The prognostic effects of somatic mutations in ER-positive breast cancer

Griffith, O. L.; Spies, N. C.; Anurag, M.; Griffith, M.; Luo, J.; Tu, D.; Yeo, B.; Kunisaki, J.; Miller, C. A.; Krysiak, K.; Hundal, J.; Ainscough, B.; Skidmore, Z.; Campbell, K.; Kumar, R.; Fronick, C.; Cook, L.; Snider, J. E.; Davies, S.; Kavuri, S. M.; Chang, E. C.; Magrini, V.; Larson, D. E.; Fulton, R. S.; Liu, S.; Leung, S.; Voduc, D.; Bose, R.; Dowsett, M.; Wilson, R. K.; Nielsen, T. O.; Mardis, E. R.; Ellis, M. J.

doi:10.1101/235846

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bioRxiv · 10.1101/235846

The prognostic effects of somatic mutations in ER-positive breast cancer

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Abstract

More than 50 genes are recurrently affected by somatic mutation in estrogen receptor positive (ER+) breast cancer but prognostic effects have not been definitively established. Primary tumor DNA was therefore subjected to targeted sequencing from 625 postmenopausal (UBC-TAM series) and 328 premenopausal (MA12 trial) hormone receptor-positive (HR+) patients. Independent validation of prognostic interactions was achieved using independent data from the METABRIC study. Associations between MAP3K1 and PIK3CA with luminal A status and TP53 mutations with Luminal B/non-luminal tumors were observed, validating the methodological approach. In UBC-TAM, NF1 frame-shift nonsense (FS/NS) mutation was validated as a poor outcome driver. For MA12, poor outcome associated with PIK3R1 mutation was similarly validated. DDR1 mutations were strongly associated with poor prognosis in UBC-TAM despite stringent false-discovery correction (q=0.0003). In conclusion, uncommon recurrent somatic mutations should be further explored to create a more complete explanation of the highly variable outcomes that typify ER+ breast cancer.

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Griffith, O. L., Spies, N. C., Anurag, M., Griffith, M., Luo, J., Tu, D., Yeo, B., Kunisaki, J., Miller, C. A., Krysiak, K., Hundal, J., Ainscough, B., Skidmore, Z., Campbell, K., Kumar, R., Fronick, C., Cook, L., Snider, J. E., Davies, S., Kavuri, S. M., Chang, E. C., Magrini, V., Larson, D. E., Fulton, R. S., Liu, S., Leung, S., Voduc, D., Bose, R., Dowsett, M., Wilson, R. K., Nielsen, T. O., Mardis, E. R., Ellis, M. J.. 2017-12-19. The prognostic effects of somatic mutations in ER-positive breast cancer. https://doi.org/10.1101/235846

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