Aggregation of melanoma tumour site within Western Australian families.

BACKGROUND: Evidence is emerging that melanoma has distinct aetiologic pathways and subtypes, characterized by factors like anatomic site of the tumour. To explore genetic influences on anatomic subtypes, we examined the extent to which melanomas in first-degree relatives shared the same body site of occurrence. METHODS: Population-level linked data was used to identify the study population of over 1.5 million individuals born in Western Australia between 1945 and 2014, and their first-degree relatives. There were 1009 pairs of invasive tumours from 677 family pairs, each categorised by anatomic site. Greater than expected representation of site-concordant pairs would suggest the presence of genetic factors that predispose individuals to site-specific melanoma. RESULTS: Comparing observed versus expected totals, we observed a modest increase in site concordance for invasive head/neck and truncal tumours (P=0.02). A corresponding analysis including in situ tumours showed a similar concordance (P=0.05). No further evidence of concordance was observed when stratified by sex. CONCLUSION: In conclusion, modest evidence of aggregation was observed but with inconsistent patterns between sites. Results suggest that further investigation into the familial aggregation of melanoma by tumour site is warranted, with the inclusion of genetic data in order to disentangle the relative contributions of genetic and environmental factors.

Identifying somatic fingerprints of cancers defined by germline and environmental risk factors.

Numerous studies over the past generation have identified germline variants that increase specific cancer risks. Simultaneously, a revolution in sequencing technology has permitted high-throughput annotations of somatic genomes characterizing individual tumors. However, examining the relationship between germline variants and somatic alteration patterns is hugely challenged by the large numbers of variants in a typical tumor, the rarity of most individual variants, and the heterogeneity of tumor somatic fingerprints. In this article, we propose statistical methodology that frames the investigation of germline-somatic relationships in an interpretable manner. The method uses meta-features embodying biological contexts of individual somatic alterations to implicitly group rare mutations. Our team has used this technique previously through a multilevel regression model to diagnose with high accuracy tumor site of origin. Herein, we further leverage topic models from computational linguistics to achieve interpretable lower-dimensional embeddings of the meta-features. We demonstrate how the method can identify distinctive somatic profiles linked to specific germline variants or environmental risk factors. We illustrate the method using The Cancer Genome Atlas whole-exome sequencing data to characterize somatic tumor fingerprints in breast cancer patients with germline BRCA1/2 mutations and in head and neck cancer patients exposed to human papillomavirus.

Topical hidden genome: discovering latent cancer mutational topics using a Bayesian multilevel context-learning approach.

Inferring the cancer-type specificities of ultra-rare, genome-wide somatic mutations is an open problem. Traditional statistical methods cannot handle such data due to their ultra-high dimensionality and extreme data sparsity. To harness information in rare mutations, we have recently proposed a formal multilevel multilogistic "hidden genome" model. Through its hierarchical layers, the model condenses information in ultra-rare mutations through meta-features embodying mutation contexts to characterize cancer types. Consistent, scalable point estimation of the model can incorporate 10s of millions of variants across thousands of tumors and permit impressive prediction and attribution. However, principled statistical inference is infeasible due to the volume, correlation, and noninterpretability of mutation contexts. In this paper, we propose a novel framework that leverages topic models from computational linguistics to effectuate dimension reduction of mutation contexts producing interpretable, decorrelated meta-feature topics. We propose an efficient MCMC algorithm for implementation that permits rigorous full Bayesian inference at a scale that is orders of magnitude beyond the capability of existing out-of-the-box inferential high-dimensional multi-class regression methods and software. Applying our model to the Pan Cancer Analysis of Whole Genomes dataset reveals interesting biological insights including somatic mutational topics associated with UV exposure in skin cancer, aging in colorectal cancer, and strong influence of epigenome organization in liver cancer. Under cross-validation, our model demonstrates highly competitive predictive performance against blackbox methods of random forest and deep learning.

Adaptation of a mutual exclusivity framework to identify driver mutations within oncogenic pathways.

Distinguishing genomic alterations in cancer-associated genes that have functional impact on tumor growth and disease progression from the ones that are passengers and confer no fitness advantage have important clinical implications. Evidence-based methods for nominating drivers are limited by existing knowledge on the oncogenic effects and therapeutic benefits of specific variants from clinical trials or experimental settings. As clinical sequencing becomes a mainstay of patient care, applying computational methods to mine the rapidly growing clinical genomic data holds promise in uncovering functional candidates beyond the existing knowledge base and expanding the patient population that could potentially benefit from genetically targeted therapies. We propose a statistical and computational method (MAGPIE) that builds on a likelihood approach leveraging the mutual exclusivity pattern within an oncogenic pathway for identifying probabilistically both the specific genes within a pathway and the individual mutations within such genes that are truly the drivers. Alterations in a cancer-associated gene are assumed to be a mixture of driver and passenger mutations with the passenger rates modeled in relationship to tumor mutational burden. We use simulations to study the operating characteristics of the method and assess false-positive and false-negative rates in driver nomination. When applied to a large study of primary melanomas, the method accurately identifies the known driver genes within the RTK-RAS pathway and nominates several rare variants as prime candidates for functional validation. A comprehensive evaluation of MAGPIE against existing tools has also been conducted leveraging the Cancer Genome Atlas data.