I am thrilled to post our preprint, “The genomic landscapes of individual melanocytes from human skin” on BioRxiv. biorxiv.org/content/10.110…
Feedback is welcome. Here is a summary of what we found… (1/15)
Feedback is welcome. Here is a summary of what we found… (1/15)
Some background… @imartincorena, Philip Jones, and Peter Campbell deep sequenced “normal” skin, showing that keratinocytes are riddled with mutations. However, similar studies in melanocytes would require the ability to genotype individual cells. (2/15) 
So we pioneered an experimental and bioinformatic workflow to call mutations in individual melanocytes with extreme sensitivity and specificity (just trust me or read the preprint because I can’t fit these details in 280 characters). (3/15)
We found that sun-shielded melanocytes had fewer mutations than sun-exposed melanocytes (duh)… But we were initially surprised to learn that intermittently sun-exposed melanocytes (e.g. from the back) had MORE mutations than head/neck melanocytes (4/15)
However, upon further reflection, our finding made more sense. Melanoma disproportionately occurs on intermittently sun-exposed skin, and our finding provides a biological basis to explain this puzzling pattern (5/15)
Next, people with melanoma had more mutations in the melanocytes surrounding their melanoma than site-matched cells from people without melanoma. Could mutation burden be used as a biomarker to measure sun damage? the age of your skin? and melanoma risk? (6/15)
And the mutation burden of melanoma is comparable to its surrounding normal melanocytes, suggesting that melanomas acquire mutations at a similar rate as surrounding skin and arguing against a mutator phenotype operating in the neoplastic cells. (7/15)
But wait!... Why is there a population of cells on heavily sun-damaged skin with virtually no mutations?! (8/15)
We also sequenced the transcriptomes of our cells – turns out the low mutation population had low MDM2 (meaning more p53). Maybe that explains it? Yoshida et. al. Nature saw something similar in lung epithelia – mutational heterogeneity in normal tissues merits more study!(9/15)
Next, we explored whether melanocytes have mutations associated with cancer, and holy cow, “normal” melanocytes are teaming with pathogenic mutations! (10/15)
Some melanomas come from nevi (common moles) but most don’t. Based on our findings, we propose the following model to explain the origins of melanomas that appear suddenly, or de novo (11/15)
Finally, we elucidated the clonal architecture of melanocytes in human skin. Melanocytes often occupy fields of related cells. Some fields have pathogenic mutations, likely explaining their formation, but others don’t, possibly forming when the body surface expanded (12/15)
Thanks to all authors -- Jessica Tang, Eleanor Fewings @eleanorfewings, Darwin Chang @DarwinChang7, Hanlin Zeng @Mark_Zeng_, Shanshan Liu, Aparna Jorapur, Rachel Belote, Andrew McNeal, Iwei Yeh, Sarah Arron @arronlabucsf , Rob Judson-Torres, Boris Bastian (13/15)
Thanks to all funders -- @MelanomaReAlli, @LEOFondet, @UCSFPrecision (George and Judy Marcus Precision Medicine Fund), @NCIGDC_Updates, @CTSIatUCSF, @UCSF_RDO, @AFARorg, @UCSF dermatology, @UCSFCancer, @dermfoundation (14/15)
