Jeffrey Marks

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1-3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10-18.

Detecting microcalcification clusters in mammograms is important to the diagnosis of breast diseases. Previous studies which mainly focused on supervised methods require abundant annotated training data but these data are usually hard to acquire. In this work, we leverage unsupervised convolutional autoencoders and structural similarity (SSIM) based post-processing to detect and localize microcalcification clusters in full-field digital mammograms (FFDMs). Our models were trained by patches extracted from 3,632 normal cases, in total with 16,702 mammograms. Evaluations were conducted in three aspects, including patch-based anomaly detection, pixel-wise microcalcification localization, and microcalcification cluster detection. Specifically, the receiver operating characteristic (ROC) analysis was used for patch-based anomaly detection. Then, a pixel-wise ROC analysis and a cluster-based free-response ROC (FROC) analysis were performed to assess our detection algorithms of individual microcalcifications and microcalcification clusters, respectively. We achieved a pixel-wise AUC of 0.97 as well as a cluster-based sensitivity of 0.62 at 1 false positive per image and 0.75 at 2.5 false positives per image. Both qualitative and quantitative results demonstrated the effectiveness of our method.

We proposed a two-branch multitask learning convolutional neural network to solve two different but related tasks at the same time. Our main task is to predict occult invasive disease in biopsy proven Ductal Carcinoma in-situ (DCIS), with an auxiliary task of segmenting microcalcifications (MCs). In this study, we collected digital mammography from 604 patients, 400 of which were DCIS. The model used patches with size of 512×512 extracted within a radiologist masked ROIs as input, with outputs including noisy MC segmentations obtained from our previous algorithms, and classification labels from final diagnosis at patients' definite surgery. We utilized a deep multitask model by combining both Unet segmentation networks and prediction classification networks, by sharing first several convolutional layers. The model achieved a patch-based ROC-AUC of 0.69, with a case-based ROC-AUC of 0.61. Segmentation results achieved a dice coefficient of 0.49.