Acquired uniparental disomy (aUPD) leads to homozygosity facilitating identification of monoallelically expressed genes. We analyzed single-nucleotide polymorphism array-based genotyping data of 448 head and neck squamous cell carcinoma (HNSCC) samples from The Cancer Genome Atlas to determine the frequency and distribution of aUPD regions and their association with survival, as well as to gain a better understanding of their influence on the tumor genome. We used expression data from the same dataset to identify differentially expressed genes between groups with and without aUPD. Univariate and multivariable Cox proportional hazards models were performed for survival analysis. We found that 82.14% of HNSCC samples carried aUPD; the most common regions were in chromosome 17p (31.25%), 9p (30.13%), and 9q (27.46%). In univariate analysis, five independent aUPD regions at chromosome 9p, two regions at chromosome 9q, and the CDKN2A region were associated with poor overall survival in all groups, including training and test sets and human papillomavirus (HPV)-negative samples. Forty-three genes in areas of aUPD including PD-L1 and CDKN2A were differentially expressed in samples with aUPD compared to samples without aUPD. In multivariable analysis, aUPD at the CDKN2A region was a significant predictor of overall survival in the whole cohort and in patients with HPV-negative HNSCC. aUPD at specific regions in the genome influences clinical outcomes of HNSCC and may be beneficial for selection of personalized therapy to prolong survival in patients with this disease.

Acquired uniparental disomy (aUPD) is a chromosomal alteration that can lead to homozygosity of existing aberrations. We used data from The Cancer Genome Atlas SNP-based arrays to identify distinct and common aUPD profiles in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Moreover, we tested relevance of aUPD for homozygous deletion (HMD), overall survival (OS), and recurrence-free survival (RFS). Overall, we found significantly higher aUPD (q = 5.34E-09) in LUSC than in LUAD. A significant portion of HMD was associated with aUPD in LUSC (24.9%) and LUAD (19.7%). We identified segmental, whole-chromosome arm and whole-chromosome aUPD, in which whole 7p arm aUPD was restricted to LUSC, while whole-chromosome 3 aUPD was observed only in LUAD, and whole-chromosome 21 aUPD was common to both LUSC and LUAD. The most frequent aUPD and HMD were observed at CDKN2A/B region in both LUAD and LUSC. In LUAD, aUPD and HMD at CDKN2A/B region were associated with shorter OS (q < 0.021 and q < 0.005), and RFS (q < 0.005 and q < 0.005), while heterozygous deletion was not associated with OS and RFS. In contrast, no association was found between aUPD at CDKN2A/B region and survival in LUSC. In LUAD, CTLA expression was significantly lower in samples with aUPD at CDKN2A/B regions than in samples without copy number and allele-based changes. Immune infiltration correlated with aUPD or HMD at CDKN2A/B, gain at HLA class I region, and aUPD at whole-chromosome q-arm or whole chromosome in LUAD, but not in LUSC. Both LUSC and LUAD have common and distinct patterns of aUPD regions with differing frequencies of occurrence and associations with outcome.

Using SNP-based microarray data from The Cancer Genome Atlas (TCGA), we investigated isochromosomes (deletion of one arm and duplication of the other arm) and related acquired uniparental disomy in 12 tumor types. We observed a high frequency of isochromosomes (25.98%) across all type of tumors except thyroid cancers. The highest frequency of isochromosomes was found in lung squamous cell carcinoma (54.18%). Moreover, whole-chromosome arm acquired uniparental disomy (aUPD) was common in the deleted arms of isochromosomes. These data are consistent with whole-chromosome arm aUPD likely being a consequence of isochromosomes formation. Our findings implicated aUPD as occurring through error-prone DNA repair of a deleted arm or segment of a chromosome that leads to homozygosity for existing alterations. Isochromosomes were significantly more frequent in TP53 mutated samples than wild types in 6 types of tumors with loss of TP53 function potentially contributing to development of isochromosomes. Isochromosomes are common alterations in cancer, and losing one arm of a chromosome could result in duplication of the lost arm. Duplication of the remaining arm leads promulgation of the effects on any defects in the remaining allele, due to subsequent homozygosity.

Smoking and alcohol intake are major risk factors in head and neck squamous cell carcinomas (HNSCCs). Although the link between TP53 mutation and smoking has been well established, very little is known about the link between acquired uniparental disomy (aUPD) and smoking and/or alcohol consumption or other clinical characteristics. We used TCGA genomic data to investigate whether smoking, alcohol intake, clinical and demographic variables, HPV status and TP53 mutation are associated with aUPD at specific chromosomal regions. In multivariate analysis, we found association between aUPD regions and risk factors and clinical variables of disease. aUPD regions on chromosome 4q, 5q, 9p, 9q, 13q, 17p and CDKN2A occurred significantly more often in patients with TP53-mutated HNSCC than in those with wild-type HNSCC, while aUPD regions on chromosome 9p and at CDKN2A were significantly more frequent in females than in males. Besides, aUPD occurred more frequent in HPV-positive than in HPV-negative samples with all HNSCC and larynx cancers on chromosome 9q 15q and 17p. Moreover, aUPD on CDKN2A region occurred more often in alcohol drinkers than nondrinkers in patients with all HNSCC and oral cavity cancers, while aUPD region on chromosome 5q occurred less in alcohol drinkers than nondrinkers in patients with all HNSCC and oral cavity cancers. Similarly, aUPD region on chromosome 5q occurred less in smokers than nonsmokers in patients with all HNSCC and oral cavity cancers. In conclusion, aUPD regions are not random, and certain regions are associated with risk factors for disease, and with TP53 mutation status.