bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020–11–29
twenty-six papers selected by
Joanna Zawacka-Pankau, University of Warsaw
  1. TP53 germline mutations in the context of families with hereditary breast and ovarian cancer: a clinical challenge.
  2. Identifying potential germline variants from sequencing hematopoietic malignancies.
  3. Prevalence and clinicopathological/molecular characteristics of mismatch repair protein-deficient tumours among surgically treated patients with prostate cancer in a Japanese hospital-based population.
  4. Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements.
  5. Morphological and molecular heterogeneity of epithelial ovarian cancer: Therapeutic implications.
  6. PARP inhibitor resistance and TP53 mutations in patients treated with olaparib for BRCA-mutated cancer: Four case reports.
  7. Impact of BRCA1/2 Mutations on the Efficacy of Secondary Cytoreductive Surgery.
  8. Case Report: Double Germline Mutations in BRCA1 and MSH2 in a Patient With Mixed Serous-Endometrioid Endometrial Carcinoma.
  9. A review of inherited cancer susceptibility syndromes.
  10. Genetic predisposition in pediatric oncology.
  11. Genotype-first approach to the detection of hereditary breast and ovarian cancer risk, and effects of risk disclosure to biobank participants.
  12. Embedding a genetic counselor into oncology clinics improves testing rates and timeliness for women with ovarian cancer.
  13. PTEN Hamartoma Tumor Syndrome: A Case of Renal Cell Carcinoma in a Young Female.
  14. Interferon-lambda (IFNL) germline variations and their significance for HCC and PDAC progression: an analysis of The Cancer Genome Atlas (TCGA) data.
  15. Candidate Gene Discovery in Hereditary Colorectal Cancer and Polyposis Syndromes-Considerations for Future Studies.
  16. Clinical and Molecular Characterization of Fanconi Anemia Patients in Turkey.
  17. Association between vitamin D and ovarian cancer development in BRCA1 mutation carriers.
  18. Germline genomic patterns are associated with cancer risk, oncogenic pathways, and clinical outcomes.
  19. Germline BRCA1 mutated esophageal squamous cell carcinoma.
  20. Acute lymphoblastic leukaemia in a child with hereditary elliptocytosis.
  21. The Genomics of Myelodysplastic Syndromes: Origins of Disease Evolution, Biological Pathways, and Prognostic Implications.
  22. Expediting rare disease diagnosis: a call to bridge the gap between clinical and functional genomics.
  23. Menstruation-Associated Acute Pancreatitis in Patients with Hereditary Pancreatitis.
  24. Pancreas preserving duodenectomy for duodenal polyposis in familial adenomatous polyposis.
  25. Functional characterisation guides classification of novel BAP1 germline variants.
  26. Tumour-only sequencing for oncology management: germline-focused analysis and implications.
  1. Arch Gynecol Obstet. 2020 Nov 27.
    TP53 germline mutations in the context of families with hereditary breast and ovarian cancer: a clinical challenge.
    Sabine Grill, Juliane Ramser, Heide Hellebrand, Nicole Pfarr, Melanie Boxberg, Christine Brambs, Nina Ditsch, Alfons Meindl, Eva Groß, Thomas Meitinger, Marion Kiechle, Anne S Quante.
       PURPOSE: TP53germline (g) mutations, associated with the Li-Fraumeni syndrome (LFS), have rarely been reported in the context of hereditary breast and ovarian cancer (HBOC). The prevalence and cancer risks in this target group are unknown and counseling remains challenging. Notably an extensive high-risk surveillance program is implemented, which evokes substantial psychological discomfort. Emphasizing the lack of consensus about clinical implications, we aim to further characterize TP53g mutations in HBOC families.
    METHODS: Next-generation sequencing was conducted on 1876 breast cancer (BC) patients who fulfilled the inclusion criteria for HBOC.
    RESULTS: (Likely) pathogenic variants in TP53 gene were present in 0.6% of the BC cohort with higher occurrence in early onset BC < 36 years. (1.1%) and bilateral vs. unilateral BC (1.1% vs. 0.3%). Two out of eleven patients with a (likely) pathogenic TP53g variant (c.542G > A; c.375G > A) did not comply with classic LFS/Chompret criteria. Albeit located in the DNA-binding domain of the p53-protein and therefore revealing no difference to LFS-related variants, they only displayed a medium transactivity reduction constituting a retainment of wildtype-like anti-proliferative functionality.
    CONCLUSION: Among our cohort of HBOC families, we were able to describe a clinical subgroup, which is distinct from the classic LFS-families. Strikingly, two families did not adhere to the LFS criteria, and functional analysis revealed a reduced impact on TP53 activity, which may suit to the attenuated phenotype. This is an approach that could be useful in developing individualized screening efforts for TP53g mutation carrier in HBOC families. Due to the low incidence, national/international cooperation is necessary to further explore clinical implications. This might allow providing directions for clinical recommendations in the future.
    Keywords:  Breast cancer; Cancer surveillance; Li-fraumeni-syndrome; TP53 germline mutation; p53
    DOI:  https://doi.org/10.1007/s00404-020-05883-x
  2. Blood. 2020 Nov 26. 136(22): 2498-2506
    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/blood.2020006910
  3. Jpn J Clin Oncol. 2020 Nov 27. pii: hyaa207. [Epub ahead of print]
    Prevalence and clinicopathological/molecular characteristics of mismatch repair protein-deficient tumours among surgically treated patients with prostate cancer in a Japanese hospital-based population.
    Makoto Kagawa, Satoru Kawakami, Azusa Yamamoto, Okihide Suzuki, Hidetaka Eguchi, Yasushi Okazaki, Kiwamu Akagi, Jun-Ichi Tamaru, Tomio Arai, Tatsuro Yamaguchi, Hideyuki Ishida.
       BACKGROUND: The prevalence and molecular characteristics of deficient mismatch repair prostate cancer in the Japanese population have scarcely been investigated.
    METHODS: Immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from resected primary prostate cancers in patients who underwent prostatectomy at our institution between January 2001 and May 2016. Genetic and/or epigenetic alterations of mismatch repair genes were investigated in patients with any loss of mismatch repair protein expression in the tumour.
    RESULTS: Of the 337 patients, four (1.2%) showed loss of mismatch repair protein expression on immunohistochemistry. All four patients showed loss of both MSH2 and MSH6 protein expression. Genetic testing was performed in two of the four patients, demonstrating no pathogenic germline alterations were present. In each of these two patients, at least one somatic alteration inactivating MSH2 without MSH2 hypermethylation was identified, leading to the diagnosis of supposed 'Lynch-like syndrome'. Patients with deficient mismatch repair prostate cancer were at a significantly higher stage (pT2pN0 vs. pT3-4pN0/pTanypN1, P = 0.02) and had a greater Gleason score (<8 vs. ≥8, P < 0.01) than those with proficient mismatch repair prostate cancer.
    CONCLUSIONS: The prevalence of deficient mismatch repair prostate cancer in the Japanese hospital-based prostatectomized population was extremely low. To improve screening efficacy for deficient mismatch repair prostate cancer, screening candidates can be limited to patients with locally advanced, node-positive and/or Gleason score of 8 or greater prostate cancer. Universal tumour screening for Lynch syndrome seems ineffective in patients with prostate cancer.
    Keywords:  Lynch syndrome; immunohistochemistry; mismatch repair deficiency; prostate cancer; universal tumour screening
    DOI:  https://doi.org/10.1093/jjco/hyaa207
  4. Cancers (Basel). 2020 Nov 21. pii: E3468. [Epub ahead of print]12(11):
    Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements.
    Gulisa Turashvili, Conxi Lazaro, Shengjie Ying, George Charames, Andrew Wong, Krista Hamilton, Denise Yee, Evangeline Agro, Martin Chang, Aaron Pollett, Jordan Lerner-Ellis.
       BACKGROUND: Approximately 25% of women diagnosed with tubo-ovarian high-grade serous carcinoma have germline deleterious mutations in BRCA1 or BRCA2, characteristic of hereditary breast and ovarian cancer syndrome, while somatic mutations have been detected in 3-7%. We set out to determine the BRCA mutation rates and optimal tissue requirements for tumor BRCA testing in patients diagnosed with tubo-ovarian high-grade serous carcinoma.
    METHODS: Sequencing was performed using a multiplexed polymerase chain reaction-based approach on 291 tissue samples, with a minimum sequencing depth of 500X and an allele frequency of >5%.
    RESULTS: There were 253 surgical samples (87%), 35 biopsies (12%) and 3 cytology cell blocks (1%). The initial failure rate was 9% (25/291), including 9 cases (3%) with insufficient tumor, and 16 (6%) with non-amplifiable DNA. Sequencing was successful in 78% (228/291) and deemed indeterminate due to failed exons or variants below the limit of detection in 13% (38/291). Repeat testing was successful in 67% (28/42) of retested samples, with an overall success rate of 86% (251/291). Clinically significant (pathogenic, likely pathogenic) variants were identified in 17% (48/276) of complete and indeterminate cases. Successful sequencing was dependent on sample type, tumor cellularity and size (p ≤ 0.001) but not on neoadjuvant chemotherapy or age of blocks (p > 0.05).
    CONCLUSIONS: Our study shows a 17% tumor BRCA mutation rate, with an overall success rate of 86%. Biopsy and cytology samples and post-chemotherapy specimens can be used for tumor BRCA testing, and optimal tumors measure ≥5 mm in size with at least 20% cellularity.
    Keywords:  BRCA; PARP inhibitors; high-grade serous carcinoma; tumor sequencing
    DOI:  https://doi.org/10.3390/cancers12113468
  5. EJC Suppl. 2020 Aug;15 1-15
    Morphological and molecular heterogeneity of epithelial ovarian cancer: Therapeutic implications.
    Ignacio Romero, Susanna Leskelä, Belén Pérez Mies, Andrés Poveda Velasco, José Palacios.
      Ovarian epithelial cancer (OEC) is the most lethal gynecologic malignancy. Despite current chemotherapeutic and surgical options, this high lethality can be attributed to multiple factors, including late-stage presentation. In order to optimize OEC treatment, it is important to highlight that it is composed of five main subtypes: high-grade serous ovarian carcinoma (HGSOC), low-grade serous ovarian carcinoma (LGSOC), endometrioid ovarian carcinoma (EOC), ovarian clear cell carcinoma (CCOC), and mucinous ovarian carcinoma (MOC). These subtypes differ in their precursor lesions, as well as in epidemiological, morphological, molecular and clinical features. OEC is one of the tumours in which most pathogenic germline mutations have been identified. Accordingly, up to 20% OC show alterations in BRCA1/2 genes, and also, although with a lower frequency, in other low penetrance genes associated with homologous recombination deficiency (HRD), mismatch repair genes (Lynch syndrome) and TP53. The most important prognostic factor is the 2014 FIGO staging, while older age is also associated with worse survival. HGSOC in all stages and CCC and MOC in advanced stages have the worse prognosis among histological types. Molecular markers have emerged as prognostic factors, particularly mutations in BRCA1/2, which are associated with a better outcome. Regarding treatment, whereas a proportion of HGSOC is sensible to platinum-based treatment and PARP inhibitors due to HRD, the rest of the histological types are relatively chemoresistant. New treatments based in specific molecular alterations are being tested in different histological types. In addition, immunotherapy could be an option, especially for EOC carrying mismatch repair deficiency or POLE mutations.
    Keywords:  Hereditary cancer syndromes; Histological groups; Molecular markers; Ovarian cancer
    DOI:  https://doi.org/10.1016/j.ejcsup.2020.02.001
  6. Mol Med Rep. 2021 Jan;pii: 75. [Epub ahead of print]23(1):
    PARP inhibitor resistance and TP53 mutations in patients treated with olaparib for BRCA-mutated cancer: Four case reports.
    Thomas Collot, Julie Niogret, Marion Carnet, Sandy Chevrier, Etienne Humblin, Laure Favier, Leila Bengrine-Lefevre, Isabelle Desmoulins, Laurent Arnould, Romain Boidot.
      Loss‑of‑function BRCA mutations are frequent in high‑grade serous ovarian carcinoma. BRCA1 and ‑2 mutations lead to homologous recombination (HR) deficiency. Poly(ADP‑ribose) polymerases (PARP) are enzymes involved in DNA repair. PARP inhibitors (PARPi) lead to DNA damage accumulation in cells deficient in HR. Olaparib (a PARPi) is currently used for the treatment of high‑grade serous ovarian carcinoma with germline or somatic BRCA mutations; however, numerous patients do not respond or eventually develop resistance to these agents. The TP53 gene encodes the p53 protein, which is often referred to as the 'guardian of the genome'. TP53 mutations at diagnosis are known to promote resistance to chemotherapy. In the present study, four cases of patients with BRCA‑mutated cancer treated with olaparib, who progressed following the PARPi treatment, are reported. Exome analyses were performed on a primary tumor biopsy at diagnosis, then on a progressing metastasis following olaparib treatment. Exome analyses following olaparib treatment identified de novo TP53 mutations, as well as increased frequencies of pre‑existing TP53 mutations compared with the primary tumor. In HCT116 TP53‑/‑ cells carrying BRCA2 pathogenic mutations, TP53 inactivating mutations were associated with lower sensitivity to olaparib in vitro. Thus, inactivating TP53 mutations may be associated to olaparib resistance in the presence of BRCA mutations. In conclusion, the present findings demonstrated resistance to PARPi with de novo TP53 mutations that may be clinically relevant. As TP53 mutations are easily detectable with targeted next‑generation sequencing panels, these may serve as surrogate markers for the onset of PARPi resistance in the context of routine patient management strategies.
    DOI:  https://doi.org/10.3892/mmr.2020.11713
  7. Ann Surg Oncol. 2020 Nov 21.
    Impact of BRCA1/2 Mutations on the Efficacy of Secondary Cytoreductive Surgery.
    Felipe Leonardo Estati, Rafaela Pirolli, Viviane Teixeira Loiola de Alencar, Adriana Regina Gonçalves Ribeiro, Maria Nirvana Formiga, Giovana Tardin Torrezan, Dirce Maria Carraro, Andrea Paiva Gadelha Guimarães, Glauco Baiocchi, Alexandre André Balieiro Anastácio da Costa.
       BACKGROUND: Phase III trials evaluating the role of secondary cytoreductive surgery (SCS) in recurrent ovarian cancer have pointed to the importance of patient selection. Two studies showed conflicting results regarding the benefit of SCS in BRCA1/2 mutation carriers. Our aim was to evaluate the impact of SCS on recurrent ovarian cancer according to BRCA1/2 status.
    METHODS: All patients with ovarian carcinoma with platinum-sensitive recurrent disease and tested for BRCA1/2 germline mutations were included. Cox regression and log rank test were used to evaluate the impact of SCS on progression-free survival (PFS) and the influence of BRCA1/2 mutations on the effect of SCS.
    RESULTS: 127 patients were included, 45.6% were treated with SCS and chemotherapy and 54.3% treated with chemotherapy only. Patients treated with SCS were younger, presented better performance status, had lower CA125, and had a longer platinum-free interval. In multivariate analysis SCS was associated with longer PFS (HR 0.42, 95% CI 0.25-0.72, p = 0.002). BRCA1/2 mutations were found in 35 patients (27.5%), and 11.8% of patients were treated with PARP inhibitors. Although not statistically significant, both BRCA1/2 wild type patients (PFS: 21.6 vs 18.4 months; p = 0.114) and BRCA1/2 mutation carriers (PFS: 23.1 vs 18.2 months, p = 0.193) appeared to derive benefit from SCS.
    DISCUSSION: The present study suggests a benefit of SCS irrespective of BRCA1/2 status among patients mostly not treated with PARP inhibitor. Further data on post hoc analysis from the phase III trials are warranted to confirm whether BRCA1/2 mutated patients should be selected for SCS.
    DOI:  https://doi.org/10.1245/s10434-020-09366-w
  8. Front Med (Lausanne). 2020 ;7 581982
    Case Report: Double Germline Mutations in BRCA1 and MSH2 in a Patient With Mixed Serous-Endometrioid Endometrial Carcinoma.
    Hong Zheng, Mingming Yuan, Huanwen Wu, Rongrong Chen, Yunong Gao.
      Mixed serous-endometrioid endometrial carcinoma is a type of endometrial cancer with relatively low incidence. The genetic factors contributing to the tumorigenesis of mixed carcinoma remains to be explored. Here, we report the first identification of two germline mutations in BRCA1 and MSH2 in a woman with mixed serous papillary adenocarcinoma and endometrioid carcinoma. Immunohistochemistry analysis showed loss of MSH2 and MSH6 protein expression in the endometrioid component. The patient showed partial response to tislelizumab treatment following progression on chemotherapy. Two germline mutations in BRCA1 and MSH2 may collectively promote the tumorigenesis of uterine endometrium with two distinct histological components.
    Keywords:  double germline mutations; mixed serous-endometrioid endometrial carcinoma; next-generation sequencing; tislelizumab; tumor heterogeneity
    DOI:  https://doi.org/10.3389/fmed.2020.581982
  9. JAAPA. 2020 Dec;33(12): 10-16
    A review of inherited cancer susceptibility syndromes.
    Gina R Brown, Madeline Simon, Chris Wentling, Danielle M Spencer, Ashley N Parker, Corey A Rogers.
      Inherited cancer syndromes are caused by genetic mutations that place patients at an increased risk for developing cancer. Although most cancers are not caused by genetic inheritance, clinicians must understand these syndromes and be able to recognize their common characteristics. A thorough family history and identification of common patterns as well as specific clinical signs and symptoms can help with early recognition. This article describes symptoms of the more common cancer syndromes, including hereditary breast and ovarian cancer, Li-Fraumeni, Lynch, familial adenomatous polyposis, retinoblastoma, multiple endocrine neoplasia, and von Hippel-Lindau. Important patient education regarding genetic testing also is covered.
    DOI:  https://doi.org/10.1097/01.JAA.0000721648.46099.2c
  10. Med Pharm Rep. 2020 Oct;93(4): 323-334
    Genetic predisposition in pediatric oncology.
    Doina Paula Pruteanu, Diana Elena Olteanu, Rodica Cosnarovici, Emilia Mihut, Viorica Nagy.
      Identifying patients with a genetic predisposition for developing malignant tumors has a significant impact on both the patient and family. Recognition of genetic predisposition, before diagnosing a malignant pathology, may lead to early diagnosis of a neoplasia. Recognition of a genetic predisposition syndrome after the diagnosis of neoplasia can result in a change of treatment plan, a specific follow-up of adverse treatment effects and, of course, a long-term follow-up focusing on the early detection of a second neoplasia. Responsible for genetic syndromes that predispose individuals to malignant pathology are germline mutations. These mutations are present in all cells of conception, they can be inherited or can occur de novo. Several mechanisms of inheritance are described: Mendelian autosomal dominant, Mendelian autosomal recessive, X-linked patterns, constitutional chromosomal abnormality and non-Mendelian inheritance. In the following review we will present the most important genetic syndromes in pediatric oncology.
    Keywords:  genetic predisposition to disease; genetic syndromes; germ-line mutation; pediatric cancer
    DOI:  https://doi.org/10.15386/mpr-1576
  11. Eur J Hum Genet. 2020 Nov 23.
    Genotype-first approach to the detection of hereditary breast and ovarian cancer risk, and effects of risk disclosure to biobank participants.
    Liis Leitsalu, Marili Palover, Timo Tõnis Sikka, Anu Reigo, Mart Kals, Kalle Pärn, Tiit Nikopensius, Tõnu Esko, Andres Metspalu, Peeter Padrik, Neeme Tõnisson.
      Genotype-first approach allows to systematically identify carriers of pathogenic variants in BRCA1/2 genes conferring a high risk of familial breast and ovarian cancer. Participants of the Estonian biobank have expressed support for the disclosure of clinically significant findings. With an Estonian biobank cohort, we applied a genotype-first approach, contacted carriers, and offered return of results with genetic counseling. We evaluated participants' responses to and the clinical utility of the reporting of actionable genetic findings. Twenty-two of 40 contacted carriers of 17 pathogenic BRCA1/2 variants responded and chose to receive results. Eight of these 22 participants qualified for high-risk assessment based on National Comprehensive Cancer Network criteria. Twenty of 21 counseled participants appreciated being contacted. Relatives of 10 participants underwent cascade screening. Five of 16 eligible female BRCA1/2 variant carriers chose to undergo risk-reducing surgery, and 10 adhered to surveillance recommendations over the 30-month follow-up period. We recommend the return of results to population-based biobank participants; this approach could be viewed as a model for population-wide genetic testing. The genotype-first approach permits the identification of individuals at high risk who would not be identified by application of an approach based on personal and family histories only.
    DOI:  https://doi.org/10.1038/s41431-020-00760-2
  12. Gynecol Oncol. 2020 Nov 20. pii: S0090-8258(20)34111-1. [Epub ahead of print]
    Embedding a genetic counselor into oncology clinics improves testing rates and timeliness for women with ovarian cancer.
    Huma Q Rana, Lindsay Kipnis, Kristin Hehir, Angel Cronin, Tim Jaung, Samantha M Stokes, Fatemeh Fekrmandi, Donna Vatnick, Ursula A Matulonis, Judy E Garber, Alexi A Wright.
       OBJECTIVE: Germline genetic testing is crucial to the care of ovarian cancer patients, and as part of the guideline-based care for ovarian cancer patient's adherence to this recommendation has been low. We sought to determine whether embedding a genetic counselor (GC) within a medical and gynecologic oncology clinic would increase testing rates and improve the timeliness of testing.
    METHODS: Prospective cohort study of 358 ovarian cancer patients seen by medical and gynecologic oncologists between 2013 and 2015. Rates of referrals, completion of counseling, and genetic testing and timeliness of counseling were abstracted before and after a GC was embedded in the clinic in 2014. An additional year of data (2015) was collected to evaluate sustainability of the intervention.
    RESULTS: Between 2013 and 2015, 88-92% of women were referred for genetic testing, but in 2013 only 66% completed counseling and 61% were tested. After a GC was embedded in the clinic in 2014, more than 80% of referred women completed counseling and germline genetic testing. Time to genetic counseling also decreased from a median of 107 to 40 days, irrespective of age and cancer family history (p < 0.01).
    CONCLUSIONS: Embedding a GC into the workflow for ovarian cancer patients is an effective way of improving access to genetic counseling, testing rates, and the timeliness of testing.
    Keywords:  Counselor; Genetic counseling; Genetic testing; Germline; Ovarian cancer
    DOI:  https://doi.org/10.1016/j.ygyno.2020.11.003
  13. Urology. 2020 Nov 20. pii: S0090-4295(20)31401-1. [Epub ahead of print]
    PTEN Hamartoma Tumor Syndrome: A Case of Renal Cell Carcinoma in a Young Female.
    Rathika R Ramkumar, Prithvi B Murthy, Jane K Nguyen, Jesse McKenney, Charis Eng, Steven C Campbell.
      PTEN Hamartoma-Tumor-Syndrome (PHTS) describes a series of conditions characterized by germline-mutation of the PTEN tumor-suppressor gene. PHTS patients have an increased lifetime risk of multiple malignancies, including thyroid, breast, and endometrial cancers. PHTS patients also have 20-30 fold increased risk of renal cell carcinoma (RCC) compared to age-matched controls. As with many hereditary RCC syndromes, tumors present early and multifocally. We present a case of one of the youngest patients diagnosed with RCC in PHTS and review the urologic implications of this syndrome.
    DOI:  https://doi.org/10.1016/j.urology.2020.11.024
  14. BMC Cancer. 2020 Nov 23. 20(1): 1131
    Interferon-lambda (IFNL) germline variations and their significance for HCC and PDAC progression: an analysis of The Cancer Genome Atlas (TCGA) data.
    Henriette Huschka, Sabine Mihm.
       BACKGROUND: Hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) are malignancies with a leading lethality. With reference to interferons (IFNs) known to mediate antitumor activities, this study investigated the relationship between germline genetic variations in type III IFN genes and cancer disease progression from The Cancer Genome Atlas (TCGA) data. The genetic variations under study tag a gain-or-loss-of-function dinucleotide polymorphism within the IFNL4 gene, rs368234815 [TT/ΔG].
    METHODS: The entirety of the TCGA sequencing data was used to assess genotypes of 187 patients with HCC and of 162 patients with PDAC matched for ethnicity. Stratified for IFNL genotypes, both cohorts were subjected to time-to-event analyses according to Kaplan-Meier with regard to the length of the specific progression free interval (PFI) and the overall survival (OS) time as two clinical endpoints for disease progression.
    RESULTS: Logrank analysis revealed a significant relationship between IFNL genotypes and disease outcome for PDAC. This relationship was not found for HCC. A multiple Cox regression analysis employing patients' age, tumor grade and tumor stage as further covariates proved IFNL genotypes to be independent predictors for PDAC disease outcome.
    CONCLUSION: This repository-based approach unveiled clinical evidence suggestive for an impact of IFNL germline variations for PDAC progression with an IFNL haplotype predisposing for IFNL4 expression being favorable.
    Keywords:  Antitumor host response; Hepatocellular carcinoma (HCC); IFNL4 rs368234815; Interferon-lambda4 (IFNL4); Overall survival (OS); Pancreatic ductal adenocarcinoma (PDAC); Progression free interval (PFI); Type III interferons
    DOI:  https://doi.org/10.1186/s12885-020-07589-4
  15. Int J Mol Sci. 2020 Nov 19. pii: E8757. [Epub ahead of print]21(22):
    Candidate Gene Discovery in Hereditary Colorectal Cancer and Polyposis Syndromes-Considerations for Future Studies.
    Iris B A W Te Paske, Marjolijn J L Ligtenberg, Nicoline Hoogerbrugge, Richarda M de Voer.
      To discover novel high-penetrant risk loci for hereditary colorectal cancer (hCRC) and polyposis syndromes many whole-exome and whole-genome sequencing (WES/WGS) studies have been performed. Remarkably, these studies resulted in only a few novel high-penetrant risk genes. Given this observation, the possibility and strategy to identify high-penetrant risk genes for hCRC and polyposis needs reconsideration. Therefore, we reviewed the study design of WES/WGS-based hCRC and polyposis gene discovery studies (n = 37) and provide recommendations to optimize discovery and validation strategies. The group of genetically unresolved patients is phenotypically heterogeneous, and likely composed of distinct molecular subtypes. This knowledge advocates for the screening of a homogeneous, stringently preselected discovery cohort and obtaining multi-level evidence for variant pathogenicity. This evidence can be collected by characterizing the molecular landscape of tumors from individuals with the same affected gene or by functional validation in cell-based models. Together, the combined approach of a phenotype-driven, tumor-based candidate gene search might elucidate the potential contribution of novel genetic predispositions in genetically unresolved hCRC and polyposis.
    Keywords:  colorectal tumors; genetic predisposition; missing heritability; molecular biomarkers; molecular diagnosis; rare variants
    DOI:  https://doi.org/10.3390/ijms21228757
  16. Mol Syndromol. 2020 Nov;11(4): 183-196
    Clinical and Molecular Characterization of Fanconi Anemia Patients in Turkey.
    Güven Toksoy, Dilek Uludağ Alkaya, Gülendam Bagirova, Şahin Avcı, Agharza Aghayev, Nilay Günes, Umut Altunoğlu, Yasemin Alanay, Seher Başaran, Ezgi G Berkay, Birsen Karaman, Tiraje T Celkan, Hilmi Apak, Hülya Kayserili, Beyhan Tüysüz, Zehra O Uyguner.
      Fanconi anemia (FA) is a rare multigenic chromosomal instability syndrome that predisposes patients to life-threatening bone marrow failure, congenital malformations, and cancer. Functional loss of interstrand cross-link (ICL) DNA repair system is held responsible, though the mechanism is not yet fully understood. The clinical and molecular findings of 20 distinct FA cases, ages ranging from perinatal stage to 32 years, are presented here. Pathogenic variants in FANCA were found responsible in 75%, FANCC, FANCE, FANCJ/BRIP1, FANCL in 5%, and FANCD1/BRCA2 and FANCN/PALB2 in 2.5% of the subjects. Altogether, 25 different variants in 7 different FA genes, including 10 novel mutations in FANCA, FANCN/PALB2, FANCE, and FANCJ/BRIP1, were disclosed. Two compound heterozygous germline cases were mosaic for one allele, revealing that the incidence of reverse mutations may not be uncommon in FA. Another case with de novo FANCD1/BRCA2 and paternally inherited FANCN/PALB2 pathogenic alleles at first glance suggested a digenic inheritance, because the presence of a second pathogenic variant in the unexamined regions of FANCD1/BRCA2 and FANCN/PALB2 were exluded by sequencing and deletion/duplication analysis. A better understanding of the complexity of the FA genotype may provide further access to undiscovered ICL components and apparently dispensable cellular pathways where FA proteins may play important roles.
    Keywords:  Cancer; Digenic; Fanconi anemia; Reverse mutation; Somatic mosaicism
    DOI:  https://doi.org/10.1159/000509838
  17. Oncotarget. 2020 Nov 10. 11(45): 4104-4114
    Association between vitamin D and ovarian cancer development in BRCA1 mutation carriers.
    Tanja Pejovic, Sonali Joshi, Shawn Campbell, Sarah Thisted, Fuhua Xu, Jing Xu.
       OBJECTIVE: Women with inherited mutations in BRCA1 gene have a high (40-70%) genetic risk of developing ovarian cancer. Epidemiological studies suggest an inverse correlation between serum vitamin D (VD) levels and the risk of ovarian cancer, but there is a lack of data from BRCA1 mutation (BRCA1 mut) carriers. Therefore, we investigated VD levels and actions in cancer free women with BRCA1 mutations.
    MATERIALS AND METHODS: Blood, ovary and fallopian tube samples were collected from healthy pre-menopausal women with BRCA1 mut and without BRCA1 mutations (BRCA wt). Serum calcifediol (major circulating form of VD) concentrations were measured by electrochemiluminescence immunoassay. Immunohistochemistry was performed on paraffin-embedded ovarian and fallopian tube sections to determine vitamin D receptor (VDR) expression. Ovarian surface epithelial cells (OSEs) from BRCA1 mut carriers were cultured with or without calcitriol supplementation for 72 hrs. VDR protein levels, cell proliferation and cell viability were analyzed.
    RESULTS: BRCA1mut women had lower serum calcifediol levels compared to BRCA wt women (p = 0.003). VDR protein expression was evident in ovarian and the fallopian tube epithelium of BRCA wt patients, but was reduced in BRCA1 mut women. Calcitriol (biologically active VD) supplementation elevated VDR expression in cultured BRCA1 mut OSEs (p = 0.005) and decreased cell proliferation rates in a dose-dependent manner without inducing apoptosis.
    CONCLUSIONS: VD biosynthesis and signaling via VDR in the ovarian and fallopian tube epithelium are impaired in BRCA1 mut women. VD treatment may limit BRCA1 mut epithelial cell proliferation without affecting cell viability, providing a rationale for exploring the potential for VD in ovarian cancer prevention in BRCA1 mut carriers.
    Keywords:  BRCA1 mutation carriers ; cancer prevention; epithelial ovarian cancer; vitamin D
    DOI:  https://doi.org/10.18632/oncotarget.27803
  18. Sci Adv. 2020 Nov;pii: eaba4905. [Epub ahead of print]6(48):
    Germline genomic patterns are associated with cancer risk, oncogenic pathways, and clinical outcomes.
    Xue Xu, Yuan Zhou, Xiaowen Feng, Xiong Li, Mohammad Asad, Derek Li, Bo Liao, Jianqiang Li, Qinghua Cui, Edwin Wang.
      There is an ongoing debate on the importance of genetic factors in cancer development, where gene-centered cancer predisposition seems to show that only 5 to 10% of the cancer cases are inheritable. By conducting a systematic analysis of germline genomes of 9712 cancer patients representing 22 common cancer types along with 16,670 noncancer individuals, we identified seven cancer-associated germline genomic patterns (CGGPs), which summarized trinucleotide mutational spectra of germline genomes. A few CGGPs were consistently enriched in the germline genomes of patients whose tumors had smoking signatures or correlated with oncogenesis- and genome instability-related mutations. Furthermore, subgroups defined by the CGGPs were significantly associated with distinct oncogenic pathways, tumor histological subtypes, and prognosis in 13 common cancer types, suggesting that germline genomic patterns enable to inform treatment and clinical outcomes. These results provided evidence that cancer risk and clinical outcomes could be encoded in germline genomes.
    DOI:  https://doi.org/10.1126/sciadv.aba4905
  19. Rare Tumors. 2020 ;12 2036361320972218
    Germline BRCA1 mutated esophageal squamous cell carcinoma.
    Jason Starr, Brian Ramnaraign.
      The most common associated malignancies with BRCA mutations include breast and ovarian cancers. Less common malignancies associated with BRCA mutation include: pancreatic, prostate, colon, gastric, and biliary cancers. Esophageal cancer, particularly squamous cell carcinoma, has rarely been reported to harbor BRCA mutations. Here we report, to our knowledge, the first case of germline BRCA1 mutated associated esophageal squamous cell carcinoma.
    Keywords:  BRCA mutation; BRCA1 mutation; esophageal cancer; squamous esophageal cancer
    DOI:  https://doi.org/10.1177/2036361320972218
  20. Int J Lab Hematol. 2020 Nov 24.
    Acute lymphoblastic leukaemia in a child with hereditary elliptocytosis.
    Peng Sun, Rong Wen, Xiangmao Bu, Wenjie Li, Wenfeng Mu.
      
    DOI:  https://doi.org/10.1111/ijlh.13408
  21. Cells. 2020 Nov 20. pii: E2512. [Epub ahead of print]9(11):
    The Genomics of Myelodysplastic Syndromes: Origins of Disease Evolution, Biological Pathways, and Prognostic Implications.
    Hassan Awada, Bicky Thapa, Valeria Visconte.
      The molecular pathogenesis of myelodysplastic syndrome (MDS) is complex due to the high rate of genomic heterogeneity. Significant advances have been made in the last decade which elucidated the landscape of molecular alterations (cytogenetic abnormalities, gene mutations) in MDS. Seminal experimental studies have clarified the role of diverse gene mutations in the context of disease phenotypes, but the lack of faithful murine models and/or cell lines spontaneously carrying certain gene mutations have hampered the knowledge on how and why specific pathways are associated with MDS pathogenesis. Here, we summarize the genomics of MDS and provide an overview on the deregulation of pathways and the latest molecular targeted therapeutics.
    Keywords:  MDS; deregulated expression; mutations
    DOI:  https://doi.org/10.3390/cells9112512
  22. Mol Med. 2020 Nov 25. 26(1): 117
    Expediting rare disease diagnosis: a call to bridge the gap between clinical and functional genomics.
    Samantha N Hartin, John C Means, Joseph T Alaimo, Scott T Younger.
      Approximately 400 million people throughout the world suffer from a rare disease. Although advances in whole exome and whole genome sequencing have greatly facilitated rare disease diagnosis, overall diagnostic rates remain below 50%. Furthermore, in cases where accurate diagnosis is achieved the process requires an average of 4.8 years. Reducing the time required for disease diagnosis is among the most critical needs of patients impacted by a rare disease. In this perspective we describe current challenges associated with rare disease diagnosis and discuss several cutting-edge functional genomic screening technologies that have the potential to rapidly accelerate the process of distinguishing pathogenic variants that lead to disease.
    Keywords:  Functional genomics; Massively parallel genomic assays; Pooled CRISPR screening; Rare disease diagnosis
    DOI:  https://doi.org/10.1186/s10020-020-00244-5
  23. J Pediatr. 2020 Nov 22. pii: S0022-3476(20)31436-0. [Epub ahead of print]
    Menstruation-Associated Acute Pancreatitis in Patients with Hereditary Pancreatitis.
    Racha Khalaf, Michael Narkewicz, Maisam Abu El-Haija.
      Two adolescent females present with recurrent episodes of menstrual cycle associated acute pancreatitis and are diagnosed with hereditary pancreatitis, a cause of chronic pancreatitis. Hereditary pancreatitis should remain in the differential diagnosis for teenage females with catamenial acute pancreatitis and family history of pancreatic disease.
    DOI:  https://doi.org/10.1016/j.jpeds.2020.11.024
  24. S Afr J Surg. 2020 Sep;58(3): 161
    Pancreas preserving duodenectomy for duodenal polyposis in familial adenomatous polyposis.
    J Lindemann, J E J Krige, E Jonas.
       SUMMARY: Duodenal polyposis is common in familial adenomatous polyposis with a significant associated lifetime risk of cancer. Screening and regular surveillance is recommended, guided by the Spigelman stage. Pancreas preserving duodenectomy (PPD) is the preferred operation in patients needing removal of the whole duodenum. This presentation demonstrates the technique of PPD with particular emphasis on the resection and ampullary reconstruction. Initial early feeding tube placement through the cystic duct stump into the duodenum enables identification of the papilla and pancreatic duct as well as subsequent dissection. Separate trans-anastomotic pancreatic and biliary stents facilitate creation and patency of the pancreato-biliary anastomosis. The operation has similar outcomes compared to pancreaticoduodenectomy, however, the anatomical reconstruction allows for postoperative surveillance.
  25. NPJ Genom Med. 2020 ;5 50
    Functional characterisation guides classification of novel BAP1 germline variants.
    Jing Han Hong, Siao Ting Chong, Po-Hsien Lee, Jing Tan, Hong Lee Heng, Nur Diana Binte Ishak, Sock Hoai Chan, Bin Tean Teh, Joanne Ngeow.
      We have identified six patients harbouring distinct germline BAP1 mutations. In this study, we functionally characterise known BAP1 pathogenic and likely benign germline variants out of these six patients to aid in the evaluation and classification of unknown BAP1 germline variants. We found that pathogenic germline variants tend to encode truncated proteins, show diminished expression of epithelial-mesenchymal transition (EMT) markers, are localised in the cytosol and have reduced deubiquitinase capabilities. We show that these functional assays are useful for BAP1 variant curation and may be added in the American College of Medical Genetics and Genomics (ACMG) criteria for BAP1 variant classification. This will allow clinicians to distinguish between BAP1 pathogenic and likely benign variants reliably and may aid to quickly benchmark newly identified BAP1 germline variants. Classification of novel BAP1 germline variants allows clinicians to inform predisposed patients and relevant family members regarding potential cancer risks, with appropriate clinical interventions implemented if required.
    Keywords:  Clinical genetics; Genetics research
    DOI:  https://doi.org/10.1038/s41525-020-00157-6
  26. Genes Chromosomes Cancer. 2020 Nov 22.
    Tumour-only sequencing for oncology management: germline-focused analysis and implications.
    Angela George, Clare Turnbull.
      As patients are now routinely having large somatic genomic testing panels undertaken as part of routine management, there is the rising likelihood of uncovering the presence of a germline pathogenic variant. This may be found on testing undertaken on plasma (ctDNA) or tissue. This has led to the need for clear guidelines for oncologists about how to manage such results, including which variants require validation, how this should be undertaken, and what potential problems may arise. This requires an understanding of the limits of testing, and the pitfalls that may be encountered. In this review, we assess the frequency of detecting germline variants through tumour-only sequencing, the necessary considerations for such information to be analysed and the role of the molecular tumour board in considering results. We assess the additional considerations for interpretation of the underlying tumour, use of ctDNA or tissue for testing, clonal haematopoiesis and hypermutation. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/gcc.22919
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