Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL). Using a combination of discovery exome and extended targeted sequencing, we identified recurrent somatic mutations in RRAGC uniquely enriched in patients with follicular lymphoma (17%). More than half of the mutations preferentially co-occurred with mutations in ATP6V1B2 and ATP6AP1, which encode components of the vacuolar H+-ATP ATPase (V-ATPase) known to be necessary for amino acid−induced activation of mTORC1. The RagC variants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation. The activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting.Experimental Cancer Medicine Centre

Testing the assumptions for the analysis of survival data arising from a prevalent cohort study with follow-up

In a prevalent cohort study with follow-up subjects identified as prevalent cases are followed until failure (defined suitably) or censoring. When the dates of the initiating events of these prevalent cases are ascertainable, each observed datum point consists of a backward recurrence time and a possibly censored forward recurrence time. Their sum is well known to be the left truncated lifetime. It is common to term these left truncated lifetimes "length biased" if the initiating event times of all the incident cases (including those not observed through the prevalent sampling scheme) follow a stationary Poisson process. Statistical inference is then said to be carried out under stationarity. Whether or not stationarity holds, a further assumption needed for estimation of the incident survivor function is the independence of the lifetimes and their accompanying truncation times. That is, it must be assumed that survival does not depend on the calendar date of the initiating event. We show how this assumption may be checked under stationarity, even though only the backward recurrence times and their associated (possibly censored) forward recurrence times are\ud observed. We prove that independence of the lifetimes and truncation times is equivalent to equality in distribution of the backward and forward recurrence times, and exploit this equivalence as a means of testing the former hypothesis. A simulation study is conducted to investigate the power and Type 1 error rate of our proposed tests, which include a bootstrap procedure that takes into account the pairwise dependence between the forward and backward recurrence times, as well as the potential censoring of only one of the members of each pair. We illustrate our methods using data from the Canadian Study of Health and Aging. We also point out an equivalence of the\ud problem presented here to a non-standard changepoint problem