Normal cells must become cancer-enabling before anything else occurs, according to latest literature. The goal in this mini-review is to demonstrate special tetraploidy in the enabling process. This we have shown from genomic damage, DDR (DNA Damage Response) activity with skip of mitosis leading to diploid G2 cells at the G1 border in need of chromatin repair for continued cell cycling to the special tetraploid division system. In several studies specific methylation transferase genes were activated in normal human cells in tissue fields, containing different cell growth stages of the cancerous process. Histology studies, in addition to molecular chemistry for identification of oncogenic mutational change, were a welcome change (see below). In a study on melanoma origin, DDR also showed arrested diploid cells regaining cycling from methylation transferase activity with causation of 2n melanocytes transforming to 4n melanoblasts, giving rise to epigenetic tumorigenesis enabled First Cells. Such First Cells were from Barrett’s esophagus shown to have inherited the unique division system from 4n diplochromosomal cells, first described in mouse ascites cancer cells (below). We discovered that the large nucleus prior to chromosomal division turned 90° relative to the cytoskeleton axis, and divided genome reductive to diploid, First Cells, in a perpendicular orientation to the surrounding normal cells they had originated from. This unique division system was herein shown to occur at metastasis stage, implying activity throughout the cancerous evolution. Another study showed 4-chromatid tetraploidy in development to B-cell lymphoma, and that such cancer cells also proliferated with participation of this unusual division system. Such participation has long been known from Bloom’s inherited syndrome with repair chiasmas between the four chromatids, also an in vitro observation by us. Our cytogenetic approach also revealed that they believed mitotic division in cancer cells is wrong because such cell divisions were found to be from an adaptation between amitosis and mitosis, called amitotic-mitosis. Amitosis means division without centrosomes, which has long been known from oral cancer cells, in that MOTCs (microtubule organizing center) were lacking centrioles. This observation calls for re-introduction of karyotype and cell division studies in cancer cell proliferation. It has high probability of contributing novel approaches to cancer control from screening of drugs against the amitotic-mitotic division apparatus.