1/ Are you a cancer genomicist on the hunt for more genes with recurrent somatic mutations relevant to multiple cancer types? Allow me to introduce this work now at @NatMetabolism with @EdReznik @sloan_kettering and @mito_oncogene @CRUK_BI
nature.com/articles/s4225…
2/ For the uninitiated, the 37 genes in mitochondrial genome encode proteins and RNAs necessary for the electron transport chain to generate cells' ATP. mtDNA mutations are well-known to cause potent disease (e.g. MELAS), but poorly understood in cancer.
3/ Why? chrM usually isn't targeted when sequencing tumors, so progress was slow until large cohorts of whole-genome sequenced tumors became possible, and even with PCAWG, sample size is still limited for finding recurrent mutations and phenotypic associations.
4/ We exploited MTs ultra-high copy number (100-1000s/cell) to call variants from off-target reads in 10K TCGA pts and 40K MSK-IMPACT pts (MSK's targeted NGS clinical data), boosting sample size and enabling a deeper dive into mtDNA variants in cancer.
5/ Many of these 37 genes are mutated at rates ~the most highly mutated cancer genes. MT-ND1/4/5 (ETC Complex 1, CI) are up there with VHL/CDKN2A; MT-CYB (CIII) on par with PIK3CA. Truncating muts to protein-coding mtDNA genes are 80x more likely in tumors than germline!
6/ They are also highly specific. C1 truncating variants are enriched esp. in renal, colorectal and thyroid (affecting 20-30% of all patients!) and arise primarily at 6 "hotspot" regions of single nucleotide repeats (40% of all truncating were indels at these regions)
7/ Truncating muts were the major hotspots, but we also found 7 recurrent non-truncating hotspots. Among these are SNVs known to cause disease in germline (MT-ND1 R25Q, MT-TL1 m.3243), yet tumors somatically enrich for them (and at high VAFs to be detectable in off-target reads)
8/ To check for potential phenotypic effects, we compared diff-exp genes between tumors with truncating muts vs those without any somatic MT muts, i.e. "WT". In most tumor types, truncating muts correlated with upreg of genes related to OXPHOS, and down-reg of genes rel to TNFa.
9/ This expression signature came up even in lineages with few truncating variants (e.g. glioma, breast, meso), suggesting a lineage-agnostic effect of MT loss of function (and potentially selection for this effect in certain types e.g. renal, thyroid, CRC)
10/ We also looked at effect on overall survival, and unexpectedly found starkly improved OS among stage 1-3 CRC with somatic MT variants compared to wild-type. This validated in the MSK-IMPACT cohort (inc advanced/treated pts), controlling for known prognostic covariates.
11/ What does it all mean? Clearly mtDNA muts are doing something in cancer. We squeezed as much as we could from retrospective data, but this is just scratching the surface. Thankfully @EdReznik and
@mito_oncogene will be digging deeper with followup analysis and experiments.
12/ There is much much more in the paper. Proud to have spent 2 years working on this with Ed and Payam. I hope mt-genomics remains a part of my research, clearly there is much more to do and learn about how they influence disease!
13/13 And please stop throwing away chrM reads from your BAM files!

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