bims-lifras Biomed News
on Li-Fraumeni Syndrome
Issue of 2019‒12‒15
twenty-one papers selected by
Joanna Zawacka-Pankau
  1. Difficulties of Management of Multiple Synchronous Bone Tumors in Li-Fraumeni Syndrome.
  2. Metachronous Wilms Tumor, Glioblastoma, and T-cell Leukemia in an Child With Constitutional Mismatch Repair Deficiency syndrome due to Novel Mutation in MSH6 (c.2590G>T).
  3. Germline mutations in Thai patients with nonmucinous epithelial ovarian cancer.
  4. Paraneoplastic opsoclonus-myoclonus syndrome as a presentation of high grade serous ovarian cancer.
  5. Rare BRIP1 missense alleles confer risk for ovarian and breast cancer.
  6. Hereditary Leiomyomatosis and Renal Cell Cancer: Clinical, Molecular, and Screening Features in a Cohort of 185 Affected Individuals.
  7. Germline BLM mutations and metastatic prostate cancer.
  8. Incident colorectal cancer in Lynch syndrome is usually not preceded by compromised quality of colonoscopy.
  9. Prostatic carcinoma with neuroendocrine differentiation harboring the EWSR1-FEV fusion transcript in a man with the WRN G327X germline mutation: A new variant of prostatic carcinoma or a member of the Ewing sarcoma family of tumors?
  10. Low Rates of Genetic Counseling and Testing in Individuals at Risk for Lynch Syndrome reported in the National Health Interview Survey.
  11. Systemic investigations into the molecular features of bilateral breast cancer for diagnostic purposes.
  12. Succinate detection using in vivo 1H-MR spectroscopy identifies germline and somatic SDHx mutations in paragangliomas.
  13. Single nucleotide polymorphisms associated with susceptibility for development of colorectal cancer: Case-control study in a Basque population.
  14. Germline MUTYH Mutation in a Pediatric Cancer Survivor Developing a Secondary Malignancy.
  15. BRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance.
  16. Germline genetic testing for breast cancer: which patients? What genes?
  17. Mapping the Germline and Somatic Mutation Interaction Landscape in Indolent and Aggressive Prostate Cancers.
  18. Novel gene mutation in von Hippel-Lindau disease - a report of two cases.
  19. Angiosarcoma: a review of diagnosis and current treatment.
  20. Familial myeloid malignancies with germline TET2 mutation.
  21. Response to Olaparib in a Patient with Germline BRCA2 Mutation and Breast Cancer Leptomeningeal Carcinomatosis.
  1. Case Rep Orthop. 2019 ;2019 8732089
    Difficulties of Management of Multiple Synchronous Bone Tumors in Li-Fraumeni Syndrome.
    Huby M, Brugières L, Mascard E, Gaspar N, Pannier S, Aurégan JC.
      Li-Fraumeni syndrome is a rare inherited disease characterized by the early onset of multiple primary malignant tumors. Sarcomas account for more than 30% of all malignant tumors occurring at pediatric age. Furthermore, it was shown that the rates of second cancer were higher in childhood cancer survivors. We report the case of a patient with Li-Fraumeni syndrome who was referred to us with three synchronous skeletal tumors. This unique situation led to difficulties for the medical team regarding the diagnosis of malignancy and the surgical treatment to propose. The discovery of multiple lesions in the extension assessment underlines the usefulness of whole-body imaging for the follow-up of patients with germline TP53 mutations. Most recent guidelines now recommend annual whole-body MRI for screening for cancer patients carrying germline TP53. With this report, we aim to share our experience with this rare situation in order to improve care about these specific cases.
    DOI:  https://doi.org/10.1155/2019/8732089
  2. J Pediatr Hematol Oncol. 2019 Dec 04.
    Metachronous Wilms Tumor, Glioblastoma, and T-cell Leukemia in an Child With Constitutional Mismatch Repair Deficiency syndrome due to Novel Mutation in MSH6 (c.2590G>T).
    Citak EC, Sagcan F, Gundugan BD, Bozdogan ST, Yilmaz EB, Avci E, Balci Y, Karabulut YY.
      Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessively inherited childhood cancer predisposition syndrome results from biallelic germline mutations affecting the key DNA mismatch repair gene: MLH1, MSH2, MSH6, or PMS2. CMMRD is associated with a high risk of developing early onset of central nervous system tumors, hematological, and intestinal tract tumors. Clinical manifestations, genetic screening, and cancer prevention strategies are limited. In this report we present a patient with metachronous Wilms tumor, glioblastoma, and acute T-cell lymphoblastic leukemia. He had cutaneous features of neurofibromatosis type 1 (NF1). Molecular testing revealed a novel homozygous mutation in MSH6 (c.2590G>T; p.G864) that has not been reported previously. CMMRD should be considered in patients with cutaneous features similar to NF1 if tumor is found other than expected tumors in NF, early onset cancer, and strong family history of cancer.
    DOI:  https://doi.org/10.1097/MPH.0000000000001687
  3. World J Clin Oncol. 2019 Nov 24. 10(11): 358-368
    Germline mutations in Thai patients with nonmucinous epithelial ovarian cancer.
    Manchana T, Phowthongkum P, Teerapakpinyo C.
      BACKGROUND: Genetic testing is widely recommended for all epithelial ovarian cancer (EOC) patients. However, an increased probability of identifying germline mutations has been reported in selected patients with risk factors such as a family history or personal history of cancer and high-grade serous carcinoma (HGSC) subtype. HGSC has been reported to be the most common subtype of EOC worldwide (approximately 70%). However, this subtype is less prevalent in Thai patients (reported as only 20%). The difference in the distribution of various subtypes of EOC may reflect the incidence of germline mutations in Thai EOC patients.AIM: To evaluate the frequencies of germline mutations in EOC patients and to compare the frequencies in those with and without clinical risk factors for hereditary ovarian cancer.
    METHODS: This cross-sectional study included 112 nonmucinous EOC patients who underwent primary surgery at our tertiary care hospital. Clinical risk factors for hereditary ovarian cancer were defined as follows: Age below 40 years, a significant family history of cancer, synchronous ovarian and endometrial cancer, and HGSC. Comprehensive germline mutations were detected by next-generation sequencing.
    RESULTS: Of a total of 112 patients, 82 (73.2%) patients had ≥ 1 risk factor and 30 (26.8%) patients had no risk factors. Germline mutations were detected in 26 patients: 20 (17.8%) patients had BRCA1/2 mutations, but 6 (5.4%) patients had mutations in other genes, including 1 in MLH1, 1 in MSH2, 1 in RAD51C, 2 in ATM and 1 in CDH1. Germline mutations were only detected in patients with risk factors (26 of 82, 31.7%), not in patients without risk factors (P < 0.001). A significant family history of cancer and HGSC were the only two significant risk factors associated with a higher proportion of germline mutations (56.3% vs 10% for those with and without a history of cancer, respectively, 40.8% vs 9.5% for those with and without HGSC). Germline BRCA mutations were detected in 38.8% of patients with HGSC but in only 1.6% of those with non-HGSC. An age below 40 years, personal history of breast cancer, and synchronous ovarian and endometrial cancer were not significant factors (14.3% vs 23.5%, 33.3% vs 21%, 22.2% vs 22.3%).
    CONCLUSION: Approximately one-third of EOC patients with risk factors had germline mutations. Almost all germline BRCA mutations were found in patients with the HGSC subtype. Selected patients with HGSC and a family history of cancer should be initially considered for genetic analysis in Thailand.
    Keywords:   BRCA mutation; Epithelial ovarian cancer; Germline mutation; Thai
    DOI:  https://doi.org/10.5306/wjco.v10.i11.358
  4. Gynecol Oncol Rep. 2019 Nov;30 100511
    Paraneoplastic opsoclonus-myoclonus syndrome as a presentation of high grade serous ovarian cancer.
    Stewart KT, Lee JS, Stuart G.
      Opsoclonus-myoclonus syndrome (OMS) is a rare paraneoplastic disorder that is most often seen in association with pediatric neuroblastoma, breast cancer, small cell lung cancer, and prostate cancer. There are only three previously documented cases relating paraneoplastic OMS to ovarian cancer. We present a unique case of OMS related to a stage IIIC high grade serous ovarian carcinoma in a patient with germline BRCA2 mutation, with ten years of clinical follow up. This case report is presented to document the rare association of OMS with epithelial ovarian cancer. Additionally, in this case, OMS and epithelial cancer were successfully treated with medical therapy alone. This is the first report to our knowledge to document ten years of clinical follow up in this context, and to report that the association may not be evident at the time of ovarian cancer recurrence.
    Keywords:  BRCA2; High grade serous ovarian cancer; Opsoclonus-myoclonus syndrome; Paraneoplastic syndrome; Recurrence
    DOI:  https://doi.org/10.1016/j.gore.2019.100511
  5. Cancer Res. 2019 Dec 10. pii: canres.1991.2019. [Epub ahead of print]
    Rare BRIP1 missense alleles confer risk for ovarian and breast cancer.
    Moyer CL, Ivanovich J, Gillespie JL, Doberstein R, Radke MR, Richardson ME, Kaufmann SH, Swisher EM, Goodfellow PJ.
      Germline loss-of-function mutations in BRIP1 are associated with ovarian carcinoma and may also contribute to breast cancer risk, particularly among patients who develop disease at an early age. Normal BRIP1 activity is required for DNA interstrand crosslink repair, and is thus central to the maintenance of genome stability. Although pathogenic mutations have been identified in BRIP1, genetic testing more often reveals missense variants for which the impact on molecular function and subsequent roles in cancer risk are uncertain. Next generation sequencing of germline DNA in 2,160 early-onset breast cancer and 1,199 ovarian cancer patients revealed nearly 2% of patients carry a very rare missense variant (MAF<0.0001) in BRIP1. This is 3 fold higher than the frequency of all rare BRIP1 missense alleles reported in more than 60,000 individuals of the general population (p<0.0001, Chi-square). Using CRISPR-Cas9 gene editing technology and rescue assays, we functionally characterized 20 of these missense variants, focusing on the altered protein's ability to repair interstrand crosslink damage. 75% of the characterized variants rendered the protein hypomorph or null. In a clinical cohort of >117,000 breast and ovarian cancer patients who underwent panel testing, the combined odds ratio associated with BRIP1 hypomorph or null missense carriers compared to the general population was 2.30 (95%CI=1.60-3.30, p<0.0001). These findings suggest that novel missense variants within the helicase domain of BRIP1 may confer risk for both breast and ovarian cancer and highlight the importance of functional testing for additional variants.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-1991
  6. Eur Urol Oncol. 2019 Dec 09. pii: S2588-9311(19)30161-0. [Epub ahead of print]
    Hereditary Leiomyomatosis and Renal Cell Cancer: Clinical, Molecular, and Screening Features in a Cohort of 185 Affected Individuals.
    Forde C, Lim DHK, Alwan Y, Burghel G, Butland L, Cleaver R, Dixit A, Evans DG, Hanson H, Lalloo F, Oliveira P, Vialard L, Wallis Y, Maher ER, Woodward ER.
      BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome characterised by predisposition to cutaneous and uterine leiomyomata and renal cell carcinoma (RCC).OBJECTIVE: To define the clinical findings, molecular genetics, and prognosis in a cohort of 69 families with a fumarate hydratase (FH) pathogenic variant and/or clinical features of HLRCC.
    DESIGN, SETTING, AND PARTICIPANTS: Clinical and molecular findings were obtained for 185 individuals from 69 families from four UK regional genetics clinics.
    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Ages at confirmed diagnoses, last dates of follow-up, and molecular results were attained for probands and relatives. To study the effect of potential ascertainment bias, phenotypes of probands and their affected relatives were compared.
    RESULTS AND LIMITATIONS: A germline FH variant (19 novel and 21 known, >50% missense variants) was identified in 68/69 probands and 90 relatives. Cutaneous leiomyomata occurred in 90/185 (48.6%) individuals (mean age 45.9 yr) and uterine leiomyomata in 33/107 (30.8%) females (mean age 35.0 yr). Of 185 individuals, 23 (12.4%) had a confirmed renal tumour, and histopathology where known (n = 18) was variable: seven clear cell RCCs, nine papillary RCCs (six of type 2), one collecting duct tumour, and one tumour with oncocytic cystic morphology. Mean age at symptomatic RCC diagnosis was 44.0 yr and median survival was 21.0 mo. Eighty-one individuals underwent 187 renal imaging surveillance scans; three stage 1 RCCs were detected. Mean survival of individuals diagnosed with stage 1/2 RCC was significantly longer than those diagnosed with stage 3/4 RCC (p = 0.0004).
    CONCLUSIONS: Management of HLRCC is challenging as RCC occurs in a minority of cases but is highly aggressive. This large multicentre series has identified novel features and evidence that renal screening in HLRCC detects early-stage RCCs.
    PATIENT SUMMARY: We show that hereditary leiomyomatosis and renal cell cancer is associated with a 21% lifetime risk of renal cell carcinoma (RCC; 95% confidence interval 8.2-37.1), and renal imaging screening detects early-stage RCC.
    Keywords:  Fumarate hydratase; Hereditary leiomyomatosis and renal cell cancer; Leiomyomata; Renal cell carcinoma
    DOI:  https://doi.org/10.1016/j.euo.2019.11.002
  7. Prostate. 2019 Nov 05.
    Germline BLM mutations and metastatic prostate cancer.
    Ledet EM, Antonarakis ES, Isaacs WB, Lotan TL, Pritchard C, Sartor AO.
      BACKGROUND: Biallelic loss-of-function BLM mutations result in Bloom syndrome: a genetic disorder characterized by growth deficiencies, photosensitivity, and multiple cancer susceptibilities. There are conflicting reports about whether or not heterozygous BLM carriers are at a higher risk of various cancers. Without BLM protein functionality, there is evidence of increased sister chromatid exchange and chromosomal instability.METHODS: Metastatic prostate cancer patients (N = 796) underwent germline genetic testing as part of routine care at three academic centers. Patients with heterozygous BLM mutations were identified. Tumor tissue was analyzed for somatic alterations in those patients who had a germline pathogenic mutation. Control data using a population sample were extracted from the Genome Aggregation Database.
    RESULTS: Heterozygous BLM germline mutations in 5 of 796 patients (prevalence, 0.63%). All mutations were loss-of-function truncating alterations. None of the mutations were BLMAsh . The control population (gnomAD) frequency of pathogenic or likely pathogenic BLM mutations was 0.18% (212 of 116 653). The relative risk (RR) of BLM mutations in metastatic prostate cancer patients was 3.4 (95% CI, 1.42-8.33; P < .0062) compared to gnomAD controls. Tumor DNA sequencing in the BLM carriers showed no evidence of somatic BLM mutations. Interestingly, 3 of 5 BLM germline carriers had bi-allelic BRCA2 inactivation evident on tumor sequencing. One patient had both germline and somatic mutations in BRCA2. Excluding the patient with the germline BRCA2 mutation (BLM prevalence, 4 of 796: 0.50%) still yielded a statistically significant finding vs the gnomAD controls (RR, 2.8; 95% CI, 1.02-7.39; P < .04).
    CONCLUSION: Truncating BLM germline mutations occur at a higher frequency in patients with advanced prostate cancer as compared to control populations. Though no biallelic loss of BLM was no noted in cancers, a surprising number of the BLM germline heterozygotes had pathogenic BRCA2 mutations in their tumor.
    Keywords:  BLM; BRCA2; DNA-repair; germline testing; metastatic prostate cancer
    DOI:  https://doi.org/10.1002/pros.23924
  8. Scand J Gastroenterol. 2019 Dec 12. 1-8
    Incident colorectal cancer in Lynch syndrome is usually not preceded by compromised quality of colonoscopy.
    Lappalainen J, Holmström D, Lepistö A, Saarnio J, Mecklin JP, Seppälä T.
      Background: Lifetime incidence of colorectal cancer (CRC) especially in carriers of MLH1 and MSH2 pathogenic germline variants in mismatch repair genes is high despite ongoing colonoscopy surveillance. Lynch syndrome (LS) registries have been criticized for not reporting colonoscopy quality adequately.Methods: Prospective follow-up data from the national registry were combined with a retrospective assessment of the colonoscopy reports from Helsinki University Hospital electronic patients records in 2004-2019.Results: Total of 366 MLH1, MSH2 and MSH6 carriers underwent 1564 colorectal endoscopies (mean 4.3 per patient, range 1-10) at a single unit. At least one subsequent examination was performed on 336 patients.Bowel preparation was suboptimal (Boston Bowel Preparation Scale 0-2) on either right or left side of the colon in 12.9% of planned surveillance examinations. Caecal intubation rate for full-length colonoscopies was 98.9%. Adenoma detection rate (ADR) was 15.8% in 2004-2014 but substantially increased (21.9%) after introduction of high-definition (HD) technology in 2015-2019 (p = .004; 18.7% across all examinations).CRCs were detected in 23 cases. Nineteen cancers were detected after 977 optimal quality colonoscopies and 4 after 151 compromised quality (BBPS <3 or non-complete examination; p = .16). Advanced neoplasias were not more frequently reported after compromised quality examinations.Conclusion: The majority of LS-associated incident CRCs were detected after colonoscopies with proper bowel preparation and complete examination. There is a considerable time trend towards higher ADR after introducing HD technology of endoscopes. The effect of time trend in ADR to CRC incidence in LS needs to be studied in larger, prospective settings.
    Keywords:  Lynch Syndrome; colonoscopy; colorectal cancer; hereditary non-polyposis colorectal cancer; surveillance colonoscopy
    DOI:  https://doi.org/10.1080/00365521.2019.1698651
  9. Pathol Res Pract. 2019 Nov 22. pii: S0344-0338(19)32252-6. [Epub ahead of print] 152758
    Prostatic carcinoma with neuroendocrine differentiation harboring the EWSR1-FEV fusion transcript in a man with the WRN G327X germline mutation: A new variant of prostatic carcinoma or a member of the Ewing sarcoma family of tumors?
    Febres-Aldana CA, Krishnamurthy K, Delgado R, Kochiyil J, Poppiti R, Medina AM.
      Since the discovery of the TMPRSS2-ERG fusion transcript in prostatic carcinoma (PCa) more than ten years ago, a long list of recurrent genomic rearrangements involving other transcription factors of the ETS family has been described. Fusions of ETS with the EWSR1 partner gene define many members of the Ewing family of tumors, including primitive neuroectodermal tumor (PNET). Although the expression of EWSR1 appears to be necessary for the oncogenic effects of ETS factors, the EWSR1-ETS rearrangement has never been reported in PCa. Herein, we discuss the pathologic diagnosis of a prostatic tumor in a 44 year-old man, recently treated with finasteride, with the EWSR1-FEV fusion (exon 7: exon 2, join in-frame) discovered by RNA-sequencing and fluorescence in situ hybridization. The tumor was morphologically and immunophenotypically equivocal for a Ewing sarcoma/PNET, and most consistent with a PCa with neuroendocrine differentiation. The patient's family history of PCa led to germline mutation testing by next-generation sequencing showing heterozygosity for the WRNG327X mutation. The WRN protein along with ATM, BRCA1, BRCA2, and RAD51 among others, comprise a DNA repair system by homologous recombination, and its alterations are associated with forms of hereditary PCa. We dispute whether the detection of EWSR1-FEV mandates one to diagnose the patient's tumor as a member of the Ewing sarcoma family.
    Keywords:  EWSR1; Fluorescence in situ hybridization; Gene fusion; Next-generation sequencing; Primitive neuroectodermal tumors; Prostate cancer
    DOI:  https://doi.org/10.1016/j.prp.2019.152758
  10. Gastroenterology. 2019 Dec 06. pii: S0016-5085(19)41896-9. [Epub ahead of print]
    Low Rates of Genetic Counseling and Testing in Individuals at Risk for Lynch Syndrome reported in the National Health Interview Survey.
    Faust N, Muller C, Prenner J, Lee SM, Kupfer SS.
      
    Keywords:  Lynch syndrome; genetic testing; hereditary cancer
    DOI:  https://doi.org/10.1053/j.gastro.2019.11.297
  11. Expert Rev Mol Diagn. 2019 Dec 13.
    Systemic investigations into the molecular features of bilateral breast cancer for diagnostic purposes.
    Imyanitov EN, Ekatherina K.
      Introduction: Many breast cancer (BC) patients develop the disease bilaterally. Emergence of two tumors in the same host is unlikely to be a random co-incidence: bilateral BC (biBC) patients are enriched by women who are susceptible to this disease due to genetic or non-genetic factors.Areas covered: Data on molecular pathogenesis and translational aspects of biBC research are summarized.Expert opinion: Studies on concordant and discordant molecular events occurring in paired tumors resemble twin studies, as they help to reveal core components of BC pathogenesis and to analyze interactions between host factors and tumor phenotype. Mutation profiling of biBC pairs suggested that most biBCs are clonally independent malignancies, although some instances of presumably contralateral metastatic spread were shown as well. Many biBCs, especially synchronous ones, demonstrate similarity of essential tumor characteristics, which can be explained by sharing of genetic background, hormonal milieu, metabolic environment and external exposures. biBC is strongly associated with BC-predisposing germ-line mutations, therefore clinical management of biBC patients must include comprehensive genetic testing. Some contralateral metachronous BCs demonstrate high-level microsatellite instability (MSI-H). MSI-H is sometimes observed in radiation- and chemotherapy-induced tumors, therefore it is possible that some second BCs are causally related to the therapy applied for the first cancer. MSI-H tumors are responsive to immune checkpoint blockade, hence MSI-H analysis is advisable for biBC molecular testing. Systematic cataloging of biBC molecular portraits is likely to provide valuable information on fundamental aspects of cancer pathogenesis.
    Keywords:  BRCA1; BRCA2; bilateral breast cancer; hereditary cancer syndromes; molecular portraits; review; twins
    DOI:  https://doi.org/10.1080/14737159.2020.1705157
  12. Eur J Nucl Med Mol Imaging. 2019 Dec 13.
    Succinate detection using in vivo 1H-MR spectroscopy identifies germline and somatic SDHx mutations in paragangliomas.
    Lussey-Lepoutre C, Bellucci A, Burnichon N, Amar L, Buffet A, Drossart T, Fontaine S, Clement O, Benit P, Rustin P, Groussin L, Meatchi T, Gimenez-Roqueplo AP, Tavitian B, Favier J.
      PURPOSE: Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequent in patients with pheochromocytoma and paraganglioma (PPGL). They lead to SDH inactivation, mediating a massive accumulation of succinate, which constitutes a highly specific biomarker of SDHx-mutated tumors when measured in vitro. In a recent pilot study, we showed that magnetic resonance spectroscopy (1H-MRS) optimized for succinate detection (SUCCES) could detect succinate in vivo in both allografted mouse models and PPGL patients. The objective of this study was to prospectively assess the diagnostic performances of 1H-MRS SUCCES sequence for the identification of SDH deficiency in PPGL patients.METHODS: Forty-nine patients presenting with 50 PPGLs were prospectively enrolled in our referral center for 1H-MRS SUCCES. Two observers blinded to the clinical characteristics and genetic status analyzed the presence of a succinate peak and confronted the results to a composite gold standard combining PPGL genetic testing and/or in vitro protein analyses in the tumor.
    RESULTS: A succinate peak was observed in 20 tumors, all of which had proven SDH deficiency using the gold standard (17 patients with germline SDHx mutations, 2 with a somatic SDHD mutation, and 1 with negative SDHB IHC and SDH loss of function). A false negative result was observed in 3 tumors. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 1H-MRS SUCCES were respectively 87%, 100%, 100%, 90%, and 94%.
    CONCLUSIONS: Detection of succinate using 1H-MRS is a highly specific and sensitive hallmark of SDH-deficiency in PPGLs.
    Keywords:  Magnetic resonance spectroscopy; Paraganglioma; Succinate; Succinate dehydrogenase
    DOI:  https://doi.org/10.1007/s00259-019-04633-9
  13. PLoS One. 2019 ;14(12): e0225779
    Single nucleotide polymorphisms associated with susceptibility for development of colorectal cancer: Case-control study in a Basque population.
    Alegria-Lertxundi I, Aguirre C, Bujanda L, Fernández FJ, Polo F, Ordovás JM, Etxezarraga MC, Zabalza I, Larzabal M, Portillo I, de Pancorbo MM, Palencia-Madrid L, Rocandio AM, Arroyo-Izaga M.
      Given the significant population diversity in genetic variation, we aimed to investigate whether single nucleotide polymorphisms (SNPs) previously identified in studies of colorectal cancer (CRC) susceptibility were also relevant to the population of the Basque Country (North of Spain). We genotyped 230 CRC cases and 230 healthy controls for 48 previously reported CRC-susceptibility SNPs. Only the rs6687758 in DUPS10 exhibited a statistically significant association with CRC risk based on the crude analysis. The rs6687758 AG genotype conferred about 2.13-fold increased risk for CRC compared to the AA genotype. Moreover, we found significant associations in cases between smoking status, physical activity, and the rs6687758 SNP. The results of a Genetic Risk Score (GRS) showed that the risk alleles were more frequent in cases than controls and the score was associated with CRC in crude analysis. In conclusion, we have confirmed a CRC susceptibility locus and the existence of associations between modifiable factors and the rs6687758 SNP; moreover, the GRS was associated with CRC. However, further experimental validations are needed to establish the role of this SNP, the function of the gene identified, as well as the contribution of the interaction between environmental factors and this locusto the risk of CRC.
    DOI:  https://doi.org/10.1371/journal.pone.0225779
  14. J Pediatr Hematol Oncol. 2019 Dec 04.
    Germline MUTYH Mutation in a Pediatric Cancer Survivor Developing a Secondary Malignancy.
    Lavergne V, Sabnis A, Tupule A, Davidson PR, Kline C, Matthay K, Nicolaides T, Goldsby R, Braunstein S, Fogh SE, Sneed PK, Menzel P, Nakamura A, DuBois SG, Haas-Kogan DA, Nakamura JL.
      Radiotherapy-induced second malignant neoplasms (SMNs) are a severe late complication in pediatric cancer survivors. Germline mutations in tumor suppressor genes contribute to SMNs; however, the most relevant germline variants mediating susceptibility are not fully defined. The authors performed matched whole-exome sequencing analyses of germline and tumor DNA from 4 pediatric solid tumor survivors who subsequently developed radiation-associated SMNs. Pathogenic and predicted deleterious germline variants were identified for each patient and validated with Sanger sequencing. These germline variants were compared with germline variants in a cohort of 59 pediatric patients diagnosed with primary sarcomas. Pathway analysis was performed to test for similarities in the germline variant profiles between individuals diagnosed with SMNs or primary sarcomas. One index patient was found to have a pathogenic germline monoallelic mutation in the MUTYH gene, which encodes the base excision repair enzyme adenine DNA glycosylase. This specific germline mutation is associated with a form of familial adenomatous polyposis, a new diagnosis in the patient. Germline-level genetic similarity exists between SMN-developing patients and patients developing primary sarcomas, with relevant genes involved in signal transduction and DNA repair mechanisms. The authors identify a germline MUTYH mutation in a pediatric cancer survivor developing an SMN. Germline mutations involving specific pathways such as base excision repair may identify individuals at risk for developing SMNs. The composition of germline variants in individual patients may enable estimates of patient-specific risk for developing SMNs. The authors anticipate that further analyses of germline genomes and epigenomes will reveal diverse genes and mechanisms influencing cancer risk.
    DOI:  https://doi.org/10.1097/MPH.0000000000001668
  15. Nat Commun. 2019 Dec 11. 10(1): 5661
    BRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance.
    Wang Y, Bernhardy AJ, Nacson J, Krais JJ, Tan YF, Nicolas E, Radke MR, Handorf E, Llop-Guevara A, Balmaña J, Swisher EM, Serra V, Peri S, Johnson N.
      BRCA1 mutant carcinomas are sensitive to PARP inhibitor (PARPi) therapy; however, resistance arises. BRCA1 BRCT domain mutant proteins do not fold correctly and are subject to proteasomal degradation, resulting in PARPi sensitivity. In this study, we show that cell lines and patient-derived tumors, with highly disruptive BRCT domain mutations, have readily detectable BRCA1 protein expression, and are able to proliferate in the presence of PARPi. Peptide analyses reveal that chemo-resistant cancers contain residues encoded by BRCA1 intron 15. Mechanistically, cancers with BRCT domain mutations harbor BRCA1 gene breakpoints within or adjacent to Alu elements in intron 15; producing partial gene duplications, inversions and translocations, and terminating transcription prior to the mutation-containing BRCT domain. BRCA1 BRCT domain-deficient protein isoforms avoid mutation-induced proteasomal degradation, support homology-dependent DNA repair, and promote PARPi resistance. Taken together, Alu-mediated BRCA1 gene rearrangements are responsible for generating hypomorphic proteins, and may represent a biomarker of PARPi resistance.
    DOI:  https://doi.org/10.1038/s41467-019-13530-6
  16. Genet Med. 2019 Dec 13.
    Germline genetic testing for breast cancer: which patients? What genes?
    Domchek SM.
      
    DOI:  https://doi.org/10.1038/s41436-019-0721-9
  17. J Oncol. 2019 ;2019 4168784
    Mapping the Germline and Somatic Mutation Interaction Landscape in Indolent and Aggressive Prostate Cancers.
    Mamidi TKK, Wu J, Hicks C.
      Background: A majority of prostate cancers (PCas) are indolent and cause no harm even without treatment. However, a significant proportion of patients with PCa have aggressive tumors that progress rapidly to metastatic disease and are often lethal. PCa develops through somatic mutagenesis, but emerging evidence suggests that germline genetic variation can markedly contribute to tumorigenesis. However, the causal association between genetic susceptibility and tumorigenesis has not been well characterized. The objective of this study was to map the germline and somatic mutation interaction landscape in indolent and aggressive tumors and to discover signatures of mutated genes associated with each type and distinguishing the two types of PCa.Materials and Methods: We integrated germline mutation information from genome-wide association studies (GWAS) with somatic mutation information from The Cancer Genome Atlas (TCGA) using gene expression data from TCGA on indolent and aggressive PCas as the intermediate phenotypes. Germline and somatic mutated genes associated with each type of PCa were functionally characterized using network and pathway analysis.
    Results: We discovered gene signatures containing germline and somatic mutations associated with each type and distinguishing the two types of PCa. We discovered multiple gene regulatory networks and signaling pathways enriched with germline and somatic mutations including axon guidance, RAR, WINT, MSP-RON, STAT3, PI3K, TR/RxR, and molecular mechanisms of cancer, NF-kB, prostate cancer, GP6, androgen, and VEGF signaling pathways for indolent PCa and MSP-RON, axon guidance, RAR, adipogenesis, and molecular mechanisms of cancer and NF-kB signaling pathways for aggressive PCa.
    Conclusion: The investigation revealed germline and somatic mutated genes associated with indolent and aggressive PCas and distinguishing the two types of PCa. The study revealed multiple gene regulatory networks and signaling pathways dysregulated by germline and somatic alterations. Integrative analysis combining germline and somatic mutations is a powerful approach to mapping germline and somatic mutation interaction landscape.
    DOI:  https://doi.org/10.1155/2019/4168784
  18. BMC Med Genet. 2019 Dec 10. 20(1): 194
    Novel gene mutation in von Hippel-Lindau disease - a report of two cases.
    Wang J, Cao W, Wang Z, Zhu H.
      BACKGROUND: Von Hippel-Lindau (VHL) syndrome is a familial autosomal dominant hereditary neoplastic disease caused by mutations in the VHL gene. Approximately 503 kinds of VHL gene mutations have been reported. Different types of mutations manifest various clinical phenotypes, from benign to malignant tumours or coexisting cysts. Thus, a gene mutation test is essential in the diagnosis of VHL syndrome.CASE PRESENTATION: We reported two cases in which a novel mutation site in the c530-536delGACTGGA region in exon 3 of the VHL gene resulted in the development of VHL syndrome. According to the ACMG guidelines, this variation is pathogenic and consistent with autosomal dominant inheritance. This variation has not been reported anywhere in the databases or literature.
    CONCLUSION: This report will add a new mutation site to VHL gene databases. The newly added gene mutation and its associated clinical phenotypes will help improve the accuracy of VHL diagnosis and benefit the community of VHL gene mutation carriers.
    Keywords:  Novel mutation; von Hippel-Lindau gene; von Hippel-Lindau syndrome
    DOI:  https://doi.org/10.1186/s12881-019-0930-8
  19. Am J Cancer Res. 2019 ;9(11): 2303-2313
    Angiosarcoma: a review of diagnosis and current treatment.
    Cao J, Wang J, He C, Fang M.
      Angiosarcoma is a highly malignancy of endothelial tumor and represents 1-2% of all soft tissue sarcomas in humans. The aetiology of angiosarcoma is not clear but there are definite risk factors including chronic lymphoedema, history of radiation, environmental carcinogens and certain familial syndromes. Ultrasound, CT and MR are diagnostic tools, but final diagnosis requires pathological and immunohistochemical confirmation. The conventional options of treatment include surgery, radiotherapy and chemotherapy. Targeted medicines and immunotherapy have been studied as promising treatment of angiosarcoma. The goal of this review is to summarize the current data regarding of angiosarcoma and its clinical presentation and management, providing a useful clinical tool to explore the optimal treatment.
    Keywords:  Angiosarcoma; aetiology; chemotherapy; diagnosis; prognostic factors; targeted therapy
  20. Leukemia. 2019 Dec 11.
    Familial myeloid malignancies with germline TET2 mutation.
    Duployez N, Goursaud L, Fenwarth L, Bories C, Marceau-Renaut A, Boyer T, Fournier E, Nibourel O, Roche-Lestienne C, Huet G, Beauvais D, Berthon C, Cambier N, Quesnel B, Preudhomme C.
      
    DOI:  https://doi.org/10.1038/s41375-019-0675-6
  21. NPJ Breast Cancer. 2019 ;5 46
    Response to Olaparib in a Patient with Germline BRCA2 Mutation and Breast Cancer Leptomeningeal Carcinomatosis.
    Exman P, Mallery RM, Lin NU, Parsons HA.
      Leptomeningeal carcinomatosis (LC) is a devastating complication of metastatic cancer that disproportionately affects patients with advanced breast cancer. Moreover, those with BRCA1/2-mutated disease more often experience leptomeningeal metastasis. Treatment options for LC are limited and often include significant toxicities. PARP inhibitors offer an important potential treatment for patients with BRCA1/2-mutated breast and ovarian cancers, but clinical studies excluded patients with central nervous system (CNS) metastases, including LC. Efficacy data in this area are therefore limited, although a phase I study of olaparib in glioblastoma did show CNS penetration. Here we report a case of a patient with BRCA2-mutated breast cancer and solitary recurrence in the leptomeninges with ongoing complete response to treatment with the PARP inhibitor olaparib. PARP inhibitors may be an important treatment option for patients with BRCA-mutated disease and LC, and warrant further study.
    Keywords:  Breast cancer
    DOI:  https://doi.org/10.1038/s41523-019-0139-1
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