Identifying somatic fingerprints of cancers defined by germline and environmental risk factors Journal Article
| Authors: | Chakraborty, S.; Guan, Z.; Kostrzewa, C. E.; Shen, R.; Begg, C. B. |
| Article Title: | Identifying somatic fingerprints of cancers defined by germline and environmental risk factors |
| Abstract: | 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. © 2024 Wiley Periodicals LLC. |
| Keywords: | somatic mutations; germline mutations; germline-somatic associations; meta-features; multilevel regression modeling; topic models |
| Journal Title: | Genetic Epidemiology |
| Volume: | 48 |
| Issue: | 8 |
| ISSN: | 0741-0395 |
| Publisher: | John Wiley & Sons, Inc. |
| Date Published: | 2024-12-01 |
| Start Page: | 455 |
| End Page: | 467 |
| Language: | English |
| DOI: | 10.1002/gepi.22565 |
| PUBMED: | 38686586 |
| PROVIDER: | scopus |
| PMCID: | PMC11522022 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Colin B. Begg -- Source: Scopus |
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