bims-lifras Biomed News
on Li-Fraumeni Syndrome
Issue of 2020‒01‒19
fourteen papers selected by
Joanna Zawacka-Pankau



  1. High Throughput. 2020 Jan 10. pii: E1. [Epub ahead of print]9(1):
    Zelli V, Compagnoni C, Cannita K, Capelli R, Capalbo C, Di Vito Nolfi M, Alesse E, Zazzeroni F, Tessitore A.
      Next generation sequencing (NGS) provides a powerful tool in the field of medical genetics, allowing one to perform multi-gene analysis and to sequence entire exomes (WES), transcriptomes or genomes (WGS). The generated high-throughput data are particularly suitable for enhancing the understanding of the genetic bases of complex, multi-gene diseases, such as cancer. Among the various types of tumors, those with a familial predisposition are of great interest for the isolation of novel genes or gene variants, detectable at the germline level and involved in cancer pathogenesis. The identification of novel genetic factors would have great translational value, helping clinicians in defining risk and prevention strategies. In this regard, it is known that the majority of breast/ovarian cases with familial predisposition, lacking variants in the highly penetrant BRCA1 and BRCA2 genes (non-BRCA), remains unexplained, although several less penetrant genes (e.g., ATM, PALB2) have been identified. In this scenario, NGS technologies offer a powerful tool for the discovery of novel factors involved in familial breast/ovarian cancer. In this review, we summarize and discuss the state of the art applications of NGS gene panels, WES and WGS in the context of familial breast/ovarian cancer.
    Keywords:  BRCA1; BRCA2; familial breast/ovarian cancer; next generation sequencing (NGS), whole exome sequencing (WES), whole genome sequencing (WGS), hereditary tumors
    DOI:  https://doi.org/10.3390/ht9010001
  2. Jpn J Clin Oncol. 2020 Jan 11. pii: hyz147. [Epub ahead of print]
    Ryu JM, Nam SJ, Kim SW, Lee JE, Chae BJ, Lee SK, Yu J.
      OBJECTIVE: Demands for genetic counseling with BRCA1/2 examination have markedly increased. Accordingly, the incidence of uninformative results on BRCA1/2 mutation status has also increased. Because most patients examined for BRCA1/2 mutation have a high risk of hereditary breast and/or ovarian cancer, many patients suffer psychological distress even when the BRCA1/2 result is negative. We compared oncological outcomes between BRCA1/2-negative breast cancer with high risk of hereditary breast and/or ovarian cancer and sporadic breast cancer without risk of hereditary breast and/or ovarian cancer.METHODS: The criteria for high risk for hereditary breast and/or ovarian cancer were defined as family history of breast and/or ovarian cancer in first- or second-degree relative, early onset breast cancer at <35 years old and bilateral breast cancer. Patients were matched maximally 1:3 into those who identified as negative for BRCA1/2 mutation with risk of hereditary breast and/or ovarian cancer (study group) and those who were not examined for BRCA1/2 mutation without risk for hereditary breast and/or ovarian cancer (control group). Matched variables were pathologic stage, estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 status.
    RESULTS: All matching variables were successfully matched. Median follow-up duration was 57.8 months. There was no significant difference between the groups in disease-free survival (log-rank P = 0.197); however, the study group showed significantly better overall survival and breast cancer-specific survival (both P < 0.0001). We conducted subgroup analysis in the middle-aged group (36-54) and showed no significant difference for disease-free survival (P = 0.072) but significantly better overall survival and breast cancer-specific survival in the study group (P = 0.002 and P < 0.0001).
    CONCLUSIONS: BRCA1/2-negative breast cancer patients who had hereditary breast and/or ovarian cancer risk factors showed similar disease-free survival and better overall survival and breast cancer-specific survival compared with those with sporadic breast cancer without hereditary breast and/or ovarian cancer risk factors.
    Keywords:  BRCA mutation; breast neoplasm; hereditary breast and ovarian cancer syndrome
    DOI:  https://doi.org/10.1093/jjco/hyz147
  3. Trends Cancer. 2020 Jan;pii: S2405-8033(19)30240-7. [Epub ahead of print]6(1): 31-39
    Mandelker D, Ceyhan-Birsoy O.
      Molecular tests assist at various stages of cancer patient management, including providing diagnosis, predicting prognosis, identifying therapeutic targets, and determining hereditary cancer risk. The current testing paradigm involves germline testing in a subset of patients determined to be at high risk for having a hereditary cancer syndrome, and tumor-only sequencing for treatment decisions in advanced cancer patients. A major limitation of tumor-only sequencing is its inability to distinguish germline versus somatic mutations. Tumor-normal sequencing has emerged as a comprehensive analysis for both hereditary cancer predisposition and somatic profiling. Here, we review recent studies involving tumor-normal sequencing, discuss its benefits in clinical care, challenges for its implementation, and novel insights it has provided regarding tumor biology and germline contribution to cancer.
    Keywords:  hereditary cancer predisposition; tumor sequencing; tumor-normal sequencing
    DOI:  https://doi.org/10.1016/j.trecan.2019.11.006
  4. J Med Genet. 2020 Jan 14. pii: jmedgenet-2019-106657. [Epub ahead of print]
    Shen E, Xiu J, Lopez GY, Bentley R, Jalali A, Heimberger AB, Bainbridge MN, Bondy ML, Walsh KM.
      BACKGROUND: The shelterin complex is composed of six proteins that protect and regulate telomere length, including protection of telomeres 1 (POT1). Germline POT1 mutations are associated with an autosomal dominant familial cancer syndrome presenting with diverse malignancies, including glioma, angiosarcoma, colorectal cancer and melanoma. Although somatic POT1 mutations promote telomere elongation and genome instability in chronic lymphocytic leukaemia, the contribution of POT1 mutations to development of other sporadic cancers is largely unexplored.METHODS: We performed logistic regression, adjusted for tumour mutational burden, to identify associations between POT1 mutation frequency and tumour type in 62 368 tumours undergoing next-generation sequencing.
    RESULTS: A total of 1834 tumours harboured a non-benign mutation of POT1 (2.94%), of which 128 harboured a mutation previously reported to confer familial cancer risk in the setting of germline POT1 deficiency. Angiosarcoma was 11 times more likely than other tumours to harbour a POT1 mutation (p=1.4×10-20), and 65% of POT1-mutated angiosarcoma had >1 mutations in POT1. Malignant gliomas were 1.7 times less likely to harbour a POT1 mutation (p=1.2×10-3) than other tumour types. Colorectal cancer was 1.2 times less likely to harbour a POT1 mutation (p=0.012), while melanoma showed no differences in POT1 mutation frequency versus other tumours (p=0.67).
    CONCLUSIONS: These results confirm a role for shelterin dysfunction in angiosarcoma development but suggest that gliomas arising in the context of germline POT1 deficiency activate a telomere-lengthening mechanism that is uncommon in gliomagenesis.
    Keywords:  POT1 mutation; atrx; hereditary cancer syndrome families; telomere; tert
    DOI:  https://doi.org/10.1136/jmedgenet-2019-106657
  5. Int J Clin Exp Pathol. 2018 ;11(3): 1667-1673
    Quintanilla-Guzman A, Luevano-Gonzalez A, Rangel-Gomez AN, Rojas-Martinez A, Garza-Guajardo R, Barboza-Quintana O, Ancer-Rodriguez J, Rios-Ibarra CP, Ortiz-Lopez R.
      Diagnosis of colorectal cancer in patients under 45 years old should alert us to possible hereditary forms of this neoplasia. Most cases of hereditary colorectal cancer correspond to Lynch syndrome which is caused by mutations in DNA mismatch repair genes, particularly MLH1 and MSH2. The dysfunction is associated with microsatellite instability which occurs in 95% cases of this syndrome and in 15% of sporadic colorectal cancer. In sporadic colon tumors, downregulation of MLH1 is observed in cases with the BRAF V600E variant, which induces hypermetylation of the MLH1 promoter. Mutation screening for hereditary cancer has impacted the diagnosis, genetic counseling, and early tumor detection in families affected by hereditary colorectal cancer syndromes but mutation screening technologies are seldom available in public health care centers in developing countries. This study aimed to describe immunohistochemistry and microsatellite instability abnormalities in tumor samples archived in a public hospital in Mexico. Paraffin-embedded samples of patients with colorectal cancer, diagnosed at under 50 years old, were studied to analyze correlations among clinical variables, MLH1 and MSH2 protein expression (immunohistochemistry), microsatellite instability (fluorescent PCR-based assay), and BRAF V600E variant (real time PCR). Forty-seven tumor specimens from patients with TNM stage II and above were analyzed. Tumors were mainly located in the proximal colon segment and displayed histologic intestinal variety and infiltration to serosa. Twenty samples showed decreased expression of mismatch repair proteins and 10 of these presented microsatellite instability (7 high and 3 low instability patterns, respectively). There were no instances of BRAF V600E mutation found. Altered MLH1 or MSH2 expression was found in 42.5% of the samples and microsatellite instability was observed in 21.3% of the tumors. These results suggested that about a fifth of the patients were candidates for family assessment and genetic counseling.
    Keywords:  Colorectal cancer; DNA mismatch repair; microsatellite instability
  6. J Gastrointest Oncol. 2019 Dec;10(6): 1164-1170
    Ng C, Li H, Wu WKK, Wong SH, Yu J.
      Colorectal cancer (CRC) is a common cancer globally. It is a complex disease influenced by genetic and environmental factors. Early studies on familial cases have identified major genes involved in CRC, such as proto-oncogenes KRAS, PIK3CA and BRAF, and tumour-suppressor genes APC and TP53. These genes have provided valuable insight into the molecular pathogenesis of CRC, and some have made ways to clinical utility to help diagnose cancer syndromes, prognosticate oncological outcomes and predict treatment responses. While these genetic factors are important, recent studies have suggested contribution of microorganisms to colorectal carcinogenesis. Observational studies, animal experiments and translational works have identified several microorganisms as potential carcinogenic bacteria, such as Fusobacterium nucleatum and Peptostreptococcus anaerobius. With the advent of sequencing technology and bioinformatics, more genomic and metagenomic factors are being uncovered as important players in CRC carcinogenesis. This article aims to review recent genomic and metagenomic discoveries relating to CRC.
    Keywords:  Colorectal cancer (CRC); cancer syndrome; genomics; metagenomics; microbiota
    DOI:  https://doi.org/10.21037/jgo.2019.06.04
  7. Ann Transl Med. 2019 Nov;7(22): 677
    Wang J, Qi F, Zhang P, Xu Z, Zheng Y, Cai H, Yu B, Xu T, Li X, Zou Q.
      Background: A case of familial bilateral von Hippel-Lindauzon (VHL) renal cell carcinoma (RCC) was retrospectively reviewed and the etiological diagnosis was based on clinical characteristics and genetic testing.Methods: The clinical manifestations and imaging data were gained from the hospital information system (HIS). Peripheral blood samples were collected and genomic DNA and RNA were extracted. Additionally, mutations of VHL gene such as tiny insertion and deletion of base, point mutation and large deletion of gene were then detected and analyzed by DNA sequencing, real-time quantitative PCR and RT-PCR.
    Results: Real-time quantitative PCR and RT-PCR products sequencing showed that the number of VHL gene copies in peripheral blood of the patient was decreased, and pathological germline mutation was detected caused by single copy deletion of exon 2 of VHL gene. The patient was diagnosed as atypical VHL RCC according to clinical manifestations and genetic testing outcomes.
    Conclusions: VHL RCC can be diagnosed based on its clinical manifestations and genetic testing results.
    Keywords:  Von Hippel-Lindau Syndrome; diagnosis; genetic testing; germline mutation; von Hippel-Lindauzon gene (VHL gene)
    DOI:  https://doi.org/10.21037/atm.2019.10.09
  8. J Gastrointest Oncol. 2019 Dec;10(6): 1133-1139
    Palacio S, McMurry HS, Ali R, Donenberg T, Silva-Smith R, Wideroff G, Sussman DA, Rocha Lima CMS, Hosein PJ.
      Patients with pathogenic germline and somatic variants in DNA damage repair (DDR) genes may derive greater benefit with platinum-based chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC). This study investigates the role of DDR genes as a predictive biomarker for response to first-line platinum chemotherapy with FOLFIRINOX in metastatic PDAC patients. Demographic, clinical, and pathologic variables were collected for patients with metastatic PDAC who received FOLFIRINOX as frontline treatment and who had germline and somatic genetic testing. Kaplan-Meier analysis of overall survival (OS) and progression free survival (PFS) were correlated to the presence of DDR pathogenic variants. Forty patients with metastatic PDAC met inclusion criteria. Germline genetic testing revealed germline pathogenic variants in DDR genes in 5 patients (12%), and somatic pathogenic variants in DDR genes in 4 patients (10%). Median PFS was significantly longer in patients with any (germline or somatic) pathogenic variant in DDR genes than in those without alterations 18.5 vs. 6.9 months (log-rank P=0.003). When restricted to the presence or absence of germline pathogenic variants in DDR genes, the median PFS was 18.5 vs. 7.4 months (log-rank P=0.005). The median OS for the entire cohort was 11.5 months was not statistically different between the two groups, however there were no deaths in the subgroup with germline pathogenic variants in DDR genes treated with frontline FOLFIRINOX. A subset of patients with metastatic PDAC and germline or somatic pathogenic variants in DDR genes have a statistically superior PFS when treated with the platinum containing regimen FOLFIRINOX. The role of DDR gene alterations as a predictive biomarker for FOLFIRINOX benefit should be further evaluated in prospective trials.
    Keywords:  DNA repair; FOLFIRINOX; pancreatic neoplasms; progression-free survival
    DOI:  https://doi.org/10.21037/jgo.2019.09.12
  9. Int J Endocrinol. 2019 ;2019 1761030
    Torresan F, Iacobone M.
      Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by parathyroid tumors in association with fibro-osseous jaw tumors and uterine and renal lesions. HPT-JT syndrome is caused by germline mutations of the cell division cycle 73 (CDC73) gene that encodes the parafibromin, a 531-amino acid protein with antiproliferative activity. Primary hyperparathyroidism is the main finding of HPT-JT syndrome, usually caused by a single-gland parathyroid involvement (80% of cases), at variance with other variants of hereditary hyperparathyroidism, in which a multiglandular involvement is more frequent. Moreover, parathyroid carcinoma may occur in approximately 20% of cases. Surgery is the treatment of choice for primary hyperparathyroidism, but the extent of surgery remains controversial, varying between bilateral neck and focused exploration, with subtotal or limited parathyroidectomy. Recently, more limited approaches and parathyroid excisions have been suggested in order to decrease the risk of permanent hypoparathyroidism, the main surgical morbidity following more extensive surgical approaches. Ossifying fibromas of the mandible or maxilla may present only in a minority of cases and, even if benign, they should be surgically treated to avoid tumor growth and subsequent functional limitations. Benign and malignant uterine involvement (including leiomyomas, endometrial hyperplasia, adenomyosis, multiple adenomyomatous polyps, and adenosarcomas) is the second most common clinical feature of the syndrome, affecting more than 50% of CDC73-carrier women. Genetic testing should be performed in all family members of affected individuals, in young patients undergoing surgery for primary hyperparathyroidism, or in presence of other associated tumors, allowing early diagnosis and prompt treatment with more tailored surgery. Moreover, CDC73 mutation carriers should be also periodically screened for primary hyperparathyroidism and the other associated tumors. The present review was aimed to summarize the main clinical features of HPT-JT syndrome, focusing on genetic screening and surgical treatment, and to revise the available literature.
    DOI:  https://doi.org/10.1155/2019/1761030
  10. Pediatr Neurol. 2019 Aug 15. pii: S0887-8994(19)30449-7. [Epub ahead of print]
    Malbari F, Lindsay H.
      Central nervous system tumors are the most common solid tumors in pediatrics and represent the largest cause of childhood cancer-related mortality. Improvements have occurred in the management of these patients leading to better survival, but significant morbidity persists. With the era of next generation sequencing, considerable advances have occurred in the understanding of these tumors both biologically and clinically. This information has impacted diagnosis and management. Subgroups have been identified, improving risk stratification. Novel therapeutic approaches, specifically targeting the biology of these tumors, are being investigated to improve overall survival and decrease treatment-related morbidity. The intent of this review is to discuss the genetics of common pediatric brain tumors and the clinical implications. This review will include known genetic disorders associated with central nervous system tumors, neurofibromatosis, tuberous sclerosis, Li-Fraumeni syndrome, Gorlin syndrome, and Turcot syndrome, as well as somatic mutations of glioma, medulloblastoma, and ependymoma.
    Keywords:  Familial cancer predisposition syndromes; Genetics; Li-Fraumeni syndrome; Neurocutaneous syndromes; Pediatric brain tumors; Turcot syndrome
    DOI:  https://doi.org/10.1016/j.pediatrneurol.2019.08.004
  11. Eur Urol Oncol. 2020 Jan 13. pii: S2588-9311(19)30169-5. [Epub ahead of print]
    Wu Y, Yu H, Li S, Wiley K, Zheng SL, LaDuca H, Gielzak M, Na R, Sarver BAJ, Helfand BT, Walsh PC, Lotan TL, Cooney KA, Black MH, Xu J, Isaacs WB.
      BACKGROUND: Rare germline mutations in several genes, primarily DNA repair genes, have been proposed to predict worse prognosis of prostate cancer (PCa).OBJECTIVE: To compare the frequency of germline pathogenic mutations in commonly assayed PCa genes between high- and low-grade PCa in patients initially presenting with clinically localized disease.
    DESIGN, SETTING, AND PARTICIPANTS: A retrospective case-case study of 1694 PCa patients who underwent radical prostatectomy at Johns Hopkins Hospital, including 706 patients with high-grade (grade group [GG] 4 and GG5) and 988 patients with low-grade (GG1) disease. Germline DNA was sequenced for 13 candidate PCa genes using a targeted next-generation sequencing assay by Ambry Genetics.
    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Carrier rates of pathogenic mutations were compared between high- and low-grade PCa patients using the Fisher's exact test.
    RESULTS AND LIMITATIONS: Overall, the carrier rate of germline pathogenic mutations in the 13 genes was significantly higher in high-grade patients (8.64%) than in low-grade patients (3.54%, p = 9.98 × 10-6). Individually, significantly higher carrier rates for patients with high- versus low-grade PCa were found for three genes: ATM (2.12% and 0.20%, respectively, p = 9.35 × 10-5), BRCA2 (2.55% and 0.20%, respectively, p = 8.99 × 10-6), and MSH2 (0.57% and 0%, respectively, p = 0.03). The mutation carrier rate was significantly higher in patients with GG5 than in patients with GG1 disease for the 13 genes overall (13.07% and 3.54%, respectively, p = 1.27 × 10-9); for the three genes ATM, BRCA2, and MSH2 (7.73% and 0.40%, respectively, p = 3.20 × 10-13); and for the remaining nine DNA repair genes (5.07% and 2.43%, respectively, p = 0.02).
    CONCLUSIONS: In men undergoing treatment for clinically localized disease, pathogenic mutations in 13 commonly assayed genes, especially ATM, BRCA2, and MSH2, are most strongly associated with GG5 PCa. These findings emphasize the importance of genetic testing in men with high-grade PCa, particularly GG5 disease, to inform both treatment decisions and familial risk assessment.
    PATIENT SUMMARY: Prostate cancer in men with inherited mutations in 13 commonly assayed susceptibility genes is more likely to be high-grade, high-risk disease.
    Keywords:  DNA repair genes; Germline; High grade; Mutation; Prostate cancer
    DOI:  https://doi.org/10.1016/j.euo.2019.12.003
  12. Balkan J Med Genet. 2019 Dec;22(2): 5-16
    Staninova-Stojovska M, Matevska-Geskovska N, Panovski M, Angelovska B, Mitrevski N, Ristevski M, Jovanovic R, Dimovski AJ.
      Hereditary factors are assumed to play a role in ~35.0-45.0% of all colorectal cancers (CRCs) with about 5.0-10.0% associated with high penetrant disease-causing mutations in genes correlated to hereditary polyposis (HP) or hereditary non polyposis syndromes (HNPCC). Although inherited germline mutations in mismatch repair (MMR) and the APC genes contribute significantly to CRC, genetic diagnosis cannot yet be obtained in more than 50.0% of familial cases. We present updated data of 107 probands from the Macedonian population with clinically diagnosed HP (n = 41) or HNPCC (n = 66) obtained by next generation sequencing (NGS) with three different gene panels covering the coding, flanking and promoter regions of 114 cancer predisposition genes. Using this approach, we were able to detect deleterious mutations in 65/107 (60.7%) patients, 50.4% of which were in known well-established CRC susceptibility genes and 10.2% in DNA repair genes (DRG). As expected, the highest frequencies of deleterious variants were detected in familial adenomatous polyposis (FAP) and in HNPCC patients with microsatellite instability (MSI) tumors (93.8 and 87.1%, respectively). Variants of unknown significance (VUS) were detected in 24/107 (22.4%) patients, mainly in HNPCC patients with microsatellite stable (MSS) tumors or patients with oligopolyposis. The majority of VUS were also found in DRG genes, indicating the potential role of a doble-strand brake DNA repair pathway deficiency in colorectal cancerogenesis. We could not detect any variant in 18/107 (16.8%) patients, which supports the genetic heterogeneity of hereditary CRC, particularly in HNPCC families with MSS tumors and in families with oligopolyposis.
    Keywords:  Hereditary colorectal cancer (CRC); Macedonian population; mutations
    DOI:  https://doi.org/10.2478/bjmg-2019-0027
  13. JCO Clin Cancer Inform. 2020 Jan;4 1-9
    Del Fiol G, Kohlmann W, Bradshaw RL, Weir CR, Flynn M, Hess R, Schiffman JD, Nanjo C, Kawamoto K.
      PURPOSE: The ubiquitous adoption of electronic health records (EHRs) with family health history (FHH) data provides opportunities for tailoring cancer screening strategies to individuals. We aimed to enable a standards-based clinical decision support (CDS) platform for identifying and managing patients who meet guidelines for genetic evaluation of hereditary cancer.METHODS: The CDS platform (www.opencds.org) was used to implement algorithms based on the 2018 National Comprehensive Cancer Network guidelines for genetic evaluation of hereditary breast/ovarian and colorectal cancer. The platform was designed to be interfaced with different EHR systems via the Health Level Seven International Fast Healthcare Interoperability Resources standard. The platform was integrated with the Epic EHR and evaluated in a pilot study at an academic health care system.
    RESULTS: The CDS platform was executed against a target population of 143,012 patients; 5,245 (3.7%) met criteria for genetic evaluation based on the FHH recorded in the EHR. In a clinical pilot study, genetic counselors attempted to reach out to 71 of the patients. Of those patients, 25 (35%) scheduled an appointment, 10 (14%) declined, 2 (3%) did not need genetic counseling, 7 (10%) said they would consider it in the future, and 27 (38%) were unreachable. To date, 13 (52%) of the scheduled patients completed visits, and 2 (15%) of those were found to have pathogenic variants in cancer predisposition genes.
    CONCLUSION: A standards-based CDS platform integrated with EHR systems is a promising population-based approach to identify patients who are appropriate candidates for genetic evaluation of hereditary cancers.
    DOI:  https://doi.org/10.1200/CCI.19.00120
  14. Sci Rep. 2020 Jan 14. 10(1): 223
    Chirita-Emandi A, Andreescu N, Zimbru CG, Tutac P, Arghirescu S, Serban M, Puiu M.
      The benefit of reporting unsolicited findings in Next Generation Sequencing (NGS) related to cancer genes in children may have implications for family members, nevertheless, could also cause distress. We aimed to retrospectively investigate germline variants in 94 genes implicated in oncogenesis, in patients referred to NGS testing for various rare genetic diseases and reevaluate the utility of reporting different classes of pathogenicity. We used in silico prediction software to classify variants and conducted manual review to examine unsolicited findings frequencies in 145 children with rare diseases, that underwent sequencing - using a 4813 gene panel. The anonymized reanalysis revealed 18250 variants, of which 126 were considered after filtering. Six pathogenic variants (in BRCA1,BMPR1A,FANCA,FANCC,NBN genes) with cancer related phenotype and three unsolicited variants (in BRCA2,PALB2,RAD50 genes) were reported to patients. Additionally, three unsolicited variants in ATR, BLM (in two individuals), and FANCB genes presented potential cancer susceptibility, were not reported to patients. In retrospect, 4.8% (7/145) of individuals in our cohort had unsolicited NGS findings related to cancer. More efforts are needed to create an updatable consensus in reporting variants in cancer predisposing genes, especially for children. Consent process is crucial to inform of both value and risk of additional genetic information.
    DOI:  https://doi.org/10.1038/s41598-019-57080-9