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The orchestrated activity of acid-base transporters of the solute-linked carrier (SLC) family is critical for removing the end-products of fermentative metabolism (lactate\/H<jats:sup>+<\/jats:sup>) and maintaining a favourably alkaline cytoplasm. Given the critical role of pH homeostasis in enabling cellular activities, mutations in relevant SLC genes may impact the oncogenic process, emerging as negatively or positively selected, or as driver or passenger mutations. To address this, we performed a pan-cancer analysis of The Cancer Genome Atlas simple nucleotide variation data for acid\/base-transporting SLCs (ABT-SLCs). Somatic mutation patterns of monocarboxylate transporters (MCTs) were consistent with their proposed essentiality in facilitating lactate\/H<jats:sup>+<\/jats:sup> efflux. Among all cancers, tumours of uterine corpus endometrial cancer carried more ABT-SLC somatic mutations than expected from median tumour mutation burden. Among these, somatic mutations in <jats:italic>SLC4A3<\/jats:italic> had features consistent with meaningful consequences on cellular fitness. Definitive evidence for ABT-SLCs as \u2018cancer essential\u2019 or \u2018driver genes\u2019 will have to consider microenvironmental context in genomic sequencing because bulk approaches are insensitive to pH heterogeneity within tumours. Moreover, genomic analyses must be validated with phenotypic outcomes (i.e. SLC-carried flux) to appreciate the opportunities for targeting acid-base transport in cancers.<\/jats:p>","DOI":"10.1007\/s00424-023-02876-y","type":"journal-article","created":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T06:02:01Z","timestamp":1700805721000},"page":"673-688","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["What can we learn about acid-base transporters in cancer from studying somatic mutations in their genes?"],"prefix":"10.1007","volume":"476","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9327-3168","authenticated-orcid":false,"given":"Bobby","family":"White","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9945-9473","authenticated-orcid":false,"given":"Pawel","family":"Swietach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,24]]},"reference":[{"key":"2876_CR1","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","volume":"7","author":"IA Adzhubei","year":"2010","unstructured":"Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. 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