Atypical Tumor-Variant Associations in MPT-Affected Individuals
In this study, we applied multi-gene testing in all affected individuals irrespective of the tumor types diagnosed. Strikingly, this resulted in the identification of a large number of probands (29/67 [43.2%]) who harbored a P/LP CPG variant but whose tumor phenotypes were not entirely typical for the relevant CPG. This situation has been frequently reported by other studies of extensive NGS testing of cancer cohorts37, 40, 42 and represents a challenge for clinicians because the relevance of the variant to cancer risk in the consultand (including unaffected family members) is less clear. Specific atypical associations observed in this analysis were heterogeneous, and numbers were small, but some patterns were noted; for example, 5/16 (31.2%) carriers of CHEK2 variants had been previously diagnosed with renal cell carcinoma (RCC) (breast cancer occurred in 8/16 [50%]). An odds ratio of 2.1 for RCC has previously been observed in CHEK2-variant carriers but only in association with the c.470T>C (p.Ile157Thr) founder variant in a Polish population.43 2/6 (33.3%) carriers of PALB2 variants had cutaneous melanoma before the age of 40 years, and 2/10 (20%) individuals with ATM variants had thyroid cancer before that age, but an analysis of 182 melanoma families demonstrated only one pathogenic PALB2 variant,44 and thyroid malignancies have not been reported at increased frequency in carriers of homozygous or heterozygous ATM variants.1, 45
One potential interpretation of these atypical tumor phenotypes is that the tumor spectrum associated with some CPGs is wider than currently recognized given that, to date, testing of particular genes has been limited to specific phenotypes. For example, although FH variants were demonstrated to predispose to RCC in 2002, they were shown to predispose to pheochromocytoma and paraganglioma 12 years later.46, 47, 48 We therefore suggest that further “agnostic” research testing of a comprehensive panel of CPGs in MPT-affected individuals could lead to the identification of novel associations between genes and tumor phenotypes. Our observation of a significantly higher rate of loss-of-function variants associated with non-characteristic tumors in our cohort than in the gnomAD dataset suggests that at least some variants identified in individuals with atypical phenotypes are relevant. We would, however, urge caution in automatically linking a pathogenic CPG variant to the observed tumor phenotype without further evidence, such as larger studies of variant carriers or tumor studies that demonstrate a variant’s causative effect.
Another possibility is that tumors can occur coincidentally in the presence of a pathogenic constitutional CPG variant. Variants might be considered causative in some contexts or tissues (and would therefore be likely to pass our filtering and assessment) but potentially not in others. For example, an in-frame FH insertion (c.1433−1434insAAA [p.Lys477_Asn478insLys] [Ensembl: ENST00000366560; GenBank: NM_000143.3]) was identified in three individuals, none of whom had been diagnosed with typical hereditary leiomyoma or RCC tumors. This variant causes recessively inherited fumarate hydratase deficiency (MIM: 606812) and has been demonstrated to disrupt enzyme activity.49 However, its significance to cancer predisposition in the heterozygous state is less well defined.
Unusual MPT-CPG associations can occur when an individual harbors variants in multiple CPGs, either because (at least) one of the variants remains unidentified through diagnostic testing or because an interactive effect exists between them. We have previously reviewed this phenomenon and described it as multiple inherited neoplasia alleles syndrome (MINAS),50 and WGS identified two further examples in our cohort. In the case of PMS2 and BMPR1A variants, the former appears to be penetrant on the basis of tumor studies, whereas the significance of the latter is unclear. Nevertheless, the identification of MINAS cases such as this provides clinicians the opportunity to obtain further evidence. For the individual with FH and MAX variants, it is easier to attribute the diagnosed pheochromocytomas to the truncating MAX variant, but evidence for the role of FH in this tumor type is accumulating, and this variant could have contributed to tumorigenesis.