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CATHERINE BULLARD, IDRICO O TOTO
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ISSN: 0888-0018 (Print) 1521-0669 (Online) Journal homepage: http://www.tandfonline.com/loi/ipho20
A novel p.Gly187Arg TP53 variant appears to result in Li-Fraumeni syndrome
Meagan R. Doyle & J. Martin Johnston
To cite this article: Meagan R. Doyle & J. Martin Johnston (2018): A novel p.Gly187Arg TP53 variant appears to result in Li-Fraumeni syndrome, Pediatric Hematology and Oncology, DOI: 10.1080/08880018.2018.1502852
To link to this article: https://doi.org/10.1080/08880018.2018.1502852
Published online: 21 Sep 2018.
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CASE REPORT
A novel p.Gly187Arg TP53 variant appears to result in Li-Fraumeni syndrome
Meagan R. Doyleª and J. Martin Johnstonb
ªMercer University School of Medicine, Savannah, Georgia, USA; bSchool of Medicine, Renown Children’s Hospital, University of Nevada, Reno, USA
ABSTRACT
Li-Fraumeni syndrome is an autosomal dominant cancer syndrome characterized by pathogenic variants in the TP53 gene on chromosome 17. The most common cancers in Li-Fraumeni kindreds include sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma. We report a 9-month-old male who was diagnosed with an adrenocortical tumor and later found to harbor a novel TP53 c.559 G> C germline variant, resulting in p.Gly187Arg. Family history included early-onset breast cancer in his paternal grandmother and paternal great-grandfather, as well as colon cancer at age 31 in a paternal cousin. The same TP53 variant was later confirmed in his paternal grandmother. Based on this information, his father (age 28, obligate carrier for the variant) was referred for colonoscopic screening and found to have multiple adenomatous polyps. This previously undescribed variant lies at an exon/intron boundary and is predicted to decrease splice site efficiency with resulting altered splicing or exon skipping. Our patient’s family history provides limited evidence that this variant is a cause of Li-Fraumeni syndrome.
ARTICLE HISTORY
Received 19 April 2018 Revised 10 July 2018 Accepted 13 July 2018
KEYWORDS
Adrenocortical tumor; cancer screening; Li-Fraumeni syndrome; TP53
Li-Fraumeni syndrome (LFS) is a clinically heterogeneous, autosomal dominant cancer syndrome characterized by a pathogenic variant TP53 gene on chromosome 17p13.1 [1]. With partial loss of p53 function, DNA damage goes unrepaired, driver mutations accumulate in oncogenes and other cancer genes, and cells move toward malignancy. In families with LFS, the probability of developing invasive cancer reaches almost 50% by age 30 and more than 90% of pathogenic variant carriers will develop cancer by age 70 [1].
Classic LFS is defined as a proband with sarcoma before age 45, a first-degree relative with any cancer before age 45, and one additional first- or second-degree relative in the same lineage with cancer before age 45 or with sarcoma at any age [2]. More recently, the Chompret criteria have become widely accepted to identify potentially affected families beyond the Classic criteria listed above [3]. A diagnosis of LFS is considered
and TP53 gene testing is recommended for anyone with a personal and family history that meets any of the following four criteria [4]:
Criterion 1
· A tumor belonging to the LFS tumor spectrum, before the age of 46. These include: soft-tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumor, adrenocortical carcinoma (ACC), leukemia, or lung cancer; AND
. At least one first- or second-degree family member with an LFS-related tumor, except breast cancer if the individual has breast cancer, before the age of 56, OR with multiple tumors
Criterion 2
· A person with multiple tumors, except multiple breast tumors, two of which belong to the LFS tumor spectrum and the first of which occurred before age 46
Criterion 3
· A person who is diagnosed with ACC, a tumor in the choroid plexus, or rhabdomyosarcoma of embryonal anaplastic subtype, regardless of family history.
Criterion 4
· Breast cancer diagnosed before age 31 years.
We describe a 9-month-old male diagnosed with an adrenocortical tumor (ACT), who was later shown to have a previously unreported germline TP53 variant. Additional family history suggests that this variant may cause LFS.
Case report
A previously healthy 9-month-old male was admitted for a left-sided abdominal mass concerning for a neoplastic process. Physical exam revealed a vigorous male infant; height and weight were at the 85th and 97th percentiles, respectively. There was a firm, nontender, mass extending 10 cm below the left costal margin. Borderline large penis for his age was noted, but there was no axillary or pubic hair. Non-contrast abdominal CT scan showed a large left-sided mass adjacent to the kidney. Laboratory evaluation was significant for elevated lactate dehydrogenase (3871 IU/L; reference range 313-618). Gross total resection with adrenalectomy confirmed an adrenocortical neoplasm. The tumor displayed prominent cytologic atypia; atypical and increased mitoses (90 per 50 high-powered fields); predominantly eosinophilic cytoplasm; a diffuse growth pattern and focal necrosis, as well as focal invasion into but not through the capsule. Lymph nodes from left renal hilum, left paraaortic, left celiac, and right paraaortic regions were negative for tumor. The tumor measured 9 x 6.5 x 6.5 cm, weighed 211 g, and was organ-confined; based on Children’s Oncology Group criteria, it was considered
☐ Proband
Breast ca, 55 y.o.
☒ Documented TP53 variant
☐ Obligate TP53 variant
Breast ca, 24 y.o.
☐ Presumptive TP53 variant
Colon ca, 31 y.o.
Multiple adenomatous polyps, 28 y.o.
☒ Adrenocortical tumor, 9 m.o.
“Stage II” (>100 gm, completely resected). Chromosome analysis revealed a normal 46 XY karyotype.
Two days post-resection, the adrenal hormone profile (testosterone, estradiol, 17(OH) progesterone, dehydroepiandrosterone sulfate, and cortisol) was unremarkable. Metastatic work-up was negative. No adjuvant therapy was offered and there has been no evidence of disease recurrence, now more than 2 years from diagnosis.
Family history (Figure 1) was significant for breast cancer in his paternal grandmother (diagnosed at age 24) and paternal great-grandfather (diagnosed at age 55), as well as colon cancer in the father’s maternal first cousin with onset at age 31, who is deceased.
Given the diagnosis and family history, peripheral blood was sent for a Hereditary Cancer Panel, revealing a heterozygous “variant of unknown clinical significance” in TP53, c.559G> C resulting in p.Gly187Arg. The c.559G> C variant is absent from general population databases such as 1000 Genomes, the Exome Variant Server, and the Exome Aggregation Consortium browser. This variant has not been reported in medical literature for LFS, but is reported in the COSMIC database as a confirmed somatic variant in a single lung carcinoma sample (unpublished report).
Discussion
Adrenocortical tumors (ACT) are rare but often aggressive childhood endocrine neoplasms and represent only 0.2% of pediatric cancers [5]. Childhood ACT typically presents during the first 5 years of life (median age, 3-4 years), followed by a second peak during adolescence [6,7]. The clinical behavior of these tumors is highly variable and difficult to predict. The histologic findings noted in the present case would, if seen in an adult, indicate an ACC. As noted, however, in the 2017 College of American Pathologists staging protocol for ACC, “[the] criteria used in adults to separate benign from malignant cortical tumors are not entirely applicable to ACTs in pediatric age groups” [8]. Based on a classification system proposed by Wieneke et al., our patient’s
ACT would be considered “malignant,” with tumor size >1.5 cm, capsular invasion, high mitotic index, and atypical mitoses [6]. Other authors have proposed, however, that tumor weight >500 g is an independent predictor of malignant behavior [9] and current Children’s Oncology Group guidelines do not recommend chemotherapy in a patient as described herein. Our patient continues with no evidence of disease following surgical resection alone.
A diagnosis of ACC is considered sufficient evidence to screen for LFS. Small series of patients with ACT have demonstrated a variety of apparently pathogenic germline TP53 variants in as many as 80% of cases [10-12]. More recently, Wasserman et al. [13] reported that germline TP53 variants were identified in only 50% of 68 consecutive, unrelated children with ACC, unselected for family history (after excluding 20 patients with the R337H variant characteristic of pedigrees from a region in southern Brazil). Interestingly, only two of the 34 TP53 variants corresponded to “hotspot” mutations (R175H, G245S, R248Q, R248W, R273H, and R282W), which are seen in 20% of identified LFS pedigrees. Also of considerable interest, functional analyses of these novel variants revealed a wide range of residual TP53 activity. The authors speculated that residual TP53 activity might underlie low-penetrance alleles; among their subjects, there was a striking paucity of pedigrees with a strong history of cancer [13].
Among children eventually diagnosed with LFS, dominant-negative missense mutations are the most commonly identified TP53 aberration [4]. The p.Gly187Arg TP53 variant described in the current report has previously been reported only in the COSMIC database as a somatic mutation in a single lung carcinoma sample (unpublished report). The base pair at position 559 is located at an exon/intron boundary and computation prediction algorithms predict that the 559G> C variant significantly decreases splice site efficiency (MaxEnt: - 46.5%; NNSPLICE: - 85.0%; HSF: -12.1%) (Alamut v2.7.1). Moreover, computational analyses of the protein indicate a deleterious effect of the p.Gly187Arg variant (Sift: damaging; PolyPhen2: probably damaging; MutationTaster: disease-causing). We did not have the opportunity to perform functional studies that would help to clarify the nature of this variant (e.g. RNA transcript analysis on the tumor specimen, given that this is a splice site variant). We can extrapolate from the data of Wasserman et al. and speculate that, in view of the family history, this variant would demonstrate low activity in vitro.
Applying American College of Genetic Medicine criteria, TP53 559G>C is considered a variant of unknown significance on the basis of its absence from multiple general population databases (PM2); co-segregation with disease in multiple family members in a gene definitively known to cause the disease (PP1); multiple lines of computational evidence supporting a deleterious effect on the gene or gene product (PP3); and a family history highly specific for a disease with a single genetic etiology (PP4). Given our patient’s intriguing family history and the limited additional ACMG criteria met, the p.Gly187Arg variant may represent a cause of LFS. As demonstrated here, recognition of the variant can allow for targeted screening of affected individuals in hope of reducing long-term morbidity or mortality from delayed cancer diagnoses.
Disclosure statement
No potential conflict of interest was reported by the authors.
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