Thread by @jyoti_nangalia

1/ "How long have I had it for?"

Our patients with #bloodcancer have always wanted to know. We set out to answer it. We studied patients with MPN #mpnsm and found quite unexpected results. Excited to share our preprint biorxiv.org/content/10.110…

2/ We took single blood cells from patients with MPN and grew each cell into a colony. We then sequenced each colony's whole genome (>950 whole genomes).

3/ We used DNA mutations to trace the ancestral relationships between colonies - building a "family tree" of blood production for each patient. We could then time the cancer driving genetic events and trace how the mutant clones expanded over the patient’s life.

4/ JAK2 mutations were acquired early in life - in utero and childhood despite a diagnosis many decades later, up to 54 years before MPN diagnosis for one patient #JAK2V617F

5/ We found in utero and childhood acquisition of DNMT3A mutations too. In one patient, the #DNMT3A mutation was acquired within few weeks of conception – the start of life. Ageing per se didn’t drive such clonal haematopoiesis – it simply took an age for the clones to grow.

6/ Cancer driver mutations could occur sequentially - decades apart. Different orders including JAK2 mutations coming second. #clonalevolution

7/ Clone growth rates varied: <10%/yr to >200%/yr for multiply mutated clones. #JAK2V617F clones grew at different rates in different individuals - ie patient-specific factors (germline, environment) influence its consequences as shown by @bloodgenes lab and others.

8/ Importantly, the rate of expansion of mutant-JAK2 predicted the time to MPN diagnosis..... a possibility of early detection and disease prediction? #stopcancer

9/ We have loved working on this and learnt so much. Thank you to the amazing Nick Williams! To all the team, Joe Lee, @luiza_moore, Anna Godfrey. To Peter Campbell and Tony Green. Our funders @CR_UK @mpnrf @EHA_Hematology and our dear patients.

Thoughts and comments most welcome from (r)evolutionary experts :) @MoritzGerstung @jrblundell @jaiswalmdphd @Goodell_Lab @jdegregori1 @davidcwedge @imartincorena @markowetzlab @JeffTownsend @cncurtis