Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers

Abstract

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.

Genetic analysis of lung cancer reveals novel susceptibility loci and germline impact on somatic mutation burden

“…We additionally noted the variant impacting the MDM4 gene, which is an important p53 regulator. This variant was previously associated with non-glioblastoma tumours 36 and more recently squamous cell carcinomas of the lung and head / neck, 37 although here we noted weak evidence for association in lung adenocarcinoma (Table 1). At 11p11.2 colocalisation analysis showed little evidence for involvement with genes C1QTNF4 (lung) and MTCH2 (brain-cortex), suggesting that these signals are unlikely to explain the lung cancer association, one other candidate is potentially PTPRO which is hypermethylated in several cancers including lung.…”

“…We additionally noted the variant impacting MDM4 gene, an important p53 regulator. This variant was previously associated with non-glioblastoma tumours (Melin et al, 2017) and most recently squamous cell carcinomas of the lung and head and neck (Lesseur, 2020), although here we noted weak evidence for association in lung adenocarcinoma (Table 1). Additionally, our finding at 11p11.2 was reported in GTEx as an eQTL for C1QTNF4 (lung) and MTCH2 (brain-cortex) but colocalization analysis showed little evidence that these signals were the same.…”

As a Novel Tumor Suppressor, LHPP Promotes Apoptosis by Inhibiting the PI3K/AKT Signaling Pathway in Oral Squamous Cell Carcinoma

“…Whole genome sequencing showed that LHPP gene was a risk factor for alcohol dependence and severe depressive disorder [24,25]. Several GWAS revealed LHPP as a susceptibility gene for primary open-angle glaucoma, oral carcinoma, pharyngeal carcinoma, and acute lymphoblastic leukemia [26][27][28] .The researchers found that LHPP mutation, decreased expression, and elevated levels of histidine phosphorylation were the key factors for tumor genesis in esophageal, skin, head and neck, stomach, breast, bladder, lung, liver, and pancreas tumor tissues [29].Therefore, LHPP is expected to be one of the effective markers and potential therapeutic targets in the diagnosis of OSCC cancer, and its function and mechanism of function remain to be further studied. In this study, according to the TCGA database and DEG analysis, LHPP is down-regulated in OSCC and is highly expressed in normal samples, and the trend in paired samples is the same, the survival analysis indicated that LHPP is a risk factor and is interrelated with the survival and prognosis of patients.…”

“…The latest research suggested that YTHDF2 could mediate the mRNA degradation of LHPP and NKX3-1 in a m6A-dependent manner for regulating the progression of prostate cancer tumors induced by AKT phosphorylation [8]. A search in the databases of TCGA and the International Cancer Genome Consortium (ICGC) found 49 LHPP mutations, 49 LHPP mutations, (e.g., liver (1), skin (1), breast (1), bladder (1), stomach (2), head and neck (2), esophagus (2)) [9]. The genome-wide association study (GWAS) also showed that the LHPP locus 10q26.13 (rs201982221, LHPP) is a significantly related locus in oral cancer carcinoma and pharyngeal cancer carcinoma.…”

Genetic Predisposition to Persistent Human Papillomavirus-Infection and Virus-Induced Cancers

“…A recent meta-analysis of GWAS data of 61,961 controls and 13,887 cases of UADT cancers, including squamous cell carcinoma (SCC) of the lung, oropharyngeal region, larynx and esophagus in individuals of European ancestry identified a significant region within 2q33.1 (rs56321285, TMEM273) and 3 other suggestive regions at 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Genebased analyses also identify a list of SCC-related genes that are involved in DNA damage response and epigenetic regulation pathways [103]. Despite the HPV status was not systematically investigated in this study, these results suggest the possible existence of some overlap in the genetic factors influencing the risk of UADT cancers in European populations.…”