Mosaicism refers to the occurrence of two or more genomes in an individual derived from a single zygote. Germline mosaicism is a mutation that is limited to the gonads and can be transmitted to offspring. Somatic mosaicism is a postzygotic mutation that occurs in the soma, and it may occur at any developmental stage or in adult tissues. Mosaic variation may be classified in six ways: ( a) germline or somatic origin, ( b) class of DNA mutation (ranging in scale from single base pairs to multiple chromosomes), ( c) developmental context, ( d) body location(s), ( e) functional consequence (including deleterious, neutral, or advantageous), and (  f ) additional sources of mosaicism, including mitochondrial heteroplasmy, exogenous DNA sources such as vectors, and epigenetic changes such as imprinting and X-chromosome inactivation. Technological advances, including single-cell and other next-generation sequencing, have facilitated improved sensitivity and specificity to detect mosaicism in a variety of biological contexts. Expected final online publication date for the Annual Review of Genetics, Volume 54 is November 23, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Purpose Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma, a rare but aggressive cancer with a heterogenous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or in situ mammary carcinoma component, and are typically triple-negative for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER-2) amplification/overexpression. An unanswered question is the origin of metaplastic breast cancers. While they may arise independently from their ductal components, their close juxtaposition favors a model that postulates a shared origin, either as two derivatives from the same primary cancer, or one histology as an outgrowth of the other. Understanding the mechanism of development of these tumors may inform clinical decisions. Experimental Design We performed exome sequencing for paired metaplastic and adjacent conventional invasive ductal carcinomas in eight patients and created a pipeline to identify somatic variants and predict their functional impact, without having normal tissue. We then determined the genetic relationships between the histologically distinct compartments. Results In each case, the tumor components have nearly identical landscapes of somatic mutation, implying that the differing histologies do not derive from genetic clonal divergence. Conclusions A shared origin for tumors with differing histologies suggests that epigenetic or noncoding changes may mediate the metaplastic phenotype, and that alternative therapeutic approaches, including epigenetic therapies, may be required for metaplastic breast cancers. Translational relevance Metaplastic breast cancers are a rare but treatment refractory subtype of breast cancer. It remains unclear whether these tumors are separate cancers that arise independently from their ductal counterparts, or are genetically related, resulting from dedifferentiation of cells. Knowledge of the origin of metaplastic breast cancers may help to develop therapeutic strategies for this group of recalcitrant cancers. Using whole exome sequencing and new bioinformatics tools, we compared variants between paired breast cancer samples exhibiting invasive ductal carcinoma and metaplastic components. Based on the high degree of shared variants between paired tissue types from eight patients, we conclude that invasive ductal carcinomas with an associated metaplastic component are genetically related, and likely the result of epigenetic changes leading to multiple histologies. These results provide new insights into the origin of metaplastic breast cancers that could have implications for treatment strategies.

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