Genome sequencing identifies a basis for everolimus sensitivity - PubMed (original) (raw)

. 2012 Oct 12;338(6104):221.

doi: 10.1126/science.1226344. Epub 2012 Aug 23.

Aphrothiti J Hanrahan, Matthew I Milowsky, Hikmat Al-Ahmadie, Sasinya N Scott, Manickam Janakiraman, Mono Pirun, Chris Sander, Nicholas D Socci, Irina Ostrovnaya, Agnes Viale, Adriana Heguy, Luke Peng, Timothy A Chan, Bernard Bochner, Dean F Bajorin, Michael F Berger, Barry S Taylor, David B Solit

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Genome sequencing identifies a basis for everolimus sensitivity

Gopa Iyer et al. Science. 2012.

Abstract

Cancer drugs often induce dramatic responses in a small minority of patients. We used whole-genome sequencing to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations was a loss-of-function mutation in TSC1 (tuberous sclerosis complex 1), a regulator of mTOR pathway activation. Targeted sequencing revealed TSC1 mutations in about 8% of 109 additional bladder cancers examined, and TSC1 mutation correlated with everolimus sensitivity. These results demonstrate the feasibility of using whole-genome sequencing in the clinical setting to identify previously occult biomarkers of drug sensitivity that can aid in the identification of patients most likely to respond to targeted anticancer drugs.

Trial registration: ClinicalTrials.gov NCT00805129.

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Fig. 1

Fig. 1

(A) Computed tomography images of the index patient demonstrating complete resolution of metastatic disease (arrows). (B) Somatic abnormalities in the outlier responder’s genome included (from outside to inside) copy number alterations; mutations at ~10-Mb resolution; regulatory, synonymous, missense, nonsense, nonstop, and frameshift insertion and deletion mutations (black, orange, red, green, and dark green); and intra- and interchromosomal rearrangements (light and dark blue). (C) Best overall response of 14 sequenced trial patients. Negative values indicate tumor shrinkage (red line, threshold for partial response). Gradient arrow, patient with rapid progression in bone.

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References

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