癌症在人类中很常见，但在密切相关的“类人猿”中却很少见。提出了合理的解释，包括影响唾液酸生物学的人类特异性基因组改变，但因果关系尚未得到证实。在这里，综合进化遗传学-表型组-转录组方法研究了 SIGLEC12 基因（编码 Siglec-XII）在上皮转化和癌症中的作用。该蛋白在细胞系和基因工程小鼠中的外源表达概括了约 30% 的人群，其中由于固定的、纯合的、人类普遍的错义突变，该蛋白以无法结合配体的形式表达。 Siglec-XII 无效细胞/小鼠概括了剩余约 70% 的人群，其中额外的多态移码突变消除了整个蛋白质。 Siglec-XII 的表达驱动了细胞系中的几种促癌表型，并增加了受到化学致癌物和炎症攻击的小鼠的肿瘤负荷。转录组学研究产生了 Siglec-XII 阳性疾病的 29 个基因特征，当用作导航人类数据集的计算工具时，以令人惊讶的精度确定 SIGLEC12 表达（模型）概括了一种非常特殊的结直肠癌（疾病）类型，即与错配修复缺陷和炎症相关，对欧洲裔美国人的影响尤为严重，并且预后较好。他们揭示了一种迄今为止未知的种族/环境致癌倾向的进化遗传机制。

Carcinomas are common in humans but rare among closely related "great apes". Plausible explanations, including human-specific genomic alterations affecting the biology of sialic acids are proposed, but causality remains unproven. Here, an integrated evolutionary genetics-phenome-transcriptome approach studied the role of SIGLEC12 gene (encodes Siglec-XII) on epithelial transformation and cancer. Exogenous expression of the protein in cell lines and genetically engineered mice recapitulated ~30% of the human population in whom the protein is expressed in a form that cannot bind ligand due to a fixed, homozygous, human-universal missense mutation. Siglec-XII null cells/mice recapitulated the remaining ~70% of the human population in whom an additional polymorphic frameshift mutation eliminates the entire protein. Siglec-XII expression drove several pro-oncogenic phenotypes in cell lines, and increased tumor burden in mice challenged with chemical carcinogen and inflammation. Transcriptomic studies yielded a 29-gene signature of Siglec-XII-positive disease and when used as a computational tool for navigating human datasets, pinpointed with surprising precision that SIGLEC12 expression (model) recapitulates a very specific type of colorectal carcinomas (disease) that is associated with mismatch-repair defects and inflammation, disproportionately affects European-Americans, and carries a better prognosis. They revealed a hitherto unknown evolutionary genetic mechanism for an ethnic/environmental predisposition of carcinogenesis.