CA : A Cancer Journal for Clinicians

Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.

/pdf/mutational-heterogeneity-in-cancer-and-the-search-for-new-1ayo5401zx.pdf

Mutational heterogeneity in cancer and the search for new cancer-associated genes

Methods We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition. Results A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Conclusions Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)

/pdf/inhibition-of-mutated-activated-braf-in-metastatic-melanoma-1veky7tp0j.pdf

Inhibition of mutated, activated BRAF in metastatic melanoma.

Integrative genomic profiling of human prostate cancer

All cancers arise as a result of changes that have occurred in the DNA sequence of the genomes of cancer cells. Over the past quarter of a century much has been learnt about these mutations and the abnormal genes that operate in human cancers. We are now, however, moving into an era in which it will be possible to obtain the complete DNA sequence of large numbers of cancer genomes. These studies will provide us with a detailed and comprehensive perspective on how individual cancers have developed.

The cancer genome

Abstract Background For the majority of individuals with early-onset or familial breast cancer referred for genetic testing, the genetic basis of their familial breast cancer remains unexplained. To identify novel germline variants associated with breast cancer predisposition, whole-exome sequencing (WES) was performed. Methods WES on 290 BRCA1/BRCA2 -negative Singaporeans with early-onset breast cancer and/or a family history of breast cancer was done. Case–control analysis against the East-Asian subpopulation (EAS) from the Genome Aggregation Database (gnomAD) identified variants enriched in cases, which were further selected by occurrence in cancer gene databases. Variants were further evaluated in repeated case–control analyses using a second case cohort from the database of Genotypes and Phenotypes (dbGaP) comprising 466 early-onset breast cancer patients from the United States, and a Singapore SG10K_Health control cohort. Results Forty-nine breast cancer-associated germline pathogenic variants in 37 genes were identified in Singapore cases versus gnomAD (EAS). Compared against SG10K_Health controls, 13 of 49 variants remain significantly enriched (False Discovery Rate (FDR)-adjusted p &lt; 0.05). Comparing these 49 variants in dbGaP cases against gnomAD (EAS) and SG10K_Health controls revealed 23 concordant variants that were significantly enriched (FDR-adjusted p &lt; 0.05). Fourteen variants were consistently enriched in breast cancer cases across all comparisons (FDR-adjusted p &lt; 0.05). Seven variants in GPRIN2, NRG1, MYO5A, CLIP1 , CUX1, GNAS and MGA were confirmed by Sanger sequencing. Conclusions In conclusion, we have identified pathogenic variants in genes associated with breast cancer predisposition. Importantly, many of these variants were significant in a second case cohort from dbGaP, suggesting that the strategy of using case–control analysis to select variants could potentially be utilized for identifying variants associated with cancer susceptibility. 

/pdf/whole-exome-sequencing-of-brca-negative-breast-cancer-swor74nw.pdf

Whole-exome sequencing of BRCA-negative breast cancer patients and case–control analyses identify variants associated with breast cancer susceptibility

A nucleic acid probe or a set of such probes in a microarray is provided. The probe or probe set is used for the prognosis of patients with papillary cell renal cell carcinoma (PRCC), wherein aggressive and non-aggressive PRCC tumor types are characterized by differential expression profiles of genes that hybridize with one or more of these probes. Microarrays and kits for carrying out expression profiling of tumor tissue and methods of using them are disclosed.

Microarray gene expression profiling in classes of papillary renal cell carcinoma

Dear Editor, Thrombotic thrombocytopenic purpura (TTP) is a systemic disorder that presents acutely with multiple organ failure. Although defi ned classically as a syndrome with a pentad of features, it is accepted now that a diagnosis can be made with the dyad of microangiopathic haemolytic anaemia and thrombocytopenia. It is recognised that patients with malignancy have a higher risk of getting a thrombotic microangiopathy like TTP. We report a 4th case of TTP in prostate cancer and offer a feasible alternative treatment strategy.

Management of thrombotic thrombocytopenic purpura in metastatic prostate cancer with only endocrine therapy.

https://www.europeanurology.com/article/S0302-2838(15)00965-3/pdf/doubling-down-on-mtor-inhibition-harnessing-zebra-for-insights

Doubling Down on mTOR Inhibition: Harnessing ZEBRA for Insights

451 Background: Several reports have indicated that VEGF targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in the Asian versus Caucasian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterized. Methods: Eight centers participating in the International mRCC Database Consortium with available dose reduction data on patients with mRCC treated with VEGF targeted therapy were included in this analysis. Asian patients were derived from centers in Korea and Singapore. Results: 1024 patients with a median follow-up of 29.4 months were included in this analysis. Baseline characteristics are below. The percentage of dose modifications/reductions between non-Asians and Asians was similar (55% vs 61% p=0.1197) but more patients completely discontinued treatment due to toxicity in the non-Asian vs the Asian group (28% vs 21% p=0.0197). When adjusted for the Heng et al poor prognostic criteria, there was no difference in overall survival (HR 0.887...

Min-Han Tan

Papers

Whole-exome sequencing of BRCA-negative breast cancer patients and case–control analyses identify variants associated with breast cancer susceptibility

Microarray gene expression profiling in classes of papillary renal cell carcinoma

Management of thrombotic thrombocytopenic purpura in metastatic prostate cancer with only endocrine therapy.

Doubling Down on mTOR Inhibition: Harnessing ZEBRA for Insights

Vascular endothelial growth factor (VEGF) therapy in metastatic renal cell carcinoma (mRCC): Differences between Asian and non-Asian patients.