Abstract P2-09-25: Constitutional mosaicism in hereditary cancer genes
Authors: Lincoln S , Tan C , Kennemer M , Powers M , Monzon F 
Published: May 2016

Abstract
Background: Mutations conferring cancer risk are typically inherited from one biological parent. Alternatively, a mutation may be constitutional mosaic, meaning that a fraction of cells in the body carry the mutation. This can result e.g. from a de novo mutation early in embryogenesis. Constitutional mosaicism may be an underreported cause of genetic disease [1,2] for 2 reasons: Family histories can be uninformative (mosaic mutations are typically not inherited, but can be passed on to children). Also, germline laboratory tests (if performed) are traditionally not optimized to detect low allele frequency events (in contrast to tumor tests for somatic mutations). Following our recent identification of a mosaic BRCA1 cancer patient [3], we sought to characterize additional such cases in our laboratory population.
Methods: We examined high-depth next-generation sequencing (NGS) data for pathogenic or suspected pathogenic mutations with unequal allele balance (i.e., not the expected 50-50 ratio) in blood-derived DNA. Because many factors can cause unequal allele balance in NGS, we reviewed the lab and clinical data in detail to remove cases likely due to (a) technical artifacts in NGS, (b) other somatic events, as may happen in response to chemotherapy, or (c) undiagnosed, residual or progressing blood cancers. An orthogonal assay was used for confirmation.
Results: To date, 14 cases with mosaic mutations (7-29% allele frequency) have been confirmed: 8 of these patients have breast/ovarian cancer and 6 have other cancers. These allele frequencies are unlikely to be caused by circulating tumor DNA or cells. These findings include our published BRCA1 case, 7 TP53 cases, 1 NF1 case, 2 CHEK2, 2 MLH1, and 1 PTCH1. 3 additional mutations were determined to be part of a haematopoietic neoplasm (1 previously undiagnosed). Cases of note include (i) a young breast cancer patient, with no cutaneous findings, positive for NF1 at 9%, and (ii) a patient presenting with the Muir-Torre variant of Lynch syndrome who had negative MLH1/MSH2 Sanger sequencing 14 years ago, identified to be positive for MLH1 at 25% by NGS.
Conclusion: Constitutional mosaic mutations may be an under-recognized cause of cancer and unique clinical considerations apply to such cases. First, a mosaic patient may not show the same gene-associated phenotypes as patients with inherited heterozygous mutations in the same gene. Second, patients with syndromic presentations who tested negative for the indicated gene(s) by traditional methodologies may warrant reexamination by NGS. Similarly, patients with heterozygous mutations (50-50) may have a mosaic parent, for whom the mutation could be missed by traditional testing. Testing of family members beyond first degree relatives of a mosaic patient is unlikely to modify risk assessments, unlike the situation for patients with inherited heterozygous mutations. Finally, apparent mosaicism may warrant an evaluation for a underlying haematologic malignancy. We note that the prevalence of mosaic findings in hereditary cancer genes is currently unclear but may higher than once thought. Further clinical research on this topic is clearly warranted.
(1) Campbell et al., AJHG, 2014
(2) Acuna-Hildago et al., AJHG, 2015
(3) Friedman et al., SABCS 2014; BJC 2015.
Citation Format: Lincoln S, Tan C, Kennemer M, Powers M, Monzon F. Constitutional mosaicism in hereditary cancer genes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-25.