bims-lifras Biomed News
on Li-Fraumeni Syndrome
Issue of 2019‒09‒29
ten papers selected by
Joanna Zawacka-Pankau



  1. Int J Surg Pathol. 2019 Sep 27. 1066896919878804
    Zare SY, Leivo M, Fadare O.
      Pleomorphic myxoid liposarcoma is an extremely rare, clinically aggressive subtype of liposarcoma that has been primarily reported in young patients. In this article, we report a case of a pleomorphic myxoid liposarcoma that presented as a second primary neoplasm in a 34-year-old man with history of primary mediastinal large B-cell lymphoma. During the clinical workup, the patient was diagnosed with a germline TP53 gene mutation and Li-Fraumeni syndrome. The tumor, a 2.9 × 2.3 × 2.0 cm well-demarcated and solid mass, was centered in the anterior chest wall soft tissue. Histologically, most of the tumor displayed abundantly myxoid stroma, low cellularity of mostly bland spindle cells, delicate branching capillaries, and lipoblasts; these areas transitioned to small areas whose features were reminiscent of pleomorphic liposarcoma. As assessed by fluorescence in situ hybridization, the tumor showed no DDIT3 (CHOP) (12q13) rearrangements or MDM2 gene amplification. Clinically, the tumor progressed with multiple recurrences and metastasis to the humerus bone. To our knowledge, this is the first case of pleomorphic myxoid liposarcoma diagnosed in an adult with Li-Fraumeni syndrome.
    Keywords:  Li-Fraumeni; TP53 mutation; liposarcoma; pleomorphic myxoid liposarcoma
    DOI:  https://doi.org/10.1177/1066896919878804
  2. Medicina (Kaunas). 2019 Sep 20. pii: E612. [Epub ahead of print]55(10):
    Daneberga Z, Berzina D, Borosenko V, Krumina Z, Kokaine-Sapovalova L, Gardovskis A, Berga-Svitina E, Gardovskis J, Miklasevics E.
      Background and objectives: Familial adenomatous polyposis is one of the APC-associated polyposis conditions described as genetically predetermined colorectal polyposis syndrome with a variety of symptoms. The purpose of this study was to determine sequence variants of the APC gene in patients with familial adenomatous polyposis (FAP) phenotype and positive or negative family history. Materials and Methods: Eight families with defined criteria of adenomatous polyposis underwent molecular genetic testing. Coding regions and flanking intron regions of the APC gene were analyzed by Sanger sequencing. Results: Eight allelic variants of the APC gene coding sequence were detected. All allelic variants of the APC gene were predicted to be pathogenic based on criteria according to the "Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology" (2015), four of them c.1586_1587insAT, c.2336delT, c.3066_3067insGA, and c.4303_4304insC, were considered novel. Conclusions: The timely molecular genetic analysis of APC germline variants and standardized interpretation of the pathogenicity of novel allelic variants has a high impact on choice for treatment, cancer prevention, and family genetic counseling.
    Keywords:  APC gene; CRC; FAP; germline variants; pathogenic variants
    DOI:  https://doi.org/10.3390/medicina55100612
  3. PLoS One. 2019 ;14(9): e0222709
    Fragoso-Ontiveros V, Velázquez-Aragón JA, Nuñez-Martínez PM, de la Luz Mejía-Aguayo M, Vidal-Millán S, Pedroza-Torres A, Sánchez-Contreras Y, Ramírez-Otero MA, Muñiz-Mendoza R, Domínguez-Ortíz J, Wegman-Ostrosky T, Bargalló-Rocha JE, Gallardo-Rincón D, Reynoso-Noveron N, Arriaga-Canon C, Meneses-García A, Herrera-Montalvo LA, Alvarez-Gomez RM.
      The deletion of exons 9 to 12 of BRCA1 (9-12 del BRCA1) is considered a founder mutation in the Mexican population. We evaluate the usefulness of the target detection of 9-12 del BRCA1 as the first molecular diagnostic strategy in patients with Hereditary Breast and Ovarian Cancer (HBOC). We performed the genetic assessment of 637 patients with suspected HBOC. The region corresponding to the breakpoints for the 9-12 del BRCA1 was amplified by polymerase chain reaction (PCR). An analysis of the clinical data of the carriers and non-carriers was done, searching for characteristics that correlated with the deletion. The 9-12 del BRCA1 was detected in 5% of patients with suspected HBOC (30/637). In patients diagnosed with ovarian cancer, 13 of 30 were 9-12 del BRCA1 carriers, which represents 43%. We found a significant association between the 9-12 del BRCA1 carriers with triple negative breast cancer and high-grade papillary serous ovarian cancer. We concluded that the detection of the 9-12 del BRCA1 is useful as a first molecular diagnostic strategy in the Mexican population. In particular, it shortens the gap in genetic assessment in patients with triple negative breast cancer and ovarian cancer.
    DOI:  https://doi.org/10.1371/journal.pone.0222709
  4. J Genet Couns. 2019 Sep 25.
    Halverson CME, Wessinger BC, Clayton EW, Wiesner GL.
      Patients at risk for hereditary cancer syndromes sometimes decline clinically appropriate genetic testing. The purpose of the current study was to understand what preferences, concerns, and desires informed their refusal as well as their current level of interest in being tested. We interviewed patients who had been seen in a hereditary cancer clinic at Vanderbilt University Medical Center and had declined genetic testing. In all, 21 in-depth, semi-structured qualitative interviews were conducted. Although patients provided many reasons for declining testing, they most often cited their psychosocial state at the time of the initial invitation to participate in genetic testing as their reason for refusal. The majority (67%) said that they either would or had changed their mind about testing if/when their clinicians 'mentioned it again'. Patients at risk for hereditary cancer who refuse testing at the time of genetic counseling may later change their mind. In particular, if a patient declines testing around the time of a major medical diagnosis or intervention, clinicians who are providing ongoing care may want to raise the topic afresh after the patient has had time to recover from initial distress related to diagnosis or treatment. Strategies to prompt clinicians to have these conversations are suggested.
    Keywords:  barriers to genetic testing; decision-making; ethics; genetic counseling; genetic testing; hereditary cancer; psychosocial
    DOI:  https://doi.org/10.1002/jgc4.1174
  5. J Genet Couns. 2019 Sep 25.
    Sawyer L, Creswick H, Lewandowski R, Quillin J.
      In hereditary cancer, multigene panel testing is currently replacing older single-gene approaches. Patients whose tests were previously uninformative could benefit from updated testing. Research suggests that patients desire to be recontacted about updated genetic testing, but few studies have tested the efficacy of recontact efforts. This study investigated the outcomes of a recontact effort in a hereditary cancer clinic and explored the impact of four different recontact letters, randomized in a 2X2 factorial design. Patients who had negative genetic testing for single genes or conditions were mailed letters inviting them to schedule an appointment to discuss updated testing. Patients were randomized to receive one of four letters and each letter emphasized different implications of updated multigene genetic testing: (a) personal medical management implications, (b) implications for family members, (c) both personal and family implications or (d) a control letter. The proportion of patients who arrived for appointments was assessed approximately 7 months after mailing along with associations with patient demographics and type of letter received. Letters were mailed to 586 patients who had initial testing between 2001 and 2015. Most patients were white (78%) and female (97%) with private insurance (65%). At 7 months, 25 patients (4.3%, 95% CI: 2.6% to 5.9%) had arrived for an appointment. Older age was significantly associated with response rate (p = .01), while type of recontact letter was not (p = .54). This study suggests that recontacting patients about updated genetic testing by mail does not yield a large response. It also suggests that personal and/or familial implications do not seem to be significant factors that determine response rate. Nevertheless, results provide meaningful information for cancer clinics about the outcomes of recontact efforts via informational letter.
    Keywords:  breast cancer; communication; decision making; duty to recontact; ethics; genetic testing; informational letter; multigene panel; recontact; updated genetic testing
    DOI:  https://doi.org/10.1002/jgc4.1173
  6. Int Cancer Conf J. 2019 Oct;8(4): 185-189
    Shindo T, Hirobe M, Adachi Y, Sasaki Y, Tokino T, Masumori N.
      In this report, we present familial cases of urothelial carcinoma. To investigate the possibility of hereditary urothelial cancer, we performed semiconductor-based next-generation DNA sequencing. A woman in her 80s who had bladder and left ureteral cancer was hospitalized in Sapporo Shirakaba-dai Hospital due to consciousness disturbance. Radiographic evaluation revealed multiple liver metastases and she died 38 days later. Needle necropsy was done for a left ureteral tumor that continued to her bladder tumor and for liver metastases. At the same time, her son in his 60s, who also had muscle-invasive bladder cancer, was admitted to Sapporo Medical University Hospital and underwent neoadjuvant chemotherapy followed by laparoscopic radical cystectomy. DNA was isolated from both cancers and normal controls in each case and analyzed by massive parallel sequencing of 409 cancer-related genes using a targeted, multiplex PCR approach followed by semiconductor sequencing. Somatic mutations of KMT2C and KMT2D were detected in the mother's tumor. Copy number gains of FGFR1, IkBKB, NFkB2, FGFR2, and FLT3 and copy number losses of IGF2R and TP53 were also found in her cancer. In her son's tumor, somatic mutations of FGFR3 and EP300 were identified. Copy number gains of IkBKE/MAPK1/PARP1, EGFR, BRAF, IRS2, MAPK2K1, IGF1R, and ERBB2 and copy number loss of TP53 were also found in his cancer. There were no germline gene mutations related to familial urothelial carcinoma. Although somatic mutation of TP53 was a common feature, these cases with urothelial carcinoma might not be the result of a heredity syndrome.
    Keywords:  Familial cancer; Next-generation sequencing; Urothelial cancer
    DOI:  https://doi.org/10.1007/s13691-019-00381-7
  7. Pol J Pathol. 2019 ;pii: 37393. [Epub ahead of print]70(2): 127-133
    Heise M, Jarzemski P, Bąk A, Junkiert-Czarnecka A, Pilarska-Deltow M, Haus O.
      We tested the association between HOXB13 G84E (rs138213197) germline mutation and PC risk in Polish men. DNA from 103 consecutive, newly diagnosed patients hospitalised because of PC and DNA from 103 men: volunteers, healthy at the time of the study. The G84E mutation was genotyped using Sanger sequencing. The HOXB13 G84E germline mutation was detected in 2.9% of PC men (3/103) and not detected in any healthy man. Two mutation carriers originated from two of 25 families fulfilling hereditary prostate cancer criteria (HPC) and one mutation carrier from one family among 78 families without HPC (PC frequency: 8% vs. 1.3%, OR = 6.70, p = 0.13). In two of three mutation carriers, disease was detected above 60 years of age. There was a trend for a lower probability of 5-year survival in patients with G84E than in patients without it (66.7% vs. 94.0%, p = 0.08). The HOXB13 G84E germline mutation is associated with increased prostate cancer risk in Polish men, with hereditary form of the disease, and probably with older age at PC onset (> 60 years of age) and shorter survival. However, it is not associated with PSA level, or PC stage or grade at the time of diagnosis.
    Keywords:   HOXB13 G84E mutation; clinical characteristics; hereditary predisposition; prostate cancer
    DOI:  https://doi.org/10.5114/pjp.2019.87103
  8. J Endocr Soc. 2019 Oct 01. 3(10): 1819-1824
    Nicolson NG, Healy JM, Korah R, Carling T.
      Next-generation sequencing has provided genetic profiles of a large number of sporadic adrenocortical carcinomas (ACCs), but the applicability of these results to ACC cases associated with tumor predisposition syndromes is unclear. Although the germline features of these syndromes have been well described, the somatic mutational landscape of the tumors they give rise to is less clear. Our group obtained germline and tumor tissue from a pediatric patient who developed ACC during her first year of life, which was treated successfully. She was subsequently diagnosed with additional tumors later in childhood. Whole exome sequencing analysis was performed followed by in silico protein function prediction, revealing a probably deleterious germline TP53 L265P mutation. The somatic mutational burden was comparable between the index case and a previously published cohort of 40 sporadic cases, but the mutational spectrum was distinct in terms of raw base-change frequency as well as in a trinucleotide context-specific analysis. No canonical somatic genetic drivers of ACC were identified in the reported case, suggesting that syndromic adrenocortical tumors may represent a genetically distinct entity from sporadic tumors.
    Keywords:  Beckwith-Wiedemann; Li-Fraumeni; adrenocortical carcinoma; mutational spectrum; p53
    DOI:  https://doi.org/10.1210/js.2019-00176
  9. World J Gastroenterol. 2019 Sep 14. 25(34): 5082-5096
    Lorenzo D, Rebours V, Maire F, Palazzo M, Gonzalez JM, Vullierme MP, Aubert A, Hammel P, Lévy P, de Mestier L.
      Managing familial pancreatic cancer (FPC) is challenging for gastroenterologists, surgeons and oncologists. High-risk individuals (HRI) for pancreatic cancer (PC) (FPC or with germline mutations) are a heterogeneous group of subjects with a theoretical lifetime cumulative risk of PC over 5%. Screening is mainly based on annual magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS). The goal of screening is to identify early-stage operable cancers or high-risk precancerous lesions (pancreatic intraepithelial neoplasia or intraductal papillary mucinous neoplasms with high-grade dysplasia). In the literature, target lesions are identified in 2%-5% of HRI who undergo screening. EUS appears to provide better identification of small solid lesions (0%-46% of HRI) and chronic-pancreatitis-like parenchymal changes (14%-77% of HRI), while MRI is probably the best modality to identify small cystic lesions (13%-49% of HRI). There are no specific studies in HRI on the use of contrast-enhanced harmonic EUS. EUS can also be used to obtain tissue samples. Nevertheless, there is still limited evidence on the accuracy of imaging procedures used for screening or agreement on which patients to treat. The cost-effectiveness of screening is also unclear. Certain new EUS-related techniques, such as searching for DNA abnormalities or protein markers in pancreatic fluid, appear to be promising.
    Keywords:  Endoscopic ultrasound; Familial pancreatic cancer; Fine-needle aspiration; Intraductal papillary mucinous neoplasm; Pancreatic cancer; Pancreatic cancer screening guidelines; Pancreatic intraepithelial neoplasia
    DOI:  https://doi.org/10.3748/wjg.v25.i34.5082