Interestingly, the NOTCH1 gene rs139994842 that shares linkage with SMs is associated with HNSCC risk (OR = 3.46), increasing when SMs in NOTCH1 are involved (OR = 7.74), and furthermore when there are SMs in conjunction to betel quid chewing (OR = 32.11), which is a related independent environmental risk factor after adjusting for substances use (alcohol, betel quid, cigarettes) and age.