bims-lifras 2021-06-27 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–06–27
nine papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

A patient with very early onset FH-deficient renal cell carcinoma diagnosed at age seven.
Recurrent gynandroblastoma of the ovary with germline DICER1 mutation: A case report and review of the literature.
Germline BRCA1 Mutation and Prostate Cancer: Be Careful on Causality.
Pathogenic germline IKZF1 variant alters hematopoietic gene expression profiles.
Germline RUNX1 variation and predisposition to childhood acute lymphoblastic leukemia.
Cohort profile and heritability assessment of familial pancreatic cancer: a nation-wide study.
DAGM: A novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations.
Cutaneous Expression of Familial Cancer Syndromes.
Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms.

Fam Cancer. 2021 Jun 22.

A patient with very early onset FH-deficient renal cell carcinoma diagnosed at age seven.

Rieko Taniguchi, Hideki Muramatsu, Yusuke Okuno, Taro Yoshida, Manabu Wakamatsu, Motoharu Hamada, Chiyoe Shirota, Wataru Sumida, Akinari Hinoki, Takahisa Tainaka, Yoshimitsu Gotoh, Toyonori Tsuzuki, Yukichi Tanaka, Seiji Kojima, Hiroo Uchida, Yoshiyuki Takahashi.

  Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by heterozygous germline variants in the fumarate hydratase (FH) gene and is associated with increased susceptibility to cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma (RCC). HLRCC-associated RCC usually occurs in the middle age, with the median age being 40-44 years. This report describes a seven-year-old (84-month-old) male who developed a large right kidney tumor with multiple cystic lesions that contained enhanced solid components. There was no evidence of distant metastasis. The male patient underwent right nephrectomy and has been recovering well without metastasis or recurrence. Pathological examination revealed that tumor cells with relatively prominent nucleoli and surrounded by halos, were located in a limited area. Immunohistochemical staining was negative for FH. Whole-exome sequencing identified his germline variant in the FH gene and its loss of heterozygosity in the tumor. At nine years (114 months) of age, the male patient showed no recurrence of the tumor. This was the youngest-onset case of HLRCC-associated RCC to date. This report may affect the starting age for future RCC-surveillance programs for patients with HLRCC.

Keywords:  Cystic renal disease; Fumarate hydratase-deficient renal cell carcinoma; HLRCC; Hereditary leiomyomatosis and renal cell cancer

DOI:  https://doi.org/10.1007/s10689-021-00268-8
Gynecol Oncol Rep. 2021 Aug;37 100806

Recurrent gynandroblastoma of the ovary with germline DICER1 mutation: A case report and review of the literature.

Ann Marie Mercier, Kristin K Zorn, Charles M Quick, Laura B Huffman.

  Sex cord-stromal tumors (SCSTs) are ovarian tumors that generally present with an adnexal mass and signs/symptoms of hormone excess. Gynandroblastoma is a rare subtype of SCST with a combination of female and male sex cord differentiation. These tumors typically present in premenopausal women and are diagnosed at early stages with benign clinical courses. Here, we present a rare case of recurrent gynandroblastoma in a premenopausal woman with a DICER1 germline mutation. The patient was referred to our clinic for new symptoms of hormonal imbalance with a history of ovarian juvenile granulosa cell tumor (JGCT). Evaluation revealed a 5x5cm complex right adnexal mass and rising inhibin B. Patient underwent total abdominal hysterectomy with right salpingo-oophorectomy, omentectomy and right pelvic and para-aortic lymphadenectomy. Pathology showed a right ovarian gynandroblastoma. Somatic biallelic mutations in the RNase IIIb domain of DICER1 were identified; a 23-gene germline panel confirmed a germline DICER1 pathogenic variant. Cascade testing of her children documented that both daughters inherited the pathogenic variant. Testing for DICER1 mutations has important implications for individual and familial tumor risk assessment given what we know about DICER1 mutation and increased childhood cancer risk.

Keywords:  DICER1 mutation; Gynandroblastoma; Sex cord-stromal tumor

DOI:  https://doi.org/10.1016/j.gore.2021.100806
Eur Urol Oncol. 2021 Jun 18. pii: S2588-9311(21)00119-X. [Epub ahead of print]

Germline BRCA1 Mutation and Prostate Cancer: Be Careful on Causality.

Alice Boilève, Pernelle Lavaud, Olivier Caron.

DOI: https://doi.org/10.1016/j.euo.2021.06.004
Cold Spring Harb Mol Case Stud. 2021 Jun 23. pii: mcs.a006015. [Epub ahead of print]

Pathogenic germline IKZF1 variant alters hematopoietic gene expression profiles.

Seth A Brodie, Payal Khincha, Neelam Giri, Aaron J Bouk, Mia Steinberg, Jieqiong Dai, Lea Jessop, Frank X Donovan, Settara C Chandrasekharappa, Kelvin de Andrade, Irina Maric, Steven R Ellis, Lisa Mirabello, Blanche Alter, Sharon A Savage.

  IKZF1 encodes Ikaros, a zinc-finger containing transcription factor crucial to the development of the hematopoietic system. Germline pathogenic variants in IKZF1 have been reported in patients with acute lymphocytic leukemia and immunodeficiency syndromes. Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by erythroid hypoplasia, associated with a spectrum of congenital anomalies and an elevated risk of certain cancers. DBA is usually caused by heterozygous pathogenic variants in genes which function in ribosomal biogenesis, however in many cases the genetic etiology is unknown. We identified a germline IKZF1 variant, rs757907717 C>T, in identical twins with DBA-like features and autoimmune gastrointestinal disease. rs757907717 C>T results in a p.R381C amino acid change in the IKZF1 Ik-x isoform (p.R423C on isoform Ik-1), which we show is associated with altered global gene expression and perturbation of transcriptional networks involved in hematopoietic system development. These data suggest that this missense substitution caused a DBA-like syndrome in this family due to alterations in hematopoiesis, including dysregulation of networks essential for normal erythropoiesis and the immune system.

Keywords:  Congenital hypoplastic anemia

DOI:  https://doi.org/10.1101/mcs.a006015
J Clin Invest. 2021 Jun 24. pii: 147898. [Epub ahead of print]

Germline RUNX1 variation and predisposition to childhood acute lymphoblastic leukemia.

Yizhen Li, Wentao Yang, Meenakshi Devidas, Stuart S Winter, Chimene Kesserwan, Wenjian Yang, Kimberly P Dunsmore, Colton Smith, Maoxiang Qian, Xujie Zhao, Ranran Zhang, Julie M Gastier-Foster, Elizabeth A Raetz, William L Carroll, Chunliang Li, Paul P Liu, Karen R Rabin, Takaomi Sanda, Charles G Mullighan, Kim E Nichols, William E Evans, Ching-Hon Pui, Stephen P Hunger, David T Teachey, Mary V Relling, Mignon L Loh, Jun J Yang.

  Genetic alterations in the RUNX1 gene are associated with benign and malignant blood disorders, particularly of megakaryocyte and myeloid lineages. The role of RUNX1 in acute lymphoblastic leukemia (ALL) is less clear, particularly how germline genetic variation influences the predisposition to this type of leukemia. Sequencing 4,836 children with B-ALL and 1,354 cases of T-ALL, we identified 31 and 18 germline RUNX1 variants, respectively. RUNX1 variants in B-ALL consistently showed minimal damaging effects. By contrast, 6 T-ALL-related variants result in drastic loss of RUNX1 activity as a transcription activator in vitro. Ectopic expression of dominant-negative RUNX1 variants in human CD34+ cells repressed differentiation into erythroid, megakaryocytes, and T cells, while promoting myeloid cell development. Chromatin immunoprecipitation sequencing of T-ALL models showed distinctive patterns of RUNX1 binding by variant proteins. Further whole genome sequencing identified JAK3 mutation as the most frequent somatic genomic abnormality in T-ALL with germline RUNX1 variants. Co-introduction of RUNX1 variant and JAK3 mutation in hematopoietic stem and progenitor cells in mice gave rise to T-ALL with early T-cell precursor phenotype. Taken together, these results indicated that RUNX1 is an important predisposition gene for T-ALL and pointed to novel biology of RUNX1-mediated leukemogenesis in the lymphoid lineages.

Keywords:  Genetic variation; Genetics; Leukemias; Oncology

DOI:  https://doi.org/10.1172/JCI147898
Scand J Gastroenterol. 2021 Jun 24. 1-7

Cohort profile and heritability assessment of familial pancreatic cancer: a nation-wide study.

Ming Tan, Klaus Brusgaard, Anne-Marie Gerdes, Michael Bau Mortensen, Sönke Detlefsen, Ove B Schaffalitzky de Muckadell, Maiken Thyregod Joergensen.

   BACKGROUND: Familial Pancreatic Cancer (FPC) is responsible for up to 10% of all cases of pancreatic ductal adenocarcinoma (PDAC). Individuals predisposed for FPC have an estimated lifetime risk of 16-39% of developing PDAC. While heritability of PDAC has been estimated to be 36% in a Nordic twin study, no heritability estimate specific on FPC has been reported.
METHODS: A national cohort of Danish families with predisposition for FPC is currently included in a screening program for PDAC at Odense University Hospital. Family members included in the screening program were interviewed for pedigree data including: cases of PDAC among first-degree relatives (FDRs) and number of affected/unaffected siblings. Heritability for FPC in the predisposed families was assessed by doubling the estimated intra-class correlation coefficient (ICC) from a random intercept logistic model fitted to data on FDRs.
RESULTS: Among families with predisposition for FPC, 83 cases of PDAC were identified. The median age at diagnosis of PDAC was 66 years, and median time from diagnosis to death was 7.6 months. A total of 359 individuals were found as unaffected FDRs of the 83 PDAC cases. The retrieved FDRs included a total of 247 individuals in sibship and 317 individuals in parent-offspring relatedness. We estimated an ICC of 0.25, corresponding to a narrow sense additive heritability estimate of 0.51 in the FPC family cohort.
CONCLUSION: We have established a nation-wide cohort of FPC families to facilitate clinical and genetic studies on FPC. The estimated heritability of 51% prominently underlines a strong genetic background of FPC.

Keywords:  Familial pancreatic cancer; family design; heritability; intra-class correlation

DOI:  https://doi.org/10.1080/00365521.2021.1937697
EBioMedicine. 2021 Jun 19. pii: S2352-3964(21)00239-5. [Epub ahead of print]69 103446

DAGM: A novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations.

Mei Yang, Yanhui Fan, Zhi-Yong Wu, Jin Gu, Zhendong Feng, Qiangzu Zhang, Shunhua Han, Zhonghai Zhang, Xu Li, Yi-Ching Hsueh, Yanxiang Ni, Xiaoling Li, Jieqing Li, Meixia Hu, Weiping Li, Hongfei Gao, Ciqiu Yang, Chunming Zhang, Liulu Zhang, Teng Zhu, Minyi Cheng, Fei Ji, Juntao Xu, Hening Cui, Guangming Tan, Michael Q Zhang, Changhong Liang, Zaiyi Liu, You-Qiang Song, Gang Niu, Kun Wang.

   BACKGROUND: Breast cancers can be divided into HER2-negative and HER2-positive subtypes according to different status of HER2 gene. Despite extensive studies connecting germline mutations with possible risk of HER2-negative breast cancer, the main category of breast cancer, it remains challenging to obtain accurate risk assessment and to understand the potential underlying mechanisms.
METHODS: We developed a novel framework named Damage Assessment of Genomic Mutations (DAGM), which projects rare coding mutations and gene expressions into Activity Profiles of Signalling Pathways (APSPs).
FINDINGS: We characterized and validated DAGM framework at multiple levels. Based on an input of germline rare coding mutations, we obtained the corresponding APSP spectrum to calculate the APSP risk score, which was capable of distinguish HER2-negative from HER2-positive cases. These findings were validated using breast cancer data from TCGA (AUC = 0.7). DAGM revealed that HER2 signalling pathway was up-regulated in germline of HER2-negative patients, and those with high APSP risk scores had exhibited immune suppression. These findings were validated using RNA sequencing, phosphoproteome analysis, and CyTOF. Moreover, using germline mutations, DAGM could evaluate the risk for HER2-negative breast cancer, not only in women carrying BRCA1/2 mutations, but also in those without known disease-associated mutations.
INTERPRETATION: The DAGM can facilitate the screening of subjects at high risk of HER2-negative breast cancer for primary prevention. This study also provides new insights into the potential mechanisms of developing HER2-negative breast cancer. The DAGM has the potential to be applied in the prevention, diagnosis, and treatment of HER2-negative breast cancer.
FUNDING: This work was supported by the National Key Research and Development Program of China (grant no. 2018YFC0910406 and 2018AAA0103302 to CZ); the National Natural Science Foundation of China (grant no. 81202076 and 82072939 to MY, 81871513 to KW); the Guangzhou Science and Technology Program key projects (grant no. 2014J2200007 to MY, 202002030236 to KW); the National Key R&D Program of China (grant no. 2017YFC1309100 to CL); Shenzhen Science and Technology Planning Project (grant no. JCYJ20170817095211560 574 to YN); and the Natural Science Foundation of Guangdong Province (grant no. 2017A030313882 to KW and S2013010012048 to MY); Hefei National Laboratory for Physical Sciences at the Microscale (grant no. KF2020009 to GN); and RGC General Research Fund (grant no. 17114519 to YQS).

Keywords:  Activity profiles of signalling pathways (APSP); Damage assessment of genomic mutations (DAGM); Germline rare coding mutations; HER2 signalling pathway; HER2-negative breast cancer; Immune suppression; Risk assessment

DOI:  https://doi.org/10.1016/j.ebiom.2021.103446
Acta Derm Venereol. 2021 Jun 23.

Cutaneous Expression of Familial Cancer Syndromes.

Anne-Johanne Andersen, Juliane Schierbeck, Anette Bygum, Nieves Puente-Pablo.

  Genodermatoses are inherited syndromes with cutaneous manifestations. Some genodermatoses are associated with malignancy of internal organs and tissues. Early detection of the typical signs of these syndromes is important, because those lesions are a sign of underlying predisposition to extracutaneous neoplasms. The dermatologist has an important role in the early detection of these signs and syndromes, as early detection may affect the clinical course of the disease. We report here the characteristic cutaneous findings that dermatologists should be aware of in order to identify a genodermatosis with a possible associated malignancy. An updated overview of the pathogenesis and clinical findings of these syndromes is provided. Furthermore, surveillance protocols and treatment recommendations are explored.

Keywords:   cutaneous lesions; familial cancer; genetic predisposition; hereditary neoplastic syndromes; skin diseases; genodermatoses

DOI:  https://doi.org/10.2340/00015555-3852
Leukemia. 2021 Jun 25.

Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms.

Jean Pegliasco, Pierre Hirsch, Christophe Marzac, Françoise Isnard, Jean-Côme Meniane, Caroline Deswarte, Philippe Pellet, Céline Lemaitre, Gwendoline Leroy, Graciela Rabadan Moraes, Hélène Guermouche, Barbara Schmaltz-Panneau, Florence Pasquier, Chrystelle Colas, Patrick R Benusiglio, Odile Bera, Jean-Henri Bourhis, Eolia Brissot, Olivier Caron, Samy Chraibi, Pascale Cony-Makhoul, Christine Delaunay-Darivon, Simona Lapusan, Flore Sicre de Fontbrune, Pascal Fuseau, Albert Najman, William Vainchenker, François Delhommeau, Jean-Baptiste Micol, Isabelle Plo, Christine Bellanné-Chantelot.

The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.

DOI: https://doi.org/10.1038/s41375-021-01319-w