Mingyi Wang

Objective. To determine the exposure to aflatoxin B1 (AFB1) in southern Mexico and the presence of the aflatoxin signature mutation in hepatocellular carcinoma (HCC) tissue from patients from a cancer referral center. Materials and methods. We estimated the prevalence and distribution of AFB1 in a representative sample of 100 women and men from Chiapas using the National Health and Nutrition Survey 2018-19. We also examined the presence of the aflatoxin signature mutation in codon 249 (R249S), and other relevant mutations of the TP53 gene in HCC tissue blocks from 24 women and 26 men treated in a national cancer referral center. Results. The prevalence of AFB1 in serum samples was 85.5% (95%CI 72.1-93.1) and the median AFB1 was 0.117 pg/μL (IQR, 0.050–0.350). We detected TP53 R249S in three of the 50 HCCs (6.0%) and observed four other G>T transversions potentially induced by AFB1. Conclusion. Our analysis provides evidence that AFB1 may have a relevant role on HCC etiology in Mexico.

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.

It is challenging to identify somatic variants from high-throughput sequence reads due to tumor heterogeneity, sub-clonality, and sequencing artifacts. In this study, we evaluated the performance of eight primary somatic variant callers and multiple ensemble methods using both real and synthetic whole-genome sequencing, whole-exome sequencing, and deep targeted sequencing datasets with the NA12878 cell line. The test results showed that a simple consensus approach can significantly improve performance even with a limited number of callers and is more robust and stable than machine learning based ensemble approaches. To fully exploit the multi-callers, we also developed a software package, SomaticCombiner, that can combine multiple callers and integrates a new variant allelic frequency (VAF) adaptive majority voting approach, which can maintain sensitive detection for variants with low VAFs.

Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). We investigated ITH of somatic copy number alterations (SCNAs), DNA methylation, and point mutations in lung cancer driver genes in 292 tumor samples from 84 LUAD patients. We found substantial SCNA and methylation ITH, and clonal architecture analyses showed congruent evolutionary trajectories for SCNAs and DNA methylation aberrations. Interestingly, methylation ITH mapping to gene promoter areas or tumor suppressor genes was low. Moreover, ITH composed of genetic and epigenetic mechanisms altering the same cancer driver genes was found in several tumors. To quantify ITH for valid statistical association analyses we developed an average pairwise ITH index (APITH), which does not depend on the number of samples per tumor. APITH indexes for SCNAs and methylation aberrations were both significantly associated with poor prognosis. This study further establishes the important clinical implications of genetic and epigenetic ITH in LUAD.

Disease heterogeneity of immune gene expression patterns of luminal breast cancer (BC) has not been well studied. We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 Asian luminal BC patients and identified three distinct immune subtypes. Tumors in one subtype exhibited signs of T-cell activation, lower ESR1/ESR2 expression ratio and higher expression of immune checkpoint genes, nonsynonymous mutation burden, APOBEC -signature mutations, and increasing body mass index compared to other luminal tumors. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in cases drawn from The Cancer Genome Atlas and a Korean breast cancer study. Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification.