risk factors define two risk groups of extracranial malignant rhabdoid tumours (eMRT/RTK).
  12. Identification and functional characterization of new missense SNPs in the coding region of the TP53 gene.
  13. Evidence for familial clustering in breast cancer age of onset.
  14. Common germline-somatic variant interactions in advanced urothelial cancer.
  15. Pediatric Brain Tumors.
  1. Cancers (Basel). 2020 Nov 28. pii: E3560. [Epub ahead of print]12(12):
    Pathogenic Germline Mutations of DNA Repair Pathway Components in Early-Onset Sporadic Colorectal Polyp and Cancer Patients.
    Pi-Yueh Chang, Shih-Cheng Chang, Mei-Chia Wang, Jinn-Shiun Chen, Wen-Sy Tsai, Jeng-Fu You, Chia-Chun Chen, Hsiu-Ling Liu, Jy-Ming Chiang.
      Given recent increases in the proportion of early-onset colorectal cancer (CRC), researchers are urgently working to establish a multi-gene screening test for both inherited and sporadic cancer-susceptible individuals. However, the incidence and spectrum of germline mutations in young sporadic CRC patients in East Asian countries and, especially, in sporadic polyp carriers and normal individuals are unknown. Peripheral blood samples were collected from 43 colonoscopy-proved normal controls and from 50 polyp patients and 49 CRC patients with no self-reported family history of cancer. All participants were under 50 years old. Next-generation sequencing with a panel of 30 CRC-associated susceptibility genes was employed to detect pathogenic germline mutations. The germline mutation carrier rates were 2.3%, 4.0%, and 12.2% in the normal, polyp, and cancer groups, respectively. A total of seven different mutations in six DNA repair pathway-related genes (MLH1, BRCA1, BRCA2, CHEK2, BLM, and NTHL1) were detected in nine participants. One frameshift mutation in BRCA2 and one frameshift mutation in the CHEK2 gene were found in a normal control and two colorectal polyp patients, respectively. One young sporadic CRC patient carried two heterozygous mutations, one in MLH1 and one in BRCA1. Three mutations (MLH1 p.Arg265Cys, MLH1 p.Tyr343Ter and CHEK2 p.Ile158TyrfsTer10) were each found in two independent patients and were considered "founder" mutations. This is the first report to demonstrate high percentage of germline mutations in young sporadic colorectal polyp, CRC, and general populations. A multi-gene screening test is warranted for the proactive identification of cancer-predisposed individuals.
    Keywords:  cancer susceptibility gene; colorectal cancer; early onset; germline mutation; normal control; polyp
    DOI:  https://doi.org/10.3390/cancers12123560
  2. Hematology Am Soc Hematol Educ Program. 2020 Dec 04. 2020(1): 219-227
    Identifying potential germline variants from sequencing hematopoietic malignancies.
    Ira L Kraft, Lucy A Godley.
      Next-generation sequencing (NGS) of bone marrow and peripheral blood increasingly guides clinical care in hematological malignancies. NGS data may help to identify single nucleotide variants, insertions/deletions, copy number variations, and translocations at a single time point, and repeated NGS testing allows tracking of dynamic changes in variants during the course of a patient's disease. Tumor cells used for NGS may contain germline, somatic, and clonal hematopoietic DNA alterations, and distinguishing the etiology of a variant may be challenging. We describe an approach using patient history, individual variant characteristics, and sequential NGS assays to identify potential germline variants. Our current criteria for identifying an individual likely to have a deleterious germline variant include a strong family history or multiple cancers in a single patient, diagnosis of a hematopoietic malignancy at a younger age than seen in the general population, variant allele frequency > 0.3 of a deleterious allele in a known germline predisposition gene, and variant persistence identified on clinical NGS panels, despite a change in disease state. Sequential molecular testing of hematopoietic specimens may provide insight into disease pathology, impact patient and family members' care, and potentially identify new cancer-predisposing risk alleles. Ideally, individuals should give consent at the time of NGS testing to receive information about potential germline variants and to allow future contact as research advances.
    DOI:  https://doi.org/10.1182/hematology.2020006910
  3. Int J Radiat Oncol Biol Phys. 2020 Nov 28. pii: S0360-3016(20)34598-3. [Epub ahead of print]
    Locoregional treatments and ipsilateral breast cancer recurrence rates in BRCA1/2 mutation carriers.
    Rinat Bernstein-Molho, Yael Laitman, Shira Galper, Galia Jacobson, Ben Boursi, Einav Nili Gal-Yam, Bella Kaufman, Eitan Friedman, Orit Kaidar-Person.
       BACKGROUND: There is a paucity of data on the rates of ipsilateral breast tumor recurrence (IBTR) in BRCA1/2-associated breast cancer (BC). Scarcer yet is outcomes data in BRCA1/2 mutation carriers in the setting of newer mastectomy techniques such as skin-sparing (SSM) and nipple-sparing (NSM) mastectomies.
    PATIENTS AND METHODS: Data was extracted from the medical records of BRCA1/2 carriers who were diagnosed with BC and treated at a single institution between 2006-2020. Data extracted included patient demographics, tumor characteristics, disease stage, surgical treatment, use of radiation therapy (RT) and disease outcome.
    RESULTS: Overall, 255 BC patients with BRCA1/2 germline mutations were identified. Of these, 128 (50.2%) underwent mastectomy (SSM or NSM in 82% of them): 76 (59.4%) without postmastectomy RT (non-PMRT) and 52 (40.6%) with PMRT; and 127 (49.8%) participants elected for breast conserving treatment (BCT). The non-PMRT group had earlier disease stage (82.3% were Tis and T1N0) compared to the PMRT and BCT groups (3.6% and 48.1%, respectively, p<0.05). The IBTR cumulative rate was 9/76 (11.8%) in the non-PMRT cohort compared with 0/52 in the PMRT group (p=0.01), and 6/127 (4.7%) in the BCT group (p=0.06). Cumulative incidence of IBTR at 5 and 10 years was 9.8% and 27.4% in the non- PMRT vs 2% and 11.3% in BCT group, respectively (p=0.0183). No significant difference in overall survival was observed at the time of follow-up.
    CONCLUSIONS: BRCA1/2 mutation carriers treated with mastectomy without PMRT had higher rates of IBTR than those who underwent mastectomy and PMRT or BCT, despite earlier stage disease. The safety of SSM/NSM should be evaluated in a prospective trial.
    Keywords:  BRCA1/2 germline mutations; breast cancer; ipsilateral breast tumor recurrence; mastectomy; nipple sparing; radiation; skin sparing
    DOI:  https://doi.org/10.1016/j.ijrobp.2020.11.058
  4. World J Gastroenterol. 2020 Nov 14. 26(42): 6689-6697
    Case series of three patients with hereditary diffuse gastric cancer in a single family: Three case reports and review of literature.
    Masahiro Hirakawa, Kohichi Takada, Masanori Sato, Chisa Fujita, Naotaka Hayasaka, Takayuki Nobuoka, Shintaro Sugita, Aki Ishikawa, Miyako Mizukami, Hiroyuki Ohnuma, Kazuyuki Murase, Koji Miyanishi, Masayoshi Kobune, Ichiro Takemasa, Tadashi Hasegawa, Akihiro Sakurai, Junji Kato.
       BACKGROUND: Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome often associated with germline mutations in the CDH1 gene. However, the frequency of CDH1 mutations is low in patients with HDGC in East Asian countries. Herein, we report three cases of HDGC harboring a missense CDH1 variant, c.1679C>G, from a single Japanese family.
    CASE SUMMARY: A 26-year-old female (Case 1) and a 51-year-old male (father of Case 1), who had a strong family history of gastric cancer, were diagnosed with advanced diffuse gastric cancer. After genetic counselling, a 25-year-old younger brother of Case 1 underwent surveillance esophagogastroduodenoscopy that detected small signet ring cell carcinoma foci as multiple pale lesions in the gastric mucosa. Genetic analysis revealed a CDH1 c.1679C>G variant in all three patients.
    CONCLUSION: It is important for individuals suspected of having HDGC to be actively offered genetics evaluation. This report will contribute to an increased awareness of HDGC.
    Keywords:  CDH1; Case report; E-cadherin; Endoscopic findings; Hereditary diffuse gastric cancer; Signet ring cell carcinoma
    DOI:  https://doi.org/10.3748/wjg.v26.i42.6689
  5. J Med Genet. 2020 Dec 03. pii: jmedgenet-2020-107353. [Epub ahead of print]
    Sensitivity and specificity of loss of heterozygosity analysis for the classification of rare germline variants in BRCA1/2: results of the observational AGO-TR1 study (NCT02222883).
    Jan Hauke, Philipp Harter, Corinna Ernst, Alexander Burges, Sandra Schmidt, Alexander Reuss, Julika Borde, Nikolaus De Gregorio, Dimo Dietrich, Ahmed El-Balat, Mohamad Kayali, Heidrun Gevensleben, Felix Hilpert, Janine Altmüller, André Heimbach, Werner Meier, Birgid Schoemig-Markiefka, Holger Thiele, Rainer Kimmig, Peter Nürnberg, Karin Kast, Lisa Richters, Jalid Sehouli, Rita K Schmutzler, Eric Hahnen.
      Variant-specific loss of heterozygosity (LOH) analyses may be useful to classify BRCA1/2 germline variants of unknown significance (VUS). The sensitivity and specificity of this approach, however, remains unknown. We performed comparative next-generation sequencing analyses of the BRCA1/2 genes using blood-derived and tumour-derived DNA of 488 patients with ovarian cancer enrolled in the observational AGO-TR1 trial (NCT02222883). Overall, 94 pathogenic, 90 benign and 24 VUS were identified in the germline. A significantly increased variant fraction (VF) of a germline variant in the tumour indicates loss of the wild-type allele; a decreased VF indicates loss of the variant allele. We demonstrate that significantly increased VFs predict pathogenicity with high sensitivity (0.84, 95% CI 0.77 to 0.91), poor specificity (0.63, 95% CI 0.53 to 0.73) and poor positive predictive value (PPV; 0.71, 95% CI 0.62 to 0.79). Significantly decreased VFs predict benignity with low sensitivity (0.26, 95% CI 0.17 to 0.35), high specificity (1.0, 95% CI 0.96 to 1.00) and PPV (1.0, 95% CI 0.85 to 1.00). Variant classification based on significantly increased VFs results in an unacceptable proportion of false-positive results. A significantly decreased VF in the tumour may be exploited as a reliable predictor for benignity, with no false-negative result observed. When applying the latter approach, VUS identified in four patients can now be considered benign. Trial registration number NCT02222883.
    Keywords:  genetic predisposition to disease; genetic research; genetic testing; germ-line mutation
    DOI:  https://doi.org/10.1136/jmedgenet-2020-107353
  6. J Minim Invasive Gynecol. 2020 Nov 26. pii: S1553-4650(20)31141-9. [Epub ahead of print]
    Endometrial cancer in germline BRCA mutation carriers: a systematic review and meta-analysis.
    Emad Matanes, Alexander Volodarsky-Perel, Neta Eisenberg, Misgav Rottenstreich, Amber Yasmeen, Cristina Mitric, Susie Lau, Shannon Salvador, Walter H Gotlieb, Liron Kogan.
       OBJECTIVES: Risk-reducing salpingo-oophorectomy (RRSO) is standard treatment among women with BRCA mutations. The aim of this meta-analysis is to evaluate the risk of endometrial cancer in BRCA1 or BRCA2 germline mutation carriers and to examine the justifiability of prophylactic hysterectomy at the time of RRSO DATA SOURCES: Pubmed, Cochrane Central Register of Controlled Trials, Biosis, Medline (Ovid), Web of Science, ClinicalTrials.gov, and Google Scholar were searched. Eleven articles were selected and analyzed using the OpenMetaAnalyst 2012 Software.
    METHODS OF STUDY SELECTION: Randomized controlled studies, cohort studies and case control studies evaluating the risk of EC and specifically UPSC in germline BRCA1/2 mutation carriers were included. Articles were excluded if they did not meet the inclusion criteria or if data were not reported and the authors did not respond to inquiries. We assessed the methodological quality of the included studies based on the Newcastle-Ottawa Scale. Dichotomous results from each of the studies eligible for meta-analysis were expressed as the proportion of EC or UPSC patients per total number of BRCA mutation carriers with 95% confidence interval (CI). Mantel-Haenszel statistical method was used.
    TABULATION, INTEGRATION, AND RESULTS: Eleven studies reported the outcome of interest and were included in the final meta-analysis. In total, 13871 carriers of BRCA1 and BRCA2 mutations were identified. The pooled prevalence rates of EC and UPSC in BRCA1/2 mutations carriers were 82/13827 (0.59%) and 19/11582 (0.16%), respectively. EC prevalence was 46/7429 (0.62%) in BRCA1, and 17/3546 (0.47%) in BRCA2 mutation carriers, with RR of 1.18 (95% CI 0.7-2.0). For UPSC, the prevalence was 15/7429 (0.2%) and 3/3546 (0.08%) among BRCA1 and BRCA2 mutation carriers, respectively, (RR=1.39, 95% CI 0.5-3.7).
    CONCLUSIONS: Most studies in this meta-analysis suggest a slightly increased risk of EC in BRCA mutation carriers, mainly for BRCA1. The decision regarding concurrent hysterectomy should be tailored individually to each patient, based on the patient's age, type of mutation, future need for hormonal replacement treatment, history of breast cancer, Tamoxifen use and personal operative risks.
    Keywords:  BRCA1; BRCA2; Endometrial cancer; Uterine papillary serous carcinoma (UPSC); risk reducing surgery; uterine cancer
    DOI:  https://doi.org/10.1016/j.jmig.2020.11.023
  7. Int J Mol Sci. 2020 Nov 22. pii: E8841. [Epub ahead of print]21(22):
    Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology.
    Chiara Bazzichetto, Claudio Luchini, Fabiana Conciatori, Vanja Vaccaro, Ilaria Di Cello, Paola Mattiolo, Italia Falcone, Gianluigi Ferretti, Aldo Scarpa, Francesco Cognetti, Michele Milella.
      To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial to improve the feasibility of precision medicine. In 2019, the World Health Organization classified pancreatic ductal adenocarcinoma cancer (the most common pancreatic tumor type) into eight variants, according to specific histomorphological features. They are: colloid carcinoma, medullary carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, including also rhabdoid carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, hepatoid carcinoma, and signet-ring/poorly cohesive cells carcinoma. Interestingly, despite the very low incidence of these variants, innovative high throughput genomic/transcriptomic techniques allowed the investigation of both somatic and germline mutations in each specific variant, paving the way for their possible classification according also to specific alterations, along with the canonical mutations of pancreatic cancer (KRAS, TP53, CDKN2A, SMAD4). In this review, we aim to report the current evidence about genetic/molecular profiles of pancreatic cancer variants, highlighting their role in therapeutic and clinical impact.
    Keywords:  genetic status; histology; molecular alteration; pancreatic cancer; precision medicine; variants
    DOI:  https://doi.org/10.3390/ijms21228841
  8. Cancers (Basel). 2020 Nov 30. pii: E3584. [Epub ahead of print]12(12):
    BRCA1/2 Variants and Metabolic Factors: Results From a Cohort of Italian Female Carriers.
    Andreina Oliverio, Eleonora Bruno, Mara Colombo, Angelo Paradiso, Stefania Tommasi, Antonella Daniele, Daniela Andreina Terribile, Stefano Magno, Donatella Guarino, Siranoush Manoukian, Bernard Peissel, Paolo Radice, Patrizia Pasanisi.
      Women carriers of pathogenic variants (mutations) in the BRCA1/2 genes face a high lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). However, metabolic factors may influence BRCA penetrance. We studied the association of metabolic factors with BRCA1/2 variants and the risk effect of metabolic exposures in relation to the position of the mutations within the BRCA1/2. Overall, 438 women carriers of BRCA1/2 mutations, aged 18-70, with or without a previous diagnosis of BC/OC and without metastases, who joined our randomized dietary trial, were included in the study. The pathogenic variants were divided, according to their predicted effect, into loss of function (LOF) and nonsynonymous variants. The association between metabolic exposures and variants were analyzed by a logistic regression model. LOF variant carriers showed higher levels of metabolic parameters compared to carriers of nonsynonymous variants. LOF variant carriers had significantly higher levels of plasma glucose and serum insulin than nonsynonymous variant carriers (p = 0.03 and p < 0.001, respectively). This study suggests that higher insulin levels are significantly associated with LOF variants. Further investigations are required to explore the association of metabolic factors with LOF variants and the mechanisms by which these factors may affect BRCA-related cancer risk.
    Keywords:  BRCA genes; BRCA-related cancer; metabolic factors; pathogenic variants
    DOI:  https://doi.org/10.3390/cancers12123584
  9. J Geriatr Oncol. 2020 Dec 01. pii: S1879-4068(20)30500-2. [Epub ahead of print]
    Breast cancer associated pathogenic variants among women 61 years and older with triple negative breast cancer.
    Yanin Chávarri-Guerra, Catherine A Marcum, Carolyn B Hendricks, Deborah Wilbur, Terrence Cescon, Christopher Hake, Julio Abugattas, Yenni Rodriguez, Cynthia Villarreal-Garza, Kai Yang, Aleck Cervantes, Sharon Sand, Danielle Castillo, Joseph Herzog, Janet Mokhnatkin, Mina S Sedrak, Enrique Soto-Perez-de-Celis, Jeffrey N Weitzel.
      Women with triple negative breast cancer (TNBC) have a high prevalence of BRCA1 mutations, and current clinical guidelines recommend genetic testing for patients with TNBC aged ≤60 years. However, studies supporting this recommendation have included few older women with TNBC.
    METHODS: Genetic testing results from women aged >60 years with TNBC enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) registry were included in this analysis. Prevalence of breast cancer-associated pathogenic variants (PVs) was compared across age groups.
    RESULTS: We identified 151 women with TNBC aged >60 years (median 65 years; SD 5.3). Of these, 130 (86%) underwent genetic testing, and a breast cancer-associated PV was identified in 16 (12.3%; 95% CI 7-19): BRCA1 (n = 6), BRCA2 (n = 5), PALB2 (n = 2), ATM (n = 1) and RAD51C (n = 2). We found no differences in the proportion of patients with close blood relatives with breast (≤50 years) or ovarian cancer (any age) between PV carriers (37.5%) and non-carriers (34.2%) (p = 0.79). Among PV's carriers, the proportion of older women with a BRCA1 PV was lower when compared to younger women (37.5% vs 77.2%; p < 0.01).
    CONCLUSION: Breast cancer-associated PVs were found in an important proportion of women aged >60 years with TNBC undergoing genetic testing, including greater representation of BRCA2. These results suggest that older women with TNBC should be offered genetic testing, and that their exclusion based on chronologic age alone may not be appropriate.
    Keywords:  Germline variants; Older women; Triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.jgo.2020.11.008
  10. Clin Res Hepatol Gastroenterol. 2020 Nov 27. pii: S2210-7401(20)30192-3. [Epub ahead of print]
    Clinical interpretation of PRSS1 gene variants in patients with pancreatitis.
    Emmanuelle Girodon, Vinciane Rebours, Jian Min Chen, Adrien Pagin, Philippe Levy, Claude Ferec, Thierry Bienvenu.
      Since the description of the PRSS1 gene encoding the cationic trypsinogen as being involved in dominant hereditary pancreatitis, more than 50 PRSS1 variants have been reported. Among those that have been classified as pathogenic, some are associated with a high penetrance and others with a low penetrance. Assessing the clinical relevance of PRSS1 variants is often complicated in the absence of functional evidence and interpretation regarding rare variants is not very easy in clinical practice. The aim of this study was to review the PRSS1 variants and to classify them according to their degree of deleterious effect. This classification was based on the results of in vitro experiments and on population data, in comparing the allelic frequency of each variant in patients with pancreatitis and in unaffected individuals. This review should help geneticists and clinicians in charge of patient's care and genetic counseling to interpret results of genetic studies.
    Keywords:  Hereditary pancreatitis; PRSS1; Pancreatitis; Penetrance; Variant classification
    DOI:  https://doi.org/10.1016/j.clinre.2020.07.004
  11. Eur J Cancer. 2020 Nov 26. pii: S0959-8049(20)31060-1. [Epub ahead of print]142 112-122
    Clinical and genetic risk factors define two risk groups of extracranial malignant rhabdoid tumours (eMRT/RTK).
    Karolina Nemes, Susanne Bens, Denis Kachanov, Margarita Teleshova, Peter Hauser, Thorsten Simon, Stephan Tippelt, Wilhelm Woessmann, Olaf Beck, Christian Flotho, Lorenz Grigull, Pablo H Driever, Paul-Gerhardt Schlegel, Claudia Khurana, Kathrin Hering, Reinhard Kolb, Alfred Leipold, Floor Abbink, Maria J Gil-Da-Costa, Martin Benesch, Kornelius Kerl, Stephen Lowis, Carmen H Marques, Norbert Graf, Karsten Nysom, Christian Vokuhl, Patrick Melchior, Thomas Kröncke, Reinhard Schneppenheim, Uwe Kordes, Joachim Gerss, Reiner Siebert, Rhoikos Furtwängler, Michael C Frühwald.
       INTRODUCTION: Extracranial rhabdoid tumours are rare, highly aggressive malignancies primarily affecting young children. The EU-RHAB registry was initiated in 2009 to prospectively collect data of rhabdoid tumour patients treated according to the EU-RHAB therapeutic framework.
    METHODS: We evaluated 100 patients recruited within EU-RHAB (2009-2018). Tumours and matching blood samples were examined for SMARCB1 mutations by sequencing and cytogenetics.
    RESULTS: A total of 70 patients presented with extracranial, extrarenal tumours (eMRT) and 30 with renal rhabdoid tumours (RTK). Nine patients demonstrated synchronous tumours. Distant metastases at diagnosis (M+) were present in 35% (35/100), localised disease (M0) with (LN+) and without (LN-) loco-regional lymph node involvement in 65% (65/100). SMARCB1 germline mutations (GLM) were detected in 21% (17/81 evaluable) of patients. The 5-year overall survival (OS) and event-free survival (EFS) rates were 45.8 ± 5.4% and 35.2 ± 5.1%, respectively. On univariate analyses, age at diagnosis (≥12 months), M0-stage, absence of synchronous tumours, absence of a GLM, gross total resection (GTR), radiotherapy and achieving a CR were significantly associated with favourable outcomes. In an adjusted multivariate model presence of a GLM, M+ and lack of a GTR were the strongest significant negative predictors of outcome.
    CONCLUSIONS: We suggest to stratify patients with localised disease (M0), GTR+ and without proof of a GLM (5-year OS 72.2 ± 9.9%) as 'standard risk'. Patients presenting with one of the features M+ and/or GTR- and/or GLM+ belong to a high risk group (5-year, OS 32.5 ± 6.2%). These patients need novel therapeutic strategies such as combinations of targeted agents with conventional chemotherapy or novel experimental approaches ideally within international phase I/II trials.
    Keywords:  EU-RHAB Registry; RTK; Risk stratification; SMARCB1; eMRT
    DOI:  https://doi.org/10.1016/j.ejca.2020.10.004
  12. Cell Death Differ. 2020 Nov 30.
    Identification and functional characterization of new missense SNPs in the coding region of the TP53 gene.
    Flora Doffe, Vincent Carbonnier, Manon Tissier, Bernard Leroy, Isabelle Martins, Johanna S M Mattsson, Patrick Micke, Sarka Pavlova, Sarka Pospisilova, Jana Smardova, Andreas C Joerger, Klas G Wiman, Guido Kroemer, Thierry Soussi.
      Infrequent and rare genetic variants in the human population vastly outnumber common ones. Although they may contribute significantly to the genetic basis of a disease, these seldom-encountered variants may also be miss-identified as pathogenic if no correct references are available. Somatic and germline TP53 variants are associated with multiple neoplastic diseases, and thus have come to serve as a paradigm for genetic analyses in this setting. We searched 14 independent, globally distributed datasets and recovered TP53 SNPs from 202,767 cancer-free individuals. In our analyses, 19 new missense TP53 SNPs, including five novel variants specific to the Asian population, were recurrently identified in multiple datasets. Using a combination of in silico, functional, structural, and genetic approaches, we showed that none of these variants displayed loss of function compared to the normal TP53 gene. In addition, classification using ACMG criteria suggested that they are all benign. Considered together, our data reveal that the TP53 coding region shows far more polymorphism than previously thought and present high ethnic diversity. They furthermore underline the importance of correctly assessing novel variants in all variant-calling pipelines associated with genetic diagnoses for cancer.
    DOI:  https://doi.org/10.1038/s41418-020-00672-0
  13. Int J Epidemiol. 2020 Nov 28. pii: dyaa201. [Epub ahead of print]
    Evidence for familial clustering in breast cancer age of onset.
    Ann Von Holle, Katie M O'Brien, Dale P Sandler, Clarice R Weinberg.
       BACKGROUND: Familial clustering of age at onset would have implications for both personalized screening and aetiology, but has not been studied for breast cancer.
    METHODS: We prospectively studied a cohort of 23 145 sisters to explore whether their breast cancer risk changed near the age at diagnosis of a previously affected older sister. Using an age-time-dependent variable in a Cox regression model, we estimated hazard ratios for breast cancer when participants were near their sister's diagnosis age, relative to similarly aged women whose sister was diagnosed at a very different age. To rule out a correlation driven by young-onset familial cancer, we separately investigated women who had enrolled at age 50 or older.
    RESULTS: Of the 23 145 women, 1412 developed breast cancer during follow-up (median 9.5 years). The estimated hazard ratio was 1.80 (95% confidence interval: 1.18, 2.74) at their sister's age at diagnosis, suggesting a substantial increase in risk compared with women of the same age but whose sister was diagnosed at a very different age. Restriction to women who enrolled at or after age 50 produced similar results.
    CONCLUSIONS: This familial clustering suggests that there may be important genetic and/or early environmental risk factors that influence the timing of breast cancer, even when onset is late in life. Personalized screening might need to account for the age at which a sister was earlier diagnosed with breast cancer.
    Keywords:  Age at onset; age at diagnosis; breast cancer; heritability; sister study
    DOI:  https://doi.org/10.1093/ije/dyaa201
  14. Nat Commun. 2020 12 03. 11(1): 6195
    Common germline-somatic variant interactions in advanced urothelial cancer.
    Aram Vosoughi, Tuo Zhang, Kyrillus S Shohdy, Panagiotis J Vlachostergios, David C Wilkes, Bhavneet Bhinder, Scott T Tagawa, David M Nanus, Ana M Molina, Himisha Beltran, Cora N Sternberg, Samaneh Motanagh, Brian D Robinson, Jenny Xiang, Xiao Fan, Wendy K Chung, Mark A Rubin, Olivier Elemento, Andrea Sboner, Juan Miguel Mosquera, Bishoy M Faltas.
      The prevalence and biological consequences of deleterious germline variants in urothelial cancer (UC) are not fully characterized. We performed whole-exome sequencing (WES) of germline DNA and 157 primary and metastatic tumors from 80 UC patients. We developed a computational framework for identifying putative deleterious germline variants (pDGVs) from WES data. Here, we show that UC patients harbor a high prevalence of pDGVs that truncate tumor suppressor proteins. Deepening somatic loss of heterozygosity in serial tumor samples is observed, suggesting a critical role for these pDGVs in tumor progression. Significant intra-patient heterogeneity in germline-somatic variant interactions results in divergent biological pathway alterations between primary and metastatic tumors. Our results characterize the spectrum of germline variants in UC and highlight their roles in shaping the natural history of the disease. These findings could have broad clinical implications for cancer patients.
    DOI:  https://doi.org/10.1038/s41467-020-19971-8
  15. Continuum (Minneap Minn). 2020 Dec;26(6): 1553-1583
    Pediatric Brain Tumors.
    Sonia Partap, Michelle Monje.
       PURPOSE OF REVIEW: This article focuses on primary brain tumors in the pediatric population with an emphasis on molecular classifications and treatment strategies.
    RECENT FINDINGS: Pediatric brain tumors are a heterogeneous group of tumors that differ from adult brain cancers despite similar nomenclature. With the added complexity of the developing brain, treatment regimens are tailored to protect neurocognitive outcomes without sacrificing long-term survival. The 2016 World Health Organization's classification incorporated molecular characteristics to aid in defining the diagnosis and prognosis of these tumors. These changes have enabled providers to stratify patients, thus intensifying therapies in those with high-risk diseases and modifying treatments to reduce morbidity for children and to provide better outcomes. Recent published findings from clinical trials have been especially helpful for gliomas, embryonal tumors, and ependymomas. By using this new information, molecular factors that correlate with survival have been identified in patients. In addition, genetic findings in tumor tissue have also led to revelations in predisposing germline mutations.
    SUMMARY: New findings from clinical trials and molecular stratification will shape the next generation of therapies in hopes of improving overall outcome, identifying pathways in tumorigenesis, and aiding in genetic counseling for children and their families.
    DOI:  https://doi.org/10.1212/CON.0000000000000955
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