bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒09‒13
nineteen papers selected by
Joanna Zawacka-Pankau
University of Warsaw

  1. Cancers (Basel). 2020 Sep 03. pii: E2503. [Epub ahead of print]12(9):
    Azzollini J, Schiavello E, Buttarelli FR, Clerici CA, Tizzoni L, Vecchi G, Capra F, Pisati F, Biassoni V, Runza L, Carrabba G, Giangaspero F, Massimino M, Pensotti V, Manoukian S.
      Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder caused by mutations in the TP53 gene, predisposing to a wide spectrum of early-onset cancers, including brain tumors. In medulloblastoma patients, the role of TP53 has been extensively investigated, though the prevalence of de novo mutations has not been addressed. We characterized TP53 mutations in a monocentric cohort of consecutive Sonic Hedgehog (SHH)-activated medulloblastoma patients. Germline testing was offered based on tumor p53 immunostaining positivity. Among 24 patients, three (12.5%) showed tumor p53 overexpression, of whom two consented to undergo germline testing and resulted as carriers of TP53 mutations. In the first case, family history was uneventful and the mutation was not found in either of the parents. The second patient, with a family history suggestive of LFS, unexpectedly resulted as a carrier of the mosaic mutation c.742=/C>T p.(Arg248=/Trp). The allele frequency was 26% in normal tissues and 42-77% in tumor specimens. Loss of heterozygosity (LOH) in the tumor was also confirmed. Notably, the mosaic case has been in complete remission for more than one year, while the first patient, as most TP53-mutated medulloblastoma cases from other cohorts, showed a severe and rapidly progressive disease. Our study reported the first TP53 mosaic mutation in medulloblastoma patients and confirmed the importance of germline testing in p53 overexpressed SHH-medulloblastoma, regardless of family history.
    Keywords:  Li-Fraumeni syndrome; TP53; de novo mutation; medulloblastoma; somatic mosaicism
  2. Int J Gynecol Cancer. 2020 Sep 06. pii: ijgc-2020-001556. [Epub ahead of print]
    Pietragalla A, Arcieri M, Marchetti C, Scambia G, Fagotti A.
      Several genes associated with hereditary ovarian cancer have been discovered as a result of the work done with next generation sequencing. It is estimated that approximately 23% of ovarian carcinomas have a hereditary predisposition. The most common hereditary condition is represented by germline mutations in BRCA1 or BRCA2 genes that account for 20-25% of high grade serous ovarian cancer. A number of other hereditary ovarian cancers are associated with different genes, with a crucial role in the DNA damage response pathway, such as the mismatch repair genes in Lynch syndrome, TP53 in Li-Fraumeni syndrome, STK11 in Peutz-Jeghers syndrome, CHEK2, RAD51, BRIP1, and PALB2. The goal of this manuscript is to summarize the published data regarding the molecular pathways involved in the pathogenesis of non-BRCA related hereditary ovarian cancer and to provide a tool that might be useful in discussing risk assessment, genetic testing, prevention strategies, as well as clinical and therapeutic implications for patients with ovarian cancer.
    Keywords:  BRCA1 Protein; BRCA2 Protein; homologous recombination; ovarian cancer
  3. Cancers (Basel). 2020 Sep 07. pii: E2539. [Epub ahead of print]12(9):
    Isidori F, Bozzarelli I, Ferrari S, Godino L, Innella G, Turchetti D, Bonora E.
      Breast cancer (BC) is the second leading cause of death in women. BC patients with family history or clinical features suggestive of inherited predisposition are candidate to genetic testing to determine whether a hereditary cancer syndrome is present. We aimed to identify new predisposing variants in familial BC patients using next-generation sequencing approaches. We performed whole exome sequencing (WES) in first-degree cousin pairs affected by hereditary BC negative at the BRCA1/2 (BReast CAncer gene 1/2) testing. Targeted analysis, for the genes resulting mutated via WES, was performed in additional 131 independent patients with a suspected hereditary predisposition (negative at the BRCA1/2 testing). We retrieved sequencing data for the mutated genes from WES of 197 Italian unrelated controls to perform a case-controls collapsing analysis. We found damaging variants in NPL (N-Acetylneuraminate Pyruvate Lyase), POLN (DNA Polymerase Nu), RASAL1 (RAS Protein Activator Like 1) and ROS1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase), shared by the corresponding cousin pairs. We demonstrated that the splice site alterations identified in NPL and ROS1 (in two different pairs, respectively) impaired the formation of the correct transcripts. Target analysis in additional patients identified novel and rare damaging variants in RASAL1 and ROS1, with a significant allele frequency increase in cases. Moreover, ROS1 achieved a significantly higher proportion of variants among cases in comparison to our internal control database of Italian subjects (p = 0.0401). Our findings indicate that germline variants in ROS1 and RASAL1 might confer susceptibility to BC.
    Keywords:  RASAL1; ROS1; breast cancer; whole exome sequencing
  4. JCO Precis Oncol. 2019 ;pii: PO.19.00103. [Epub ahead of print]3
    Smith ES, Da Cruz Paula A, Cadoo KA, Abu-Rustum NR, Pei X, Brown DN, Ferrando L, Sebastiao APM, Riaz N, Robson ME, Soslow RA, Reis-Filho JS, Mandelker D, Weigelt B.
      PURPOSE: Endometrial cancer (EC) is not considered a component of the hereditary breast and ovarian cancer syndrome but can arise in patients with germline BRCA1/2 (gBRCA1/2) mutations. Biallelic BRCA1/2 alterations are associated with genomic features of homologous recombination DNA repair deficiency (HRD) in cancer. We sought to determine if ECs in gBRCA1/2 mutation carriers harbor biallelic alterations and/or features of HRD.METHODS: Of 769 patients with EC who underwent germline panel testing, 10 pathogenic gBRCA1/2 mutation carriers were identified, and their tumor- and normal-derived DNA was subjected to massively parallel sequencing targeting at least 410 cancer-related genes. Three gBRCA1/2-associated ECs were identified in 232 ECs subjected to whole-exome sequencing by The Cancer Genome Atlas. Somatic mutations, copy number alterations, loss of heterozygosity, microsatellite instability (MSI), and genomic HRD features were assessed.
    RESULTS: Of the 13 patients included who had EC, eight harbored pathogenic gBRCA1 mutations and five harbored gBRCA2 mutations. Eight (100%) and two (40%) ECs harbored biallelic BRCA1 and BRCA2 alterations through loss of heterozygosity of the wild-type allele. All ECs harbored somatic TP53 mutations. One monoallelic/sporadic gBRCA2-associated EC had MLH1 promoter methylation and was MSI high. High large-scale state transition scores, a genomic feature of HRD, were found only in ECs with bi- but not monoallelic BRCA1/2 alterations. The Signature Multivariate Analysis HRD signature Sig3 was enriched in biallelic gBRCA1/2 ECs, and the three ECs from The Cancer Genome Atlas with BRCA1 biallelic alterations subjected to whole-exome sequencing displayed a dominant HRD-related mutational signature 3.
    CONCLUSION: A subset of gBRCA1/2-associated ECs harbor biallelic BRCA1/2 alterations and genomic features of HRD, which may benefit from homologous recombination-directed treatment regimens. ECs in BRCA2 mutation carriers might be sporadic and even MSI high, and may potentially benefit from immune-checkpoint inhibition.
  5. Eur J Cancer Prev. 2020 Sep 03.
    Corso G, Magnoni F.
      Scientific acquisitions concerning the risk of breast cancer in the context of hereditary breast cancer syndrome are constantly evolving: alongside the BRCA1 and BRCA2 mutations, further ones have been identified, also associated with malignancies in different sites. Therefore, management of these clinical conditions requires a multidisciplinary and shared approach, based on constantly updated guidelines. The recent Expert Panel Consensus about management of hereditary breast cancer, chaired by the Society of Surgical Oncology with the American Society of Clinical Oncology and the American Society of Radiation Oncology, based on the evidences obtained by a systematic review of the literature, delineate accurate and novel directions towards an appropriate surgical, radiation, and systemic therapy management of breast cancer patients with specific germline mutations. These recent recommendations will provide to physicians an updated and useful tool in treatment decision making of these patients in daily practice.
  6. Hum Mutat. 2020 Sep 09.
    Vargas-Parra G, Del Valle J, Rofes P, Gausachs M, Stradella A, Moreno-Cabrera JM, Velasco A, Tornero E, Menéndez M, Muñoz X, Iglesias S, López-Doriga A, Azuara D, Campos O, Cuesta R, Darder E, de Cid R, González S, Teulé A, Navarro M, Brunet J, Capellá G, Pineda M, Feliubadaló L, Lázaro C.
      BACKGROUND: CHEK2 variants are associated with intermediate breast cancer risk among other cancers. We aimed to comprehensively describe CHEK2 variants in a Spanish hereditary cancer (HC) cohort and adjust American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for their classification.METHODS: First, three CHEK2 frequent variants were screened in a retrospective Hereditary Breast and Ovarian Cancer cohort of 516 patients. After, the whole CHEK2 coding region was analyzed by next-generation sequencing in 1,848 prospective patients with HC suspicion. We refined ACMG-AMP criteria and applied different combined rules to classify CHEK2 variants and define risk alleles.
    RESULTS: We identified 10 CHEK2 null variants, 6 missense variants with discordant interpretation in ClinVar database, and 35 additional variants of unknown significance. Twelve variants were classified as (likely)-pathogenic; two can also be considered "established risk-alleles" and one as "likely risk-allele". The prevalence of (likely)-pathogenic variants in the HC cohort was 0.8% (1.3% in breast cancer patients and 1.0% in hereditary non-polyposis colorectal cancer patients).
    CONCLUSIONS: Here we provide ACMG adjustment guidelines to classify CHEK2 variants. We hope that this work would be useful for variant classification of other genes with low effect variants. This article is protected by copyright. All rights reserved.
    Keywords:  CHEK2; hereditary cancer; low penetrance; molecular diagnosis; risk allele; variant classification
  7. J Med Genet. 2020 Sep 11. pii: jmedgenet-2020-107270. [Epub ahead of print]
    Crosbie EJ, Ryan NAJ, McVey RJ, Lalloo F, Bowers N, Green K, Woodward ER, Clancy T, Bolton J, Wallace AJ, McMahon RF, Evans DG.
      BACKGROUND: Hereditary causes of ovarian cancer include Lynch syndrome, which is due to inherited pathogenic variants affecting one of the four mismatch repair genes involved in DNA repair. The aim of this study was to evaluate tumour mismatch repair deficiency and prevalence of Lynch syndrome in high-risk women referred to the Manchester Centre for Genomic Medicine with ovarian cancer over the past 20 years.METHODS: Women with ovarian cancer diagnosed before the age of 35 years and/or with a suggestive personal or family history of Lynch syndrome cancers underwent tumour testing with immunohistochemistry for mismatch repair deficiency and, where indicated, MLH1 promoter methylation testing followed by constitutional testing for Lynch syndrome.
    RESULTS: In total, 261 ovarian cancers were tested and 27 (10.3%; 95% CI 6.9% to 14.7%) showed mismatch repair deficiency by immunohistochemistry. Three of 7 with MLH1 loss showed MLH1 promoter hypermethylation, and 18 of the remaining 24 underwent constitutional testing for Lynch syndrome. A further 15 women with mismatch repair proficient tumours underwent constitutional testing because of a strong family history of Lynch syndrome cancers. Pathogenic variants were identified in 9/33 (27%) women who underwent constitutional testing, aged 33-59 years (median 48 years), including one whose tumour was mismatch repair proficient. Most Lynch syndrome tumours were of endometrioid histological subtype.
    CONCLUSIONS: Tumour mismatch repair deficiency identified by immunohistochemistry is a useful prescreen for constitutional testing in women with ovarian cancer with personal or family histories suggestive of Lynch syndrome.
    Keywords:  genetic predisposition to disease; genetic testing; gynecology; surgical oncology
  8. Gynecol Oncol. 2020 Sep 05. pii: S0090-8258(20)33813-0. [Epub ahead of print]
    Wallbillich JJ, Morris RT, Ali-Fehmi R.
      OBJECTIVE: To compare the frequencies of somatic homologous recombination (HR) gene mutations identified in next-generation sequencing (NGS) genomic profiling of uterine serous carcinomas (USCs) and high-grade serous ovarian carcinomas (HGSOCs).METHODS: Data for this analysis was obtained from AACR Project GENIE, a multi-institutional dataset of clinical-grade NGS genomic profiling results for many cancer sites and histologic subtypes, through cBioPortal. Patient/specimen groups used for analysis were USC and HGSOC. 14 HR genes were queried for each group with respect to mutation frequency. For each HR gene, the difference in mutation frequency between the two groups was evaluated using Fisher's exact test. The threshold for statistical significance was p-value < .05.
    RESULTS: In the USC group, there were 457 samples from 451 patients. In the HGSOC group, there were 1537 samples from 1515 patients. The most frequently mutated HR gene for USC was BRCA2 (4.84%) and for HGSOC was BRCA1 (9.07%). Mutation frequency was significantly different between USC and HGSOC for BRCA 1 (p < .001) and BRCA2 (p = .0379). For the 12 non-BRCA HR genes, mutation frequency was not significantly different between USC and HGSOC. The rate of patients with at least one HR gene mutation in their profiled tumor was 16.85% for USC and 25.21% of HGSOC. Most USC patients with a somatic HR mutation had only one HR gene mutated.
    CONCLUSIONS: Somatic HR gene mutations were commonly identified in NGS genomic profiling of USC. Mutation frequencies for non-BRCA HR genes were not significantly different between USC and HGSOC. These data add to the growing rationale for HR deficiency tumor testing and targeting (e.g., with PARP inhibitors) in future clinical trial development for women with USC.
  9. J Assoc Genet Technol. 2020 ;46(3): 135-139
    Donnelly L, Rankins C, Bruno XJ, McKinnon W, Devitt K, Gardner JA.
      OBJECTIVES: Acute myeloid leukemia (AML) with t(8;16)(p11.2;p13.3)/KAT6A-CREBBP is an uncommon subtype of AML accounting for less than 0.5% of AML cases. AML with t(8;16)/KAT6A-CREBBP has characteristic clinical and pathologic features including disseminated intravascular coagulation (DIC), leukemia cutis, hemophagocytosis, monocytic or myelomonocytic differentiation, is frequently associated with therapy-related AML and has a poor prognosis. We present a classic case of AML with t(8;16)/KAT6A-CREBBP occurring in a patient with both a germline NF1 mutation and recent cytotoxic therapy for embryonal rhabdomyosarcoma.
  10. Semin Oncol. 2020 Aug 18. pii: S0093-7754(20)30083-X. [Epub ahead of print]
    t'Kint de Roodenbeke MD, Pondé N, Buisseret L, Piccart M.
      Women diagnosed with breast cancers (BCs) that harbor BRCA1/2 mutations have an increased lifetime risk of a second BC and ovarian cancer. They may benefit from risk-reducing surgical strategies such as mastectomy and salpingo-oophorectomy. In cases of triple negative BC with BRCA mutation, there is some evidence that adding platinum-agents in the neoadjuvant setting improves the pathologic complete response. Lastly, ongoing clinical trials testing the efficacy of PARP inhibitor therapy in tumors with BRCA1/2 mutations will be determinant for future guideline recommendations in selecting best adjuvant treatment options for this specific population. For pre-menopausal patients whose tumors have BRCA mutations and hormone-receptor positive BC, the option of combined bilateral annexectomy and hormonal therapy with aromatase inhibitor can be discussed with high-risk patients. This review summarizes the latest results from clinical trials evaluating treatment and prevention strategies for breast cancers harboring BRCA1/2 mutations and discusses the current management of this patient population.
    Keywords:  BRCA mutations; Breast cancer; Early BC; PARP; PARP inhibitors; TNBC
  11. Fam Cancer. 2020 Sep 12.
    Power R, Leavy C, Nolan C, White N, Clarke R, Cadoo KA, Gallagher DJ, Lowery MA.
      Pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are associated with an increased lifetime risk of pancreatic ductal adenocarcinoma (PDAC), and more recently have been associated with increased risk of biliary tract cancers (BTC). This study assessed the prevalence, age and gender distribution of PDAC/BTC cases in families known to carry a BRCA1/2 PV compared to those of the Irish population. A review of all families referred to a national genetics clinic from 09/11/1997 to 01/06/2018 was performed. The BOADICEA algorithm was used to estimate the probability that an untested relative of a known BRCA1/2 PV carrier with PDAC was a carrier. We reviewed 3252 family pedigrees, 1193 contained a proband who underwent testing for BRCA1/2 based on Manchester score ≥ 15. Among 128 BRCA2 PV-positive families, 27 (21%) contained a 1st/2nd/3rd-degree relative with PDAC, while of 116 BRCA1 PV-positive families, 11 (9%) contained a 1st/2nd/3rd-degree relative with PDAC. Within these 38 families, 25 patients with PDAC had ≥ 50% likelihood of being a BRCA1/2 PV carrier. This cohort had a median age at diagnosis of 55 years (range 33-75), with a mean (55 years) lower than 8364 patients with PDAC identified through the National Cancer Registry of Ireland (71 years, p < 0.0001). Six BRCA2 positive (5%) and 2 BRCA1 positive pedigrees (2%) included an individual with BTC; median age at diagnosis was 65 years (range 33-99). PDAC and BTC are prevalent in Irish families harbouring a BRCA2 PV and are associated with early-onset malignancy. This supports current guidelines recommending universal germline testing for PDAC patients.
    Keywords:  BRCA1; BRCA2; Biliary tract cancer; Genetic testing; Irish population; Pancreatic cancer
  12. BMJ Case Rep. 2020 Sep 07. pii: e236435. [Epub ahead of print]13(9):
    De Silva DL, Winship I.
      The CHEK2 gene is mostly considered as a moderate breast cancer gene with the result that many clinicians have a narrow focus. We present the 10-year journey of a man who had five different cancers and had iterative genetic testing including for Li-Fraumeni syndrome, eventually to discover a pathogenic variant in the CHEK2 gene, possibly explaining his numerous cancers. This diagnosis offered him closure which he had desperately sought for well over a decade. A pathogenic variant in the CHEK2 gene can potentially explain these cancers because of its function as a tumour suppressor gene. Consideration is warranted of what this means for individuals with CHEK2 variants who may develop multiple cancers, their prognosis and whether different treatment modalities such as chemotherapy, radiotherapy or target agents would need modification. We encourage more research into the many faces of the CHEK2 gene and the potential for predisposition to multiple cancers.
    Keywords:  breast cancer; endocrine cancer; genetics; radiotherapy; urological cancer
  13. Acta Neuropathol. 2020 Sep 08.
    Dodgshun AJ, Fukuoka K, Edwards M, Bianchi VJ, Das A, Sexton-Oates A, Larouche V, Vanan MI, Lindhorst S, Yalon M, Mason G, Crooks B, Constantini S, Massimino M, Chiaravalli S, Ramdas J, Mason W, Ashraf S, Farah R, Van Damme A, Opocher E, Hamid SA, Ziegler DS, Samuel D, Cole KA, Tomboc P, Stearns D, Thomas GA, Lossos A, Sullivan M, Hansford JR, Mackay A, Jones C, Jones DTW, Ramaswamy V, Hawkins C, Bouffet E, Tabori U.
      Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled "Wild type-C" or "Paediatric RTK 1". Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.
    Keywords:  DNA methylation; DNA mismatch repair; DNA repair; Glioblastoma; Glioma
  14. Lung Cancer. 2020 Aug 20. pii: S0169-5002(20)30588-2. [Epub ahead of print]148 129-137
    Ang L, Chan CPY, Yau WP, Seow WJ.
      BACKGROUND: Familial risk of lung cancer has been widely studied but the effects of sociodemographic factors and geographical regions are largely unknown.METHODS: PubMed and Embase were systematically searched until 1st October 2019. A total of 84 articles were identified and (19 cohort and 66 case control studies) included in this systematic review and meta-analysis. Pooled summary estimates and 95% confidence intervals were estimated, and the analysis was stratified by sociodemographic factors and geographical regions.
    RESULTS: Geographical regions, sex, age of proband, smoking status, type of first-degree relatives, number of affected relatives, and early onset of lung cancer in affected relatives were significant determinants of familial risk of lung cancer. Higher risk of familial lung cancer was found among Asians as compared to non-Asians, younger individuals (age≤50) as compared with older individuals (age>50), individuals with ≥2 affected relatives as compared with individuals with one affected relative, ever-smokers as compared with never-smokers, Asian females as compared with Western females, and never-smokers in Asia as compared with never-smokers in the West.
    CONCLUSIONS: Familial risk of lung cancer is influenced by both genetic and environmental factors. Future studies should control for environmental factors such as air pollution and environmental tobacco smoke which are prevalent in Asia.
    Keywords:  Family history; Lung cancer; Meta-analysis
  15. J Natl Cancer Inst. 2020 Sep 07. pii: djaa139. [Epub ahead of print]
    Spector LG, Turcotte LM.
  16. Fam Cancer. 2020 Sep 11.
    Kunnackal John G, Das Villgran V, Caufield-Noll C, Giardiello F.
      To perform a systematic assessment of universal Lynch syndrome (LS) screening yield in colorectal cancer (CRC) patients around the world. Universal screening for LS is recommended in all CRC patients. However, the variation in yield of LS screening in the setting of significant global variation in CRC prevalence is unknown. A systematic review of articles in the MEDLINE database was performed to identify studies performing universal screening for LS. All cases with microsatellite instability (MSI-H) or missing one or more proteins on immunohistochemistry (IHC) were considered screening positive. The overall pooled yield of universal LS screening in 97 study arms from 89 identified studies was 11.9% (5649/47545) and the overall pooled percentage of confirmed LS patients was 1.8% (682/37220). LS screening positivity varied significantly based on geographic region (Kruskal Wallis test, p < 0.001) and reported 5-year CRC prevalence in the country (Fisher's exact, p < 0.001). Significant inverse correlation was found between LS screening positivity and 5-year CRC prevalence (Pearson correlation, r =  - 0.56, p < 0.001). The overall yield of LS screening was 15.00% (382/2553) and rate of confirmed LS was 7.7% (113/1475) in LS screening done in patients ≤ 50 years (16 studies). There is significant geographic variation in LS screening positivity with higher yield in countries with lower prevalence of CRC. Our results highlight the importance of universal LS screening in younger patients and low CRC prevalence countries.
    Keywords:  Lynch syndrome; Mismatch repair; Universal screening