LAUSR

The Li-Fraumeni cancer predisposition syndrome (LFS, MIM 151623) was originally described as an autosomal dominantly inherited syndrome characterized by childhood sarcomas and multiple other cancer types and is often due to germ-line mutations in the TP53 gene.1 Classic LFS diagnostic criteria based on the early-onset sarcoma phenotype are over 90% specific for TP53 mutations; however, sensitivity is only 40%.2 Therefore, more expansive criteria (Chompret criteria) were developed to predict the presence of a germ-line TP53 mutation, including diagnosis of a “core cancer” (sarcoma, premenopausal breast, brain, leukemia, or adrenocortical carcinoma) and/or multiple primary malignancies and/or family members with early-onset cancer.3 These criteria are over 90% sensitive for TP53 mutations, but specificity is low, ranging from 15 to 52%,2 probably owing to locus heterogeneity, a broader phenotypic spectrum associated with TP53 mutations than originally appreciated, and the existence of de novo mutations. In view of the phenotypic heterogeneity associated with germ-line TP53 mutations, TP53 is found on nearly all multiplex panels in current clinical use for cancer predisposition evaluation. There are many challenges in interpreting a TP53 mutation in this current era of multiplex panel testing, given the low pretest probability of a mutation in the majority of individuals being tested, the preponderance of missense mutations in TP53 with variable support of pathogenicity, and the potential for low or incompletely penetrant TP53 mutations. Recently, germ-line TP53 mutation testing has become further complicated by the increasing recognition that massively parallel sequencing (MPS) detects mutations in TP53—among other genes—in circulating blood cells at allelic fractions inconsistent with a heterozygous or homozygous mutation.4 These so-called “mosaic mutations” have always existed;5 however, traditional Sanger sequencing-based genetic testing probably missed the vast majority of cases. Although rare, mosaic TP53 results are creating significant clinical conundrums as the interpretation of the etiology of these results has differing clinical implications. In this issue of Genetics in Medicine, Weitzel and colleagues analyze data from a clinical testing laboratory and use ancillary testing to address the important clinical question of the frequency and possible etiologies of mosaic TP53 results.6 In their study, Weitzel and colleagues show that of 353 TP53 likely pathogenic or pathogenic mutation results identified by MPS-based multiplex panel or single-site testing, 72 results (20%) were found at less than 25% allelic fraction in peripheral blood samples. They went on to evaluate these 72 cases. Three cases were found in patients with overt hematological malignancy (myelodysplastic syndrome or chronic lymphocytic leukemia), an important reminder that blood is not an appropriate specimen for genetic testing in patients with hematological malignancies. Ancillary testing, defined as site-specific mutation testing of the identified TP53 mutation in another tissue (skin fibroblasts, eyebrow pluck, or other tissue) or testing of a family member was performed for 35 of the remaining 69 cases. Three of these 35 mutations were reported to be “germ line” (two by positive mutation testing in family members and one by a positive fibroblast result). The other thirty-two cases with ancillary testing included 18 with negative tissue testing and 14 with negative testing of one or more family member(s). These cases were presumed by the authors to be due to an abnormal clonal expansion (ACE) in the blood compartment, which the authors also termed “somatic interference.” Because the remaining 34 cases were seen to have clinical characteristics similar to those of the 32 cases with ancillary testing, the authors concluded that these 34 cases also probably have an ACE. The authors propose that these ACEs are predominantly due to clonal hematopoiesis of indeterminate potential (CHIP), although this is not proven definitively, for example, by lymphocyte clonality analysis. While CHIP is a possible explanation for many of the mosaic TP53 cases, the evidence is speculative, and other possible etiologies exist. CHIP has gained recent attention as a marker of and perhaps etiological precursor to cardiovascular disease and hematological malignancy that increases with aging.4,7,8 CHIP, and other ACEs in the blood compartment, such as those resulting from the selective pressure of chemotherapy,9 represent only one of a number of possible etiologies of a variant in a blood sample at an allelic fraction other than 50% or 100%. As delineated in a recent review by Forsberg et al.,5 the genetic variation of any particular human soma at any