bims-lifras 2021-03-21 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–03–21
sixteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Case Report: Detection of a Novel Germline PALB2 Deletion in a Young Woman With Hereditary Breast Cancer: When the Patient's Phenotype History Doesn't Lie.
Novel and recurrent BRCA1/BRCA2 germline mutations in patients with breast/ovarian cancer: a series from the south of Tunisia.
Identification of known and novel familial cancer genes in Swedish colorectal cancer families.
Recurrence of mucosal melanoma in Li-Fraumeni syndrome: A follow-up of an index case.
Hereditary Neuroendocrine Tumors: Providing Comprehensive Care for Individuals Who Have a Germline Pathogenic Variant Associated With Paragangliomas and Pheochromocytomas.
Functional impact of a germline RET mutation in alveolar rhabdomyosarcoma.
Clinical Characteristics of Patients With Pancreatic Cancer and Pathogenic ATM Alterations.
Familial pancreatic cancer: who should be considered for genetic testing?
Cancer surveillance awareness and practice among families at increased risk for pancreatic adenocarcinoma.
The landscape of the heritable cancer genome.
A distinct APC pathogenic germline variant identified in a southern Thai family with familial adenomatous polyposis.
Whole-exome sequencing reveals potential germline and somatic mutations in 60 malignant ovarian germ cell tumors.
Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in primary hematopoietic cells.
Two Cases of Possible Familial Chronic Myeloid Leukemia in a Family with Extensive History of Cancer.
Germline sequence analysis of RABL3 in a large series of pancreatic ductal adenocarcinoma patients reveals no evidence of deleterious variants.
Liposarcoma in children and young adults: a clinicopathologic and molecular study of 23 cases in one of the largest institutions of China.

Front Oncol. 2021 ;11 602523

Case Report: Detection of a Novel Germline PALB2 Deletion in a Young Woman With Hereditary Breast Cancer: When the Patient's Phenotype History Doesn't Lie.

Carmine De Angelis, Carmela Nardelli, Paola Concolino, Martina Pagliuca, Mario Setaro, Elisa De Paolis, Pietro De Placido, Valeria Forestieri, Giovanni Luca Scaglione, Annalisa Ranieri, Barbara Lombardo, Lucio Pastore, Sabino De Placido, Ettore Capoluongo.

  The partner and localizer of BRCA2 (PALB2) is a major BRCA2 binding partner that participates in homologous recombination repair in response to DNA double-strand breaks. Germline alterations of the PALB2 gene have recently been associated with a high risk of developing breast cancer. We investigated a 37-year-old Caucasian woman with breast cancer and family history of breast cancer using targeted next generation sequencing. A novel heterozygous deletion involving exons 5 and 6 was found in the PALB2 gene, and resulted in the production of a truncated PALB2 protein. These findings expand the mutational spectra of PALB2-associated breast cancer, and may improve the mutation-based screening and genetic diagnosis of breast cancer.

Keywords:  PALB2; breast-cancer risk; deletion; hereditary breast cancer; surveillance

DOI:  https://doi.org/10.3389/fonc.2021.602523
J Transl Med. 2021 Mar 16. 19(1): 108

Novel and recurrent BRCA1/BRCA2 germline mutations in patients with breast/ovarian cancer: a series from the south of Tunisia.

Dorra Ben Ayed-Guerfali, Wala Ben Kridis-Rejab, Nihel Ammous-Boukhris, Wajdi Ayadi, Slim Charfi, Afef Khanfir, Tahia Sellami-Boudawara, Mounir Frikha, Jamel Daoud, Raja Mokdad-Gargouri.

   BACKGROUND: The incidence of breast cancer (BC) and/or ovarian cancer (OC) is increasing in Tunisia especially in young women and mostly those with family history. However, the spectrum of BRCA mutations remains little explored in Tunisian patients in particular in the southern region.
METHODS: We sequenced the entire coding regions of BRCA1and BRCA2 genes using next generation sequencing (NGS) in 134 selected patients with BC and/or OC.
RESULTS: Among the 134 patients, 19 (14.17%) carried pathogenic mutations (10 are BRCA1 mutation carriers and 9 are BRCA2 mutation carriers) that are mainly frameshift index (76.9%). Interestingly, 5 out of the 13 variants (38.46%) were found at least twice in unrelated patients, as the c.1310-1313 delAAGA in BRCA2 and the c.5030_5033 delCTAA that has been identified in 4/98 BC patients and in 3/15 OC patients from unrelated families with strong history of cancer. Besides recurrent mutations, 6 variant (4 in BRCA1 and 2 in BRCA2) were not reported previously. Furthermore, 3 unrelated patients carried the VUS c.9976A > T, (K3326*) in BRCA2 exon 27. BRCA carriers correlated significantly with tumor site (p = 0.029) and TNBC cases (p = 0.008). In the groups of patients aged between 31 and 40, and 41-50 years, BRCA1 mutations occurred more frequently in patients with OC than those with BC, and conversely BRCA2 carriers are mostly affected with BC (p = 0.001, and p = 0.044 respectively).
CONCLUSIONS: The overall frequency of the BRCA germline mutations was 14.17% in patients with high risk of breast/ovarian cancer. We identified recurrent mutations as the c.1310_1313 delAAGA in BRCA2 gene and the c.5030_5033 delCTAA in BRCA1 gene that were found in 4% and 20% of familial BC and OC respectively. Our data will contribute in the implementation of genetic counseling and testing for families with high-risk of BC and/or OC.

Keywords:  BRCA1; BRCA2; Breast cancer; Genetic testing; Germline mutation; Ovarian cancer

DOI:  https://doi.org/10.1186/s12967-021-02772-y
Int J Cancer. 2021 Mar 17.

Identification of known and novel familial cancer genes in Swedish colorectal cancer families.

Hafdis T Helgadottir, Jessada Thutkawkorapin, Anna Rohlin, Margareta Nordling, Kristina Lagerstedt-Robinson, Annika Lindblom.

  Identifying new candidate colorectal cancer (CRC) genes and mutations are important for clinical cancer prevention as well as in cancer care. Genetic counseling is already implemented for known high-risk variants; however, the majority of CRC are of unknown causes. In this study, 110 CRC patients in 55 Swedish families with a strong history of CRC but unknown genetic causes, were analyzed with the aim of identifying novel candidate CRC predisposing genes. Exome sequencing was used to identify rare and high impact variants enriched in the families. No clear pathogenic variants were found in known CRC predisposing genes; however, potential pathogenic variants in novel CRC predisposing genes were identified. Over 3000 variants with minor allele frequency (MAF) <0.01 and CADD>20 were seen aggregating in the CRC families. Of those, 27 variants with MAF<0.001 and CADD>25 were considered high-risk mutations. Interestingly, more than half of the high-risk variants were detected in three families suggesting cumulating contribution of several variants to CRC. In summary, our study shows that despite a strong history of CRC within families, identifying pathogenic variants are challenging. In a small number of families, few rare mutations were shared by affected family members. This could indicate that in the absence of known CRC predisposing genes, a cumulating contribution of mutations leads to CRC observed in these families.

Keywords:  Colorectal cancer; exome-sequencing; germline; hereditary

DOI:  https://doi.org/10.1002/ijc.33567
JAAD Case Rep. 2021 Apr;10 31-33

Recurrence of mucosal melanoma in Li-Fraumeni syndrome: A follow-up of an index case.

Joseph Jebain, Alfredo Siller, Pavandeep Gill, Victor G Prieto, Stephen K Tyring.



Keywords:  LFS, Li-Fraumeni syndrome; Li-Fraumeni syndrome; MRI, magnetic resonance imaging; TP53; chemotherapy; dermato-oncology; melanoma; mucosal melanoma; oncology; radiotherapy

DOI:  https://doi.org/10.1016/j.jdcr.2021.02.008
Clin J Oncol Nurs. 2021 Apr 01. 25(2): 137-141

Hereditary Neuroendocrine Tumors: Providing Comprehensive Care for Individuals Who Have a Germline Pathogenic Variant Associated With Paragangliomas and Pheochromocytomas.

Suzanne M Mahon.

  Both paragangliomas and pheochromocytomas can be associated with germline pathogenic variants. Although these neuroendocrine tumors are relatively rare, the identification of patients and families with germline risk enables the implementation of surveillance programs to decrease the morbidity and mortality associated with these tumors. Individuals with germline risk require lifelong screening, which is implemented as early as age 5 years. In addition to ensuring that surveillance protocols are implemented, nurses provide education about symptoms that require prompt evaluation.

Keywords:  genetic testing; hereditary neuroendocrine tumor; paraganglioma; pheochromocytoma

DOI:  https://doi.org/10.1188/21.CJON.137-141
Cold Spring Harb Mol Case Stud. 2021 Mar 15. pii: mcs.a006049. [Epub ahead of print]

Functional impact of a germline RET mutation in alveolar rhabdomyosarcoma.

Noah E Berlow, Ken Crawford, Carol J Bult, Christopher Noakes, Ido Sloma, Erin R Rudzinski, Charles J Keller.

  Specific mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia type 2A, a hereditary syndrome characterized by tumorigenesis in multiple glandular elements. In rare instances, MEN2A-associated germline RET mutations have also occurred with non-MEN2A associated cancers. One such germline mutant RET mutation occurred concomitantly in a young adult diagnosed with alveolar rhabdomyosarcoma, a pediatric and young adult soft-tissue cancer with a generally poor prognosis. While tumor tissue samples were initially unable to provide a viable cell culture for study, tumor tissues were sequenced for molecular characteristics. Through a hierarchical clustering approach, the index case sample was matched to several genetically-similar cell models, which were transformed to express the same mutant RET as the index case and used to explore potential therapeutic options for mutant RET-bearing alveolar rhabdomyosarcoma. We also determined whether the RET mutation associated with the index case caused synthetic lethality to select clinical agents. From our investigation, we did not identify synthetic lethality associated with the expression of that patient's RET variant, and overall we did not find experimental evidence for the role of RET in rhabdomyosarcoma progression. .

Keywords:  Alveolar rhabdomyosarcoma; Rhabdomyosarcoma

DOI:  https://doi.org/10.1101/mcs.a006049
JNCI Cancer Spectr. 2021 Apr;5(2): pkaa121

Clinical Characteristics of Patients With Pancreatic Cancer and Pathogenic ATM Alterations.

Zain Hannan, Shun Yu, Susan Domchek, Ronac Mamtani, Kim A Reiss.

The Ataxia-Telangiesctasia, mutated (ATM) gene is involved in a number of DNA damage repair pathways and confers an increased risk for pancreatic ductal adenocarcinoma (PDAC). In this retrospective study, we identified and profiled 22 patients with PDAC and a known somatic or germline pathogenic ATM alteration (case patients). These patients were matched 2:1 by age, stage, and year at diagnosis to patients with PDAC without known ATM alterations. The median overall survival in patients with ATM alterations was 40.2 months compared with 15.5 months in the control population (hazard ratio = 0.14, 95% confidence interval = 0.04 to 0.47, 2-sided P = .001). In multivariable analysis, these findings persisted after adjustment for receipt of platinum therapy and Eastern Cooperative Oncology Group status. These findings suggest that pathogenic ATM alterations may be prognostic for improved outcomes in patients with pancreatic cancer.

DOI: https://doi.org/10.1093/jncics/pkaa121
Ir J Med Sci. 2021 Mar 17.

Familial pancreatic cancer: who should be considered for genetic testing?

Kinyas Kartal, Zoe Guan, Rong Tang, Molly Griffin, Yan Wang, Danielle Braun, Alison P Klein, Kevin S Hughes.

   BACKGROUND: Determining how many female patients who underwent breast imaging meet the eligibility criteria for genetic testing for familial pancreatic cancer (FPC).
METHODS: A total of 42,904 patients seen at the Newton-Wellesley Hospital between 2007 and 2009 were retrospectively reviewed. The first four categories were based on pancreatic cancer-associated syndromes: (1) hereditary breast and ovarian cancer (HBOC), (2) Lynch syndrome (LS), (3) familial atypical multiple mole melanoma (FAMMM), and (4) family history of FPC (FH-FPC). PancPRO (5) and MelaPRO (6) categories were based on risk scores from Mendelian risk prediction tool.
RESULTS: Exactly 4445 of 42,904 patients were found to be in at least one of the six risk categories. About 5.7% of patients were classified as being at high risk for HBOC, 2.3% as being at high risk for LS, 0.1% as being at high risk for FAMMM, 0.1% as being at high risk for FH-FPC, 2.7% as being at high risk based on PancPRO, and 0.2% as being at high risk based on MelaPRO.
CONCLUSION: About 10.4% of the female patients were classified as being at high risk for FPC. This finding emphasizes the importance of applying criteria to the general population, in order to ensure that individuals with high risk are identified early.

Keywords:  Genetic testing; High risk individuals; Pancreatic cancer; Pancreatic cancer-associated syndromes; Risk prediction

DOI:  https://doi.org/10.1007/s11845-021-02572-9
Cancer. 2021 Mar 15.

Cancer surveillance awareness and practice among families at increased risk for pancreatic adenocarcinoma.

Jessica N Everett, Gabriela Burgos, Jennifer Chun, Ariele Baptiste, Lauren G Khanna, Paul E Oberstein, Diane M Simeone.

   BACKGROUND: Early detection of pancreatic ductal adenocarcinoma (PDAC) is an important goal for improving survival. Individuals who meet published guidelines for surveillance may be underidentified, and family communication about risk represents a pathway to increasing participation in surveillance. We investigated the uptake of and barriers to surveillance in at-risk relatives of clinic patients.
METHODS: We conducted a retrospective record review of patients with personal or family history of PDAC evaluated over 12 months. The first relative presenting to clinic (proband) reported surveillance status and reasons for nonparticipation for at-risk relatives. Descriptive analyses and Fisher's exact tests were conducted to evaluate differences in surveillance participation.
RESULTS: Among 193 at-risk relatives, 21% were in surveillance. The primary reasons for nonparticipation were lack of awareness (36%) and lack of interest (24%). Neither the sex nor the cancer status of probands impacted surveillance. At-risk relatives with familial pancreatic cancer (FPC) who also carried relevant pathogenic germline variants (PGVs) were more likely to undergo surveillance than those with FPC or PGVs alone (P = .003). Among families with PGVs, 59% of relatives potentially eligible for surveillance had not completed genetic testing.
CONCLUSION: PDAC surveillance is underutilized in high-risk families. Communication interventions to address informational needs and decisional support could improve outcomes.

Keywords:  cancer surveillance; family communication; family history; germline variants; pancreatic cancer

DOI:  https://doi.org/10.1002/cncr.33500
Cancer Res. 2021 Mar 17. pii: canres.3348.2020. [Epub ahead of print]

The landscape of the heritable cancer genome.

Viola Fanfani, Luca Citi, Adrian L Harris, Francesco Pezzella, Giovanni Stracquadanio.

Genome-wide association studies (GWAS) have found hundreds of single nucleotide polymorphisms (SNPs) associated with increased risk of cancer. However, the amount of heritable risk explained by SNPs is limited, leaving most of cancer heritability unexplained. Tumor sequencing projects have shown that causal mutations are enriched in genic regions. We hypothesized that SNPs located in protein coding genes and nearby regulatory regions could explain a significant proportion of the heritable risk of cancer. To perform gene-level heritability analysis, we developed a new method, called Bayesian Gene HERitability Analysis (BAGHERA), to estimate the heritability explained by all genotyped SNPs and by those located in genic regions using GWAS summary statistics. BAGHERA was specifically designed for low heritability traits such as cancer and provides robust heritability estimates under different genetic architectures. BAGHERA-based analysis of 38 cancers reported in the UK Biobank showed that SNPs explain at least 10% of the heritable risk for 14 of them, including late onset malignancies. We then identified 1,146 genes, called cancer heritability genes (CHGs), explaining a significant proportion of cancer heritability. CHGs were involved in hallmark processes controlling the transformation from normal to cancerous cells. Importantly, 60 of them also harbored somatic driver mutations, and 27 are tumor suppressors. Our results suggest that germline and somatic mutation information could be exploited to identify subgroups of individuals at higher risk of cancer in the broader population and could prove useful to establish strategies for early detection and cancer surveillance.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-3348
BMC Med Genomics. 2021 Mar 19. 14(1): 87

A distinct APC pathogenic germline variant identified in a southern Thai family with familial adenomatous polyposis.

Worrawit Wanitsuwan, Sukanya Vijasika, Pichai Jirarattanasopa, Sukanya Horpaopan.

   BACKGROUND: Familial adenomatous polyposis (FAP) is caused by pathogenic germline variants in the APC gene. To date, multiple pathogenic variants in coding regions, splice sites, and deep intronic regions have been revealed. However, there are still pathogenic variants that remain unidentified.
METHODS: Twenty-nine primer pairs flanking exons 2-16 (i.e., coding exons 1-15) of APC and their exon-intron junctions were used for germline pathogenic variant screening in Southern Thai patients with familial adenomatous polyposis (FAP). Transcription analysis was performed to confirm the pathogenicity of a splice site deletion of intron 10. Family members were interviewed for clinical histories. Blood samples were collected from 18 family members for a segregation study. Subsequently, clinical data of affected members were collected from the hospital databases.
RESULTS: We found a distinct heterozygous 16-bp deletion at the splice donor site of intron 10 leading to a skipping of exon 10 which was confirmed by transcript analysis (APC: c 1312 + 4_1312 + 19del, r.934_1312del). Predictive testing for the pathogenic APC variant in 18 of the proband's family members (ten healthy and eight affected) from three generations showed the same heterozygous germline pathogenic variant in eight affected adult members (15-62 years old) and two children (7 and 10 years old). Seven of the ten carriers of the disease-causing variant had undergone colonoscopy, and colonic polyps were found in all cases, which confirmed the segregation of the inherited pathogenic variant. The phenotypic spectrum was found to vary within the family; and some affected family members exhibited extracolonic manifestations.
CONCLUSIONS: To our knowledge, the pathogenic APC variant, c.1312 + 4_1312 + 19del, r.934_1312del, has not previously been reported. This study is one of the few reports describing the phenotypic consequences of a pathogenic APC variant in a high number of affected family members.

Keywords:  APC; Exon skipping; Familial adenomatous polyposis; Splicing deletion

DOI:  https://doi.org/10.1186/s12920-021-00933-y
Biol Reprod. 2021 Mar 19. pii: ioab052. [Epub ahead of print]

Whole-exome sequencing reveals potential germline and somatic mutations in 60 malignant ovarian germ cell tumors.

Juan Chen, Yan Li, Jianlei Wu, Yakun Liu, Shan Kang.

   BACKGROUND: Malignant ovarian germ cell tumors (MOGCTs) are rare and heterogeneous ovary tumors. We aimed to identify potential germline mutations and somatic mutations in MOGCTs by whole-exome sequencing.
METHODS: The peripheral blood and tumor samples from these patients were used to identify germline mutations and somatic mutations, respectively. For those genes corresponding to copy number alterations (CNA) deletion and duplication region, functional annotation of was performed. Immunohistochemistry was performed to evaluate the expression of mutated genes corresponding to CNA deletion region.
RESULTS: In peripheral blood, copy number loss and gain were mostly found in yolk sac tumors (YST). Moreover, POU5F1 was the most significant mutated gene with mutation frequency > 10% in both CNA deletion and duplication region. In addition, strong cytoplasm staining of POU5F1 (corresponding to CNA deletion region) was found in 2 YST and nuclear staining in 2 dysgerminomas (DG) tumor samples. Genes corresponding to CNA deletion region were significantly enriched in the signaling pathway of regulating pluripotency of stem cells. In addition, genes corresponding to CNA duplication region were significantly enriched in the signaling pathways of RIG-I-like receptor, Toll-like receptor, NF-kappa B and Jak-STAT. KRT4, RPL14, PCSK6, PABPC3 and SARM1 mutations were detected in both peripheral blood and tumor samples.
CONCLUSIONS: Identification of potential germline mutations and somatic mutations in MOGCTs may provide a new field in understanding the genetic feature of the rare biological tumor type in the ovary.

Keywords:  functional analysis; germline mutation; malignant ovarian germ cell tumors; somatic mutation; tumor driver mutation; whole-exome sequencing

DOI:  https://doi.org/10.1093/biolre/ioab052
Leukemia. 2021 Mar 17.

Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in primary hematopoietic cells.

Melvin E Thomas, Sherif Abdelhamed, Ryan Hiltenbrand, Jason R Schwartz, Sadie Miki Sakurada, Michael Walsh, Guangchun Song, Jing Ma, Shondra M Pruett-Miller, Jeffery M Klco.

Pediatric myelodysplastic syndromes (MDS) are a heterogeneous disease group associated with impaired hematopoiesis, bone marrow hypocellularity, and frequently have deletions involving chromosome 7 (monosomy 7). We and others recently identified heterozygous germline mutations in SAMD9 and SAMD9L in children with monosomy 7 and MDS. We previously demonstrated an antiproliferative effect of these gene products in non-hematopoietic cells, which was exacerbated by their patient-associated mutations. Here, we used a lentiviral overexpression approach to assess the functional impact and underlying cellular processes of wild-type and mutant SAMD9 or SAMD9L in primary mouse or human hematopoietic stem and progenitor cells (HSPC). Using a combination of protein interactome analyses, transcriptional profiling, and functional validation, we show that SAMD9 and SAMD9L are multifunctional proteins that cause profound alterations in cell cycle, cell proliferation, and protein translation in HSPCs. Importantly, our molecular and functional studies also demonstrated that expression of these genes and their mutations leads to a cellular environment that promotes DNA damage repair defects and ultimately apoptosis in hematopoietic cells. This study provides novel functional insights into SAMD9 and SAMD9L and how their mutations can potentially alter hematopoietic function and lead to bone marrow hypocellularity, a hallmark of pediatric MDS.

DOI: https://doi.org/10.1038/s41375-021-01212-6
Acta Haematol. 2021 Mar 18. 1-6

Two Cases of Possible Familial Chronic Myeloid Leukemia in a Family with Extensive History of Cancer.

Marisa J L Aitken, Christopher B Benton, Ghayas C Issa, Koji Sasaki, Musa Yilmaz, Nicholas J Short.

  CML is defined by the presence of an oncogenic fusion protein caused by a reciprocal translocation between chromosomes 9q and 22q. While our molecular understanding of CML pathogenesis has revolutionized drug development for this disease, we have yet to identify many predisposing factors for CML. Familial occurrence of CML has been rarely reported. Here, we describe 2 cases of CML in a 24-year-old woman and in her 73-year-old maternal great aunt. We describe genetic variants in these patients and report on their environmental exposures that may have contributed to CML pathogenesis. The possible familial association of these 2 cases of CML warrants further investigation into more definitive etiologies of this disease.

Keywords:  Chronic myeloid leukemia; Familial cancer; Hereditary cancer syndromes

DOI:  https://doi.org/10.1159/000513925
Genes Chromosomes Cancer. 2021 Mar 16.

Germline sequence analysis of RABL3 in a large series of pancreatic ductal adenocarcinoma patients reveals no evidence of deleterious variants.

Familial Pancreatic Cancer Genome Sequencing Project

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of less than 10%. Individuals with a pathogenic germline variant in a pancreatic cancer susceptibility gene are at an increased risk of developing pancreatic cancer. Understanding the inherited genetic basis of pancreatic tumor development provides a unique opportunity to improve patient care and outcomes. For example, relatives of a patients with PDAC who have a pathogenic germline variant in a pancreatic cancer susceptibility gene are eligible for disease surveillance where cancers may be detected early, and 5-year survival greatly improved. Furthermore, for some patients with PDAC and a pathogenic germline variant in a pancreatic cancer susceptibility gene, their tumors may be susceptible to specific anti-cancer therapies. Recently, RABL3 was identified as a pancreatic cancer susceptibility gene. To validate these findings and inform clinical translation, we determined the prevalence of deleterious RABL3 variants in a large cohort of 1037 patients with PDAC that had undergone either whole genome or whole exome germline sequencing. We identified two synonymous variants and four missense variants classified as variants of unknown significance. We found no pathogenic RABL3 variants, indicating that the maximum prevalence of such variants in patients with PDAC is less than 0.36% (minor allele frequency 0, 97.5% one-sided confidence interval: 0-0.0036). This finding has important implications for germline genetic testing of patients with PDAC. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/gcc.22947
Virchows Arch. 2021 Mar 18.

Liposarcoma in children and young adults: a clinicopathologic and molecular study of 23 cases in one of the largest institutions of China.

Ran Peng, Nan Li, Ting Lan, Huijiao Chen, Tianhai Du, Xin He, Min Chen, You Xie, Zhang Zhang, Wei Zhao, Hongying Zhang.

  The incidence of pediatric liposarcoma is rare and most published cases lack systematic genetic analyses. We present clinicopathologic and genetic features of 23 liposarcomas aged <22 years. The study cohort comprised 10 males and 13 females (M:F=1:1.3) aged 11-21 years (median 17 years). The tumors predominantly occurred at the extremities (16/23; 69.6%), followed by the head/neck (2/23; 8.7%), chest (2/23; 8.7%), waist (2/23, 8.7%), and retroperitoneum (1/23; 4.3%). The tumor subtypes were sixteen myxoid liposarcoma (ML), one well-differentiated liposarcoma (WDL), two dedifferentiated liposarcoma (DDL), one pleomorphic liposarcoma (PL), and three myxoid pleomorphic liposarcoma (MPL) cases. Fluorescence in situ hybridization analysis identified MDM2/CDK4 amplification in all WDL/DDL cases (3/3; 100%) and DDIT3 rearrangement in all ML cases (13/13; 100%). Whole-exome sequencing indicated that one PL case and one MPL case exhibited RB1 loss. The two tested MPL cases had TP53 mutation and one of them harbored a TP53 germline mutation. Follow-up information was available for 20 patients (20/23; 87.0%) with a median follow-up duration of 42.5 months (range, 13-120 months). Three patients exhibited tumor progression (3/20;15.0%). Seventeen patients (17/20; 85.0%) survived with no evidence of disease. One MPL case (1/20; 5.0%) died of the disease. In conclusion, despite some overlaps, the occurrence, distribution of subtype, and prognosis of liposarcoma are overall different in children and adults. Most MLs and ALT/WDL/DDLs showed similar genetic aberrations with adult counterparts. Molecular features of MPL overlapped with those of conventional PL. The genetic characteristics including Tp53 status of MPL need further investigation.

Keywords:  Liposarcoma; Li–Fraumeni syndrome; Molecular analysis; Pediatric sarcoma; Prognosis

DOI:  https://doi.org/10.1007/s00428-021-03076-8