bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒03‒15
seventeen papers selected by
Joanna Zawacka-Pankau

  1. Br J Cancer. 2020 Mar 09.
    Surakhy M, Wallace M, Bond E, Grochola LF, Perez H, Di Giovannantonio M, Zhang P, Malkin D, Carter H, Parise IZS, Zambetti G, Komechen H, Paraizo MM, Pagadala MS, Pinto EM, Lalli E, Figueiredo BC, Bond GL.
      BACKGROUND: Genome-wide association studies (GWASs) have enriched the fields of genomics and drug development. Adrenocortical carcinoma (ACC) is a rare cancer with a bimodal age distribution and inadequate treatment options. Paediatric ACC is frequently associated with TP53 mutations, with particularly high incidence in Southern Brazil due to the TP53 p.R337H (R337H) germline mutation. The heterogeneous risk among carriers suggests other genetic modifiers could exist.METHODS: We analysed clinical, genotype and gene expression data derived from paediatric ACC, R337H carriers, and adult ACC patients. We restricted our analyses to single nucleotide polymorphisms (SNPs) previously identified in GWASs to associate with disease or human traits.
    RESULTS: A SNP, rs971074, in the alcohol dehydrogenase 7 gene significantly and reproducibly associated with allelic differences in ACC age-of-onset in both cohorts. Patients homozygous for the minor allele were diagnosed up to 16 years earlier. This SNP resides in a gene involved in the retinoic acid (RA) pathway and patients with differing levels of RA pathway gene expression in their tumours associate with differential ACC progression.
    CONCLUSIONS: These results identify a novel genetic component to ACC development that resides in the retinoic acid pathway, thereby informing strategies to develop management, preventive and therapeutic treatments for ACC.
  2. Ther Adv Med Oncol. 2020 ;12 1758835919897530
    Neviere Z, De La Motte Rouge T, Floquet A, Johnson A, Berthet P, Joly F.
      Poly(ADP-ribose)polymerase (PARP) inhibitors are targeted therapy for cancers with homologous repair deficiency (HRD). They were first approved for ovarian cancer and have changed current treatment strategies. They have also demonstrated efficacy in HER2-negative metastatic breast cancer and advanced prostate cancer with BRCA1/2 or ATM mutations. Patients with somatic and/or germline BRCA1/2 mutations benefit more from these treatments than other patients. Nowadays, the diagnosis of HRD is largely based on germline genetic testing, which is performed after an in-person genetic counseling session, even for patients without any family history of cancer. However, with the increasing number of PARP inhibitor indications across different tumor types, rapid access to oncogenetic consultations will become a challenge. To meet this demand, tumor genomic testing could be offered at initial diagnosis. Telephone counseling and other referral systems could replace in-person consultations for certain subgroups of patients deemed to have a low risk of harboring a germline mutation. This article reviews international guidelines for genetic counseling testing. We herein propose new care pathways for breast, prostate and ovarian cancers, including tumor genomic testing at initial diagnosis in order to help triage genetic counseling referrals.
    Keywords:  PARP inhibitors; breast cancer; genetic counseling; ovarian cancer; prostate cancer
  3. Cancers (Basel). 2020 Mar 07. pii: E621. [Epub ahead of print]12(3):
    Brondani VB, Montenegro L, Lacombe AMF, Magalhães BM, Nishi MY, Funari MFA, Narcizo AM, Cardoso LC, Siqueira SAC, Zerbini MCN, Denes FT, Latronico AC, Mendonca BB, Almeida MQ, Lerario AM, Soares IC, Fragoso MCBV.
      Adrenocortical cancer is a rare malignant neoplasm associated with a dismal prognosis. Identification of the molecular pathways involved in adrenal tumorigenesis is essential for a better understanding of the disease mechanism and improvement of its treatment. The aim of this study is to define the prevalence of alterations in DNA mismatch repair (MMR) genes in Lynch syndrome among pediatric patients with adrenocortical neoplasia from southern Brazil, where the prevalence of a specific TP53 germline mutation (p.Arg337His) is quite high. Thirty-six pediatric patients were retrospectively evaluated. Immunohistochemistry (IHC) for the MMR enzymes MLH1, MSH2, MSH6, and PMS2, as well as next-generation sequencing (NGS) were performed. For IHC, 36 pediatric tumors were tested. In all of them, the expression of all evaluated MMR proteins was well-preserved. For NGS, 35 patients with pediatric tumor were tested. Three patients (8.57%) with the TP53 p.Arg337His germline mutation presented pathogenic and likely pathogenic variants in the MMR genes (two in MLH1 and one in MSH6). The prevalence of altered MMR genes among pediatric patients was elevated (8.57%) and higher than in colorectal and endometrial cancer cohorts. Pediatric patients with adrenocortical tumors should, thus, be strongly considered as at genetic risk for Lynch syndrome.
    Keywords:  DNA mismatch repair; TP53; adrenal tumor
  4. Haematologica. 2020 Mar 12. pii: haematol.2018.214221. [Epub ahead of print]
    Wu D, Luo X, Feurstein S, Kesserwan C, Mohan S, Pineda-Alvarez DE, Godley LA.
      The broad use of next-generation sequencing and microarray platforms in the research and clinical laboratories has led to an increasing appreciation for the role of germline mutations in genes involved in hematopoiesis and lineage differentiation in contributing to myeloid neoplasms. Despite implementation of the American College of Medical Genetics and Genomics and Association for Molecular Pathology 2015 guidelines for sequence variant interpretation, the number of variants deposited in ClinVar, a genomic repository of genotype and phenotype data, and classified as having uncertain significance or being discordantly classified among clinical laboratories remains elevated and contributes to indeterminate or inconsistent patient care. In 2018, the American Society of Hematology and the Clinical Genome Resource co-sponsored the Myeloid Malignancy Variant Curation Expert Panel to develop rules for classifying gene variants associated with germline predisposition to myeloid neoplasia. Herein, we demonstrate application of our rules developed for the RUNX1 gene to variants in 6 examples to show how we would classify them within the proposed framework.
    Keywords:  RUNX1; germline familial disorders; molecular pathology; variant curation
  5. JCO Glob Oncol. 2020 Mar;6 439-452
    Achatz MI, Caleffi M, Guindalini R, Marques RM, Nogueira-Rodrigues A, Ashton-Prolla P.
      PURPOSE: The objective of this review was to address the barriers limiting access to genetic cancer risk assessment and genetic testing for individuals with suspected hereditary breast and ovarian cancer (HBOC) through a review of the diagnosis and management steps of HBOC.METHODS: A selected panel of Brazilian experts in fields related to HBOC was provided with a series of relevant questions to address before the multiday conference. During this conference, each narrative was discussed and edited by the entire group, through numerous drafts and rounds of discussion, until a consensus was achieved.
    RESULTS: The authors propose specific and realistic recommendations for improving access to early diagnosis, risk management, and cancer care of HBOC specific to Brazil. Moreover, in creating these recommendations, the authors strived to address all the barriers and impediments mentioned in this article.
    CONCLUSION: There is a great need to expand hereditary cancer testing and counseling in Brazil, and changing current policies is essential to accomplishing this goal. Increased knowledge and awareness, together with regulatory actions to increase access to this technology, have the potential to improve patient care and prevention and treatment efforts for patients with cancer across the country.
  6. Am J Med Genet A. 2020 Mar 12.
    Shiohama T, Levman J, Vasung L, Takahashi E.
      PTEN hamartoma tumor syndrome (PHTS) is a spectrum of hereditary cancer syndromes caused by germline mutations in PTEN. PHTS is of high interest, because of its high rate of neurological comorbidities including macrocephaly, autism spectrum disorder, and intellectual dysfunction. Since detailed brain morphology and connectivity of PHTS remain unclear, we quantitatively evaluated brain magnetic resonance imaging (MRI) in PHTS. Sixteen structural T1-weighted and 9 diffusion-weighted MR images from 12 PHTS patients and neurotypical controls were used for structural and high-angular resolution diffusion MRI (HARDI) tractography analyses. Mega-corpus callosum was observed in 75%, polymicrogyria in 33%, periventricular white matter lesions in 83%, and heterotopia in 17% of the PHTS participants. While gyrification index and hemispheric cortical thickness showed no significant differences between the two groups, significantly increased global and regional brain volumes, and regionally thicker cortices in PHTS participants were observed. HARDI tractography showed increased volume and length of callosal pathways, increased volume of the arcuate fasciculi (AF), and increased length of the bilateral inferior longitudinal fasciculi (ILF), bilateral inferior fronto-occipital fasciculi (IFOF), and bilateral uncinate fasciculus. A decrease in fractional anisotropy and an increased in apparent diffusion coefficient values of the AF, left ILF, and left IFOF in PHTS.
    Keywords:   PTEN hamartoma tumor syndrome; HARDI; mega corpus callosum; megalencephaly; structural brain MRI
  7. Urol Case Rep. 2020 May;30 101141
    Yonamine T, Kaname T, Chinen Y, Tamashiro K, Kosuge N, Saito S.
      Hereditary leiomyomatosis and renal cell cancer is a rare, inherited disease caused by mutations in the fumarate hydratase gene. It is characterized by cutaneous leiomyomas, uterine leiomyomas, and/or renal cell cancer. We present the case of a 42-year-old woman with a heterozygous missense mutation (p.M195T) in the fumarate hydratase gene. Although the patient did not have cutaneous leiomyoma and she had no family history of hereditary leiomyomatosis and renal cell cancer, the presence of early onset symptomatic uterine leiomyoma and type 2 papillary renal cell cancer confirmed the diagnosis of hereditary leiomyomatosis and renal cell cancer.
    Keywords:  Fumarate hydratase; Hereditary leiomyomatosis and renal cell cancer (HLRCC); Papillary renal cell cancer; Uterine leiomyoma
  8. Clin Gastroenterol Hepatol. 2020 Mar 05. pii: S1542-3565(20)30268-8. [Epub ahead of print]
    Lucia Jansen AM, Goel A.
      BACKGROUND & AIMS: Somatic mosaicism arises from genetic alterations that occur after the first division of the zygote, so that not in all cells in the body contain the same genetic variants. These variants might contribute to colorectal cancer (CRC) and polyposis syndromes. We performed a systematic review to provide a comprehensive overview of somatic mosaicism in patients with CRC and polyposis syndromes.METHODS: We searched PubMed through March 2019 to identify reports of mosaicism in patients with CRC or polyposis syndromes. We divided the final set of studies into 3 subgroups describing APC mosaicism, mosaicism in other genes associated with susceptibility to CRC susceptibility, and epigenetic mosaicism.
    RESULTS: Of the 232 articles identified in our systematic search, 46 met the criteria for further analysis. Of these, 35 studies described mosaic variants or epimutations in patients with CRC or polyposis syndromes. Nineteen studies described APC mosaicism, comprising a total of 57 patients. Six described mosaicism in genes associated with familial CRC syndromes, such as Lynch and Cowden syndromes. Ten studies described epigenetic mosaicism, sometimes resulting from a germline variant (such as deletion of EPCAM).
    CONCLUSIONS: In a systematic review, we found that many patients with polyposis syndromes have genetic mosaicism, most frequently in APC variants; this information can be used in management of patients. Mosaicism in genes associated with susceptibility to CRC contributes to development of other familial CRC syndromes. Heritable epigenetic mosaicism is likely underestimated and could have a dominant pattern of inheritance. However, the inheritance of primary mosaic epimutations, without an genetic cause, is complex and not fully understood.
    Keywords:  DNA; genomic; mutation; risk factor
  9. BMC Cancer. 2020 Mar 12. 20(1): 204
    Eoh KJ, Kim HM, Lee JY, Kim S, Kim SW, Kim YT, Nam EJ.
      BACKGROUND: Poly (ADP-ribose) polymerase inhibitors targeting BRCA1/2 mutations are available for treating patients with high-grade serous ovarian cancer. These treatments may be more appropriately directed to patients who might respond if the tumor tissue is additionally tested by next-generation sequencing with a multi-gene panel and Sanger sequencing of a blood sample. In this study, we compared the results obtained using the next-generation sequencing multi-gene panel to a known germline BRCA1/2 mutational state determined by conventional Sanger sequencing to evaluate the landscape of somatic mutations in high-grade serous ovarian cancer tumors.METHODS: Cancer tissue from 98 patients with high-grade serous ovarian cancer who underwent Sanger sequencing for germline BRCA1/2 analysis were consecutively analyzed for somatic mutations using a next-generation sequencing 170-gene panel.
    RESULTS: Twenty-four patients (24.5%) showed overall BRCA1/2 mutations. Seven patients (7.1%) contained only somatic BRCA1/2 mutations with wild-type germline BRCA1/2, indicating acquired mutation of BRCA1/2. Three patients (3.1%) showed reversion of germline BRCA1 mutations. Among the 14 patients (14.3%) with both germline and somatic mutations in BRCA1/2, two patients showed different variations of BRCA1/2 mutations. The next-generation sequencing panel test for somatic mutation detected other pathogenic variations including RAD51D and ARID1A, which are possible targets of poly (ADP-ribose) polymerase inhibitors. Compared to conventional Sanger sequencing alone, next-generation sequencing-based tissue analysis increased the number of candidates for poly (ADP-ribose) polymerase inhibitor treatment from 17.3% (17/98) to 26.5% (26/98).
    CONCLUSIONS: Somatic mutation analysis by next-generation sequencing, in addition to germline BRCA1/2 mutation analysis, should become the standard of care for managing women with high-grade serous ovarian cancer to widen the indication of poly (ADP-ribose) polymerase inhibitors.
    Keywords:  BRCA1/2 mutation; High-grade serous ovarian cancer; Next-generation sequencing; Poly (ADP-ribose) polymerase
  10. Medicina (Kaunas). 2020 Mar 10. pii: E119. [Epub ahead of print]56(3):
    Sadzevičienė I, Jarmalaitė S, Besusparis J, Liaugaudienė O, Asadauskienė J, Brasiūnienė B, Kulikienė I, Sabaliauskaitė R.
      Approximately 10% of all breast cancer (BC) cases are familial and caused by inheritance of mutant BRCA1, BRCA2, or some other genes from the same DNA reparation pathway. Genetic counseling in families with cancer history is a powerful means for early cancer detection and active risk reduction through preventive interventions. This is the first report of the rare inherited BRCA2 frameshift-deletion mutation c.3847_3848delGT in one Lithuanian pedigree with the intense familial history of BC. Three BRCA2-positive blood relatives with BC of different biological types were identified in this pedigree with the same type mutation. All three cases were diagnosed with advanced stage ductal carcinoma. Markedly, polymorphic cells and numerous mitoses were identified in BC from the cases. Two patients from the family were diagnosed with the triple negative tumors, while one case had early onset of the hormone positive BC. Despite the variation in clinical and biological presentation of BC, all cases showed a good response to conventional treatment. In conclusion, the strong influence of BRCA2 mutation on the onset of BC of various biological types reveals the complexity of genetic counselling in families with BC history.
    Keywords:  BRCA testing; BRCA2; breast cancer; c.3847_3848delGT
  11. FEBS J. 2020 Mar 09.
    Wong CW, Wang Y, Liu T, Li L, Cheung SKK, Or PM, Cheng AS, Choy KW, Burbach JPH, Bo F, Chang RCC, Chan AM.
      Germline mutation in the PTEN gene is the genetic basis of PTEN hamartoma tumor syndrome with the affected individuals harboring features of autism spectrum disorders. Characterizing a panel of 14 autism-associated PTEN missense mutations revealed reduced protein stability, catalytic activity, and subcellular distribution. Nine out of 14 (64%) PTEN missense mutants had reduced protein expression with most mutations confined to the C2 domain. Selected mutants displayed enhanced polyubiquitination and shortened protein half-life, but that did not appear to involve the polyubiquitination sites at lysine residues at codon 13 or 289. Analyzing their intrinsic lipid phosphatase activities revealed that 78% (11 out of 14) of these mutants had 2- to 10-fold reduction in catalytic activity toward phosphatidylinositol phosphate substrates. Analyzing the subcellular localization of the PTEN missense mutants showed that 64% (9 out of 14) had altered nuclear-to-cytosol ratios with four mutants (G44D, H123Q, E157G, and D326N) showing greater nuclear localization. The E157G mutant was knocked-in to an induced pluripotent stem cell line and recapitulated a similar nuclear targeting preference. Furthermore, iPSCs expressing the E157G mutant were more proliferative at the neural progenitor cell stage but exhibited more extensive dendritic outgrowth. In summary, the combination of biological changes in PTEN is expected to contribute to the behavioral and cellular features of this neurodevelopmental disorder.
    Keywords:  Autism Spectrum Disorders; Macrocephaly; Neurodevelopmental disorders; PTEN; PTEN Hamartoma Tumor Syndrome; iPSC
  12. Cancer Res. 2020 Mar 11. pii: canres.1269.2019. [Epub ahead of print]
    Li GZ, Okada T, Kim YM, Agaram NP, Sanchez-Vega F, Shen Y, Tsubokawa N, Rios J, Martin AS, Dickson MA, Qin LX, Socci ND, Singer S.
      Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) are highly genetically complex soft tissue sarcomas. Up to 50% of patients develop distant metastases, but current systemic therapies have limited efficacy. MFS and UPS have recently been shown to commonly harbor copy number alterations or mutations in the tumor suppressor genes RB1 and TP53. As these alterations have been shown to engender dependence on the oncogenic protein Skp2 for survival of transformed cells in mouse models, we sought to examine its function and potential as a therapeutic target in MFS/UPS. Comparative genomic hybridization (CGH) and next-generation sequencing (NGS) confirmed that a significant fraction of MFS and UPS patient samples (n=94) harbor chromosomal deletions and/or loss-of-function mutations in RB1 and TP53 (88% carry alterations in at least one gene; 60% carry alterations in both). Tissue microarray (TMA) analysis identified a correlation between absent Rb and p53 expression and positive expression of Skp2. Downregulation of Skp2 or treatment with the Skp2-specific inhibitor C1 revealed that Skp2 drives proliferation of patient-derived MFS/UPS cell lines deficient in both Rb and p53 by degrading p21 and p27. Inhibition of Skp2 using the neddylation-activating enzyme (NAE) inhibitor pevonedistat decreased growth of Rb/p53-negative patient-derived cell lines and mouse xenografts. These results demonstrate that loss of both Rb and p53 renders MFS and UPS dependent on Skp2, which can be therapeutically exploited and could provide the basis for promising novel systemic therapies for MFS and UPS.
  13. Hered Cancer Clin Pract. 2020 ;18 5
    Coletta AM, Peterson SK, Gatus LA, Krause KJ, Schembre SM, Gilchrist SC, Arun B, You YN, Rodriguez-Bigas MA, Strong LL, Lu KH, Basen-Engquist K.
      Introduction: Women with pathogenic germline gene variants in BRCA1 and/or BRCA2 are at increased risk of developing ovarian and breast cancer. While surgical and pharmacological approaches are effective for risk-reduction, it is unknown whether lifestyle approaches such as healthful dietary habits, weight management, and physical activity may also contribute to risk-reduction. We conducted a systematic review of evidence related to dietary habits, weight status/change, and physical activity on ovarian and breast cancer risk among women with BRCA1/2 pathogenic variants.Methods: We searched Medline, EMBASE, CENTRAL, PubMed, and up to October 3, 2019. We identified 2775 records and included 21.
    Results: There is limited evidence related to these factors and ovarian cancer risk. For breast cancer risk, evidence suggests higher diet quality, adulthood weight-loss of ≥10 pounds, and activity during adolescence and young-adulthood may be linked with decreased risk. Higher meat intake and higher daily energy intake may be linked with increased risk.
    Conclusions: There is not enough evidence to suggest tailored recommendations for dietary habits or weight management among women with BRCA1/2 pathogenic variants compared to the general population for ovarian and breast cancer risk-reduction, and physical activity recommendations should remain the same.
    Keywords:  BRCA; Breast Cancer; Diet; Ovarian Cancer; Physical activity; Weight
  14. Cancer Epidemiol Biomarkers Prev. 2020 Mar 10. pii: cebp.1113.2019. [Epub ahead of print]
    Mai PL, Sand SR, Saha N, Oberti M, Dolafi T, DiGianni L, Root EJ, Kong X, Bremer RC, Santiago KM, Bojadzieva J, Barley D, Novokmet A, Ketchum KA, Nguyen N, Jacob S, Nichols KE, Kratz CP, Schiffman JD, Evans G, Achatz MI, Strong LC, Garber JE, Ladwa SA, Malkin D, Weitzel JN.
      BACKGROUND: The success of multi-site collaborative research relies on effective data collection, harmonization and aggregation strategies. Data Coordination Centers (DCCs) serve to facilitate the implementation of these strategies. The utility of a DCC can be particularly relevant for research on rare diseases where collaboration from multiple sites to amass large aggregate data sets is essential. However, approaches to building a DCC have been scarcely documented.METHODS AND MATERIALS: The Li-Fraumeni Exploration (LiFE) Consortium's DCC was created using multiple open source packages, including LAM/G Application (Linux, Apache, MySQL, Grails), Extraction-Transformation-Loading (ETL) Pentaho Data Integration Tool, and the Saiku-Mondrian client. This document serves as a resource for building a rare disease DCC for multi-institutional collaborative research.
    RESULTS: The primary scientific and technological objective to create an online central repository into which data from all participating sites could be deposited, harmonized, aggregated, disseminated, and analyzed was completed. The cohort now include 2,193 participants from 6 contributing sites, including 1,354 individuals from families with a pathogenic or likely variant in TP53. Data on cancer diagnoses are also available. Challenges and lessons learned are summarized.
    CONCLUSION: The methods leveraged mitigate challenges associated with successfully developing a DCC's technical infrastructure, data harmonization efforts, communications, and software development and applications.
    IMPACT: These methods can serve as a framework in establishing other collaborative research efforts. Data from the consortium will serve as a great resource for collaborative research to improve knowledge on, and the ability to care for, individuals and families with Li-Fraumeni Syndrome.
  15. Appl Immunohistochem Mol Morphol. 2020 Mar;28(3): e26-e30
    Groth JV, Prabhu S, Periakaruppan R, Ohlander S, Emmadi R, Kothari R.
      Lynch syndrome is an autosomal dominant disorder, caused by an abnormality in DNA mismatch repair genes and characterized by the development of a variety of cancers. Upper urinary tract urothelial carcinoma is well characterized in Lynch syndrome; however, support for the inclusion of bladder urothelial carcinoma is limited, except for MSH2 mutation carriers. Urologic adenocarcinoma has not been documented in Lynch syndrome. Here we report, to the best of our knowledge, the first case of bladder adenocarcinoma, synchronous with uterine endometrioid dedifferentiated endometrioid adenocarcinoma in a patient with Lynch syndrome. We present a 47-year-old woman with an MLH1 gene mutation (G133X 397G>T) who presented with menorrhagia. Eleven family members have this mutation, 6 with carcinoma: 5 colorectal and 1 with a gynecologic primary of unknown type. Colonoscopy and endoscopy were unremarkable. Positron emission and computed tomography revealed a 3 cm anterior dome bladder mass without additional extrauterine disease or uterine connection. She underwent partial cystectomy, laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy. The uterus demonstrated a dedifferentiated endometrioid adenocarcinoma, immunohistochemically positive for vimentin, ER, CK7, MSH2, MSH6, and p53 (focally) and negative for CEA, CDX2, CK20, β-catenin, MLH1, and PMS2. The bladder demonstrated a well-differentiated, enteric-type adenocarcinoma without muscularis propria invasion, positive for CEA, CDX2, CK20, p53, MSH2, and MSH6 and negative for vimentin, ER, CK7, MLH1, and PMS2. Eleven nodes were negative for carcinoma. The morphologic, immunohistochemical, and clinical findings support synchronous bladder adenocarcinoma, enteric type, and uterine dedifferentiated endometrioid adenocarcinoma, in a patient with Lynch syndrome.
  16. J Med Genet. 2020 Mar 09. pii: jmedgenet-2019-106368. [Epub ahead of print]
    Monteiro AN, Bouwman P, Kousholt AN, Eccles DM, Millot GA, Masson JY, Schmidt MK, Sharan SK, Scully R, Wiesmüller L, Couch F, Vreeswijk MPG.
    Keywords:  cancer: breast; clinical genetics; genetic screening/counselling; getting research into practice; molecular genetics