bims-lifras Biomed News
on Li-Fraumeni Syndrome
Issue of 2019‒10‒06
eight papers selected by
Joanna Zawacka-Pankau



  1. Mol Genet Genomic Med. 2019 Sep 30. e913
    Imbert-Bouteille M, Gauthier-Villars M, Leroux D, Meunier I, Aerts I, Lumbroso-Le Rouic L, Lejeune S, Delnatte C, Abadie C, Pujol P, Houdayer C, Corsini C.
      BACKGROUND: Retinoblastoma (Rb) is a rare intraocular malignant tumor in children with high overall survival. Predisposition to Rb is linked to RB1 germline mutations with high penetrance, but rare RB1 low-penetrance variants are also known. Rb survivors are at risk of second primary malignancies (SPMs), mostly osteosarcoma and soft-tissue sarcoma. Nevertheless, the risk of primary osteosarcoma developing without prior Rb has not been reported in RB1 germline mutation carriers.METHODS: We report a patient in whom osteosarcoma developed at age 17 as a first primary malignancy within a family context of sarcoma.
    RESULTS: Unexpectedly, genetic testing identified a low-penetrance germline mutation in RB1 [NM_000321.2: c.45_76dup; p.(Pro26Leufs*50)]. In eight additional similar cases from published and unpublished reports of families, first primary osteosarcomas and sarcomas mostly developed in RB1 low-penetrance mutation carriers without prior Rb.
    CONCLUSION: We propose that first primary sarcoma and osteosarcoma could be a novel clinical presentation of a RB1-related hereditary predisposition syndrome linked to RB1 low-penetrance germline mutations. In these families, careful screening of primary non-Rb cancer and SPMs is required by maintaining enhanced clinical vigilance. Implementing lifelong periodic whole-body MRI screening might be a complementary strategy for unaffected carrier relatives in these families.
    Keywords:   RB1 ; Osteosarcoma; Sarcoma; cancer screening; low penetrance; whole-body MRI
    DOI:  https://doi.org/10.1002/mgg3.913
  2. Cold Spring Harb Perspect Med. 2019 Sep 30. pii: a036087. [Epub ahead of print]
    Ngeow J, Eng C.
      Germline pathogenic phosphatase and tensin homolog (PTEN) mutations cause PTEN hamartoma tumor syndrome (PHTS), characterized by various benign and malignant tumors of the thyroid, breast, endometrium, and other organs. Patients with PHTS may present with other clinical features such as macrocephaly, intestinal polyposis, cognitive changes, and pathognomonic skin changes. Clinically, deregulation of PTEN function is implicated in other human diseases in addition to many types of human cancer. PTEN is an important phosphatase that counteracts one of the most critical cancer pathways: the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathways. Although PTEN can dephosphorylate lipids and proteins, it also has functions independent of phosphatase activity in normal and pathological states. It is positively and negatively regulated at the transcriptional level as well as posttranslationally by phosphorylation, ubiquitylation, oxidation, and acetylation. Although most of its tumor-suppressor activity is likely to be caused by lipid dephosphorylation at the plasma membrane, PTEN also resides in the cytoplasm and nucleus, and its subcellular distribution is under strict control. In this review, we highlight our current knowledge of PTEN function and recent discoveries in understanding PTEN function regulation and how this can be exploited therapeutically for cancer treatment.
    DOI:  https://doi.org/10.1101/cshperspect.a036087
  3. Cold Spring Harb Perspect Med. 2019 Sep 30. pii: a036590. [Epub ahead of print]
    Forman A, Sotelo J.
      As genetic testing on somatic tumor tissue becomes a more routine part of personalized cancer treatment, a growing opportunity arises to identify hereditary germline variants within those results. These germline results can affect future cancer screening for both patients and their family members. Finding this germline information can be complicated as a result of differences between somatic and germline testing processes, nomenclature, and outcome goals (e.g., treatment impact). The goal of this review is to highlight differences between somatic and germline testing and outline a potential guide to allow for appropriate clinical interpretation of somatic testing results in order to better facilitate genetic counseling referrals and confirmatory germline testing.
    DOI:  https://doi.org/10.1101/cshperspect.a036590
  4. Horm Mol Biol Clin Investig. 2019 Oct 02. pii: /j/hmbci.ahead-of-print/hmbci-2019-0025/hmbci-2019-0025.xml. [Epub ahead of print]
    Knabben L, Imboden S, Mueller MD.
      Background Clinical practices and testing strategies in patients with ovarian cancer differ worldwide. We therefor wanted to give an overview over the current data to advise best clinical practice. Materials and methods A systematic review of the literature was performed with the aim to define which ovarian cancer patients to refer for genetic counseling and how to perform genetic testing. We also discuss the timing of genetic testing and clinical relevance of the BRCA mutation status. Results The germline mutation rate in patients with ovarian cancer is high, independent of family history, age at diagnosis and histology. BRCA mutation carriers with ovarian cancer have improved survival rates. In recurrent ovarian cancer treatment by poly ADP ribose polymerase (PARP) inhibitors improves the disease-free survival in patients with BRCA mutations or homologous recombination deficiency with hazard ratios up to 0.23. But also patients with BRCA wild type show a benefit. The recently published SOLO-1 trial demonstrated a significant benefit for patients with germline BRCA mutations in the first line setting. By tumor testing about 7% additional BRCA mutations can be found but the somatic testing and interpretation of the results remains a challenge. Despite the clinical impact, analysis of our own data and also international publications show insufficient referral rates for genetic counseling. Conclusions Genetic testing in ovarian cancer has a prognostic and predictive value. Referral rates must be improved.
    Keywords:  BRCA mutations; PARP inhibitors; genetic testing; hereditary breast and ovarian cancer syndrome; ovarian cancer
    DOI:  https://doi.org/10.1515/hmbci-2019-0025
  5. Am J Hum Genet. 2019 Oct 03. pii: S0002-9297(19)30343-X. [Epub ahead of print]105(4): 813-821
    Yehia L, Ni Y, Feng F, Seyfi M, Sadler T, Frazier TW, Eng C.
      Germline heterozygous PTEN mutations cause subsets of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS); these subsets are characterized by high risks of breast, thyroid, and other cancers and, in one subset, autism spectrum disorder (ASD). Up to 10% of individuals with PTENMUT CS, CS-like syndrome, or BRRS have germline SDHx (succinate dehydrogenase, mitochondrial complex II) variants, which modify cancer risk. PTEN contributes to metabolic reprogramming; this is a well-established role in a cancer context. Relatedly, SDH sits at the crossroad of the electron transport chain and tricarboxylic acid (TCA) cycle, two central bioenergetic pathways. Intriguingly, PTENMUT and SDHMUT individuals have reduced SDH catalytic activity, resulting in succinate accumulation; this indicates a common genotype-independent biochemical alteration. Here, we conducted a TCA targeted metabolomics study on 511 individuals with CS, CS-like syndrome, or BRRS with various genotypes (PTEN or SDHx, mutant or wild type [WT]) and phenotypes (cancer or ASD) and a series of 187 population controls. We found consistent TCA cycle metabolite alterations in cases with various genotypes and phenotypes compared to controls, and we found unique correlations of individual metabolites with particular genotype-phenotype combinations. Notably, increased isocitrate (p = 1.2 × 10-3), but reduced citrate (p = 5.0 × 10-4), were found to be associated with breast cancer in individuals with PTENMUT/SDHxWT. Conversely, increased lactate was associated with neurodevelopmental disorders regardless of genotype (p = 9.7 × 10-3); this finding was replicated in an independent validation series (n = 171) enriched for idiopathic ASD (PTENWT, p = 5.6 × 10-4). Importantly, we identified fumarate (p = 1.9 × 10-2) as a pertinent metabolite, distinguishing individuals who develop ASD from those who develop cancer. Our observations suggest that TCA cycle metabolite alterations are germane to the pathobiology of PTEN-related CS and BRRS, as well as genotype-independent ASD, with implications for potential biomarker and/or therapeutic value.
    Keywords:  Krebs cycle; PTEN hamartoma tumor syndrome; autism spectrum disorder; hereditary cancer; neurodevelopmental disorders; targeted metabolomics
    DOI:  https://doi.org/10.1016/j.ajhg.2019.09.004
  6. Histopathology. 2019 Sep 28.
    Liu C, Dillon J, Beavis AL, Liu Y, Lombardo K, Fader AN, Hung CF, Wu TC, Vang R, Garcia JE, Xing D.
      AIMS: Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by germline mutations in the fumarate hydratase (FH) gene. In young women, the syndrome often presents with symptomatic uterine leiomyomas, leading to myomectomy or hysterectomy. In this study, we aim to investigate incidence and mutational profile of FH-negative leiomyomas from young patients, thus allowing for early identification and triage of syndromic patients for surveillance.METHODS AND RESULTS: We evaluated 153 cases of uterine leiomyomas from women up to 30 years old for loss of FH expression by tissue microarray (TMA)-based immunohistochemical staining. Mutational analysis of tumors with loss of FH was carried out by polymerase chain reaction (PCR) amplification of 10 exons within the FH gene and subsequent Sanger sequencing. The status of promoter methylation was assessed by bisulfite sequencing. Loss of FH protein expression was detected in 7 (4.6%) of 153 tested uterine leiomyomas from young patients. All FH-negative leiomyomas displayed staghorn vasculature and fibrillary/neuropil-like cytoplasm. We found 6 (86%) of 7 FH-negative tumors detected by immunohistochemistry harbored FH mutations, and of which, 50% contained germline mutations. Particularly, the germline mutational rate in FH gene was 2.0% (3 of 153 cases). Bisulfite sequencing analysis failed to detect promoter methylation in any of the 7 tumors.
    CONCLUSION: Our study showed a relatively high rate of FH germline mutation in FH-negative uterine leiomyomas from patients under 30 years of age. While genetic mutations confer protein expression loss, epigenetic regulation of the FH gene appears to be unrelated to this phenotype.
    Keywords:  Fumarate hydratase; germline mutation; hereditary leiomyomatosis and renal cell cancer (HLRCC); leiomyomas
    DOI:  https://doi.org/10.1111/his.14007
  7. Cancer Biol Med. 2019 Aug;16(3): 556-564
    Hu X, Yang D, Li Y, Li L, Wang Y, Chen P, Xu S, Pu X, Zhu W, Deng P, Ye J, Zhang H, Lizaso A, Liu H, Mao X, Huang H, Chu Q, Hu C.
      Objective: Germline alterations in the breast cancer susceptibility genes type 1 and 2, BRCA1 and BRCA2, predispose individuals to hereditary cancers, including breast, ovarian, prostate, pancreatic, and stomach cancers. Accumulating evidence suggests inherited genetic susceptibility to lung cancer. The present study aimed to survey the prevalence of pathogenic germline BRCA mutations (gBRCAm) and explore the potential association between gBRCAm and disease onset in Chinese advanced non-small cell lung cancer (NSCLC) patients.Methods: A total of 6,220 NSCLC patients were screened using capture-based ultra-deep targeted sequencing to identify patients harboring germline BRCA1/2 mutations.
    Results: Out of the 6,220 patients screened, 1.03% (64/6,220) of the patients harbored the pathogenic g BRCA m , with BRCA2 mutations being the most pr edominant mutations (49/64, 76.5%). Patients who developed NSCLC before 50 years of age were more likely to carry g BRCA m (P = 0.036). Among the patients harboring classic lung cancer driver mutations, those with concurrent g BRCA m were significantly younger than those harboring the wild-type g BRCA (P = 0.029). By contrast, the age of patients with or without concurrent g BRCA m was comparable to those of patients without the driver mutations (P = 0.972). In addition, we identified EGFR-mutant patients with concurrent gBRCAm who showed comparable progression-free survival but significantly longer overall survival (P = 0.002) compared to EGFR-mutant patients with wild-type germline BRCA.
    Conclusions: Overall, our study is the largest survey of the prevalence of pathogenic g BRCA m in advanced Chinese NSCLC patients. Results suggested a lack of association between germline BRCA status and treatment outcome of EGFR-TKI. In addition, results showed a positive correlation between pathogenic g BRCA m and an early onset of NSCLC.
    Keywords:  BRCA1; BRCA2; Germline BRCA mutations; non-small cell lung cancer; prevalence
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2018.0506
  8. Melanoma Res. 2019 Sep 24.
    Li C, Liu T, Tavtigian SV, Boucher K, Kohlmann W, Cannon-Albright L, Grossman D.
      Individuals with multiple primary melanomas have rates of germline CDKN2A pathogenic variants of 3%-18%, and are also frequent carriers of variants in the melanocortin-1 receptor. Few patients with numerous (≥3) primary melanomas have been studied with respect to these or other potential germline pathogenic variants. We investigated 46 patients with ≥3 primary melanomas (3, n = 17; 4, n = 14; 5-14, n = 15) to determine if higher rates of germline pathogenic variants of CDKN2A, MC1R, or other cancer genes could explain their extreme melanoma phenotype. Most (43/46, 93%) patients had variants in MC1R and 11/46 (24%) had CDKN2A pathogenic variants, but only male sex and having two variants in MC1R correlated with increasing number of melanomas. Panel screening of 56 other cancer predisposition genes did not reveal other germline pathogenic variants associated with melanoma (CDK4, BAP1, POT1), although pathogenic variants in TP53, CHEK2, and BRCA2 were present in three separate patients and some patients had variants of uncertain significance. In summary, targeted germline sequencing of patients with ≥3 primary melanomas revealed a high rate of pathogenic variants in CDKN2A and other known cancer genes. Although further investigation of these pathogenic variants and variants of uncertain significance is needed, these results support cancer gene panel testing in individuals diagnosed with ≥3 melanomas.
    DOI:  https://doi.org/10.1097/CMR.0000000000000645