Scientific evidence established about the effects of night work on health both in the short term (insomnia, excessive sleepiness, difficulty concentrating or lack of energy) and in the long term (moderately high risk of developing cardiovascular disease, type 2 diabetes, depression, cancer). In light of the scientific evidence, the IARC (International Agency for Research on Cancer) has listed night work as a probable human carcinogen (Group 2). With respect to current knowledge, the present study could provide valuable help in understanding the mechanisms by which circadian rhythm alteration acts at the genetic level in terms of promoting oncogenesis. Furthermore, by studying its association with other risk factors, understand whether there is a pattern of women more susceptible to its oncopromoting action.

Certain bodily functions, such as wakefulness and sleep, regulation of blood pressure and body temperature, the immune system, gene expression, and secretion of hormones--think of cortisol, for example--follow variations that are stably repeated every 24 to 25 hours. The biological clock that marks this cyclical rhythm is represented by neurons in the suprachiasmatic nucleus of the hypothalamus. Of the circadian system, three components should be considered: (a) the input pathways that transmit signals to synchronize the endogenous central clock with the external environment, (b) the central clock generates rhythms, and (c) the output pathways that transmit the signal from the central clock to other regulatory systems in the brain and body. The most powerful regulator of the input pathways is light, which-as is well known-is captured by the five retinal photoreceptors, including the intrinsically photosensitive retinal ganglion cells [ipRGCs], which, through the production of melanopsin, transmit the signal to the central circadian clock. Such physiological mechanisms, which have remained unperturbed for thousands of years, have been disrupted by the spread of artificial lighting, which, inevitably, alters the natural synchronization of the internal clock with sunlight.

The effects that this misalignment produces are clearly visible in night workers who frequently have to expose themselves to light at "atypical" hours. In this sense, in fact, according to current legislation (see Art. 1, Legislative Decree No. 66 of April 8, 2003, implementing Directives 93/104/EC and 2000/34/EC, concerning certain aspects of the organization of working time), a night worker is defined as anyone who works for a period of at least seven consecutive hours including the interval between midnight and 5 a.m. It follows with palpable evidence that there is an increased risk that, under night work conditions, the alteration of the sleep-wake rhythm may take on a chronic character. In this regard, scientific evidence about the effects of night work on short-term health is well established: such as insomnia, excessive sleepiness, difficulty in concentration or lack of energy. While there is also scientific evidence that some repercussions may also occur in the long term. This is, in that case, the moderately high risk of developing cardiovascular disease, type 2 diabetes, depression, and, not least, cancer. Indeed, in 2007, in light of scientific evidence, the IARC (International Agency for Research on Cancer) listed night work as a probable human carcinogen (Group 2). Breast cancer generally represents the second most frequent neoplastic disease in women. The incidence of new cases worldwide in 2017 was estimated to be 1.9 million, higher in industrialized countries. From a pathogenetic point of view, the association between night shift work and breast cancer is highly plausible.

Inclusion Criteria:

• Health workers with any type of contract and qualification (doctors, nurses, OSS) in service at IRCSS AOUBO and AOU "G. Martino" of Messina for at least six months between 1.1.2000 and 31.12.2021
• Age between 20 and 70 years at the start of study follow-up (6 months after recruitment or 1.1.2000)
• Female gender
• For secondary objective 2 of the study only, women exposed to night work must have worked at least 6 night shifts per month in the past six months

Exclusion Criteria:

• Women found to be positive for BRCA1 and BRCA2 genetic mutation (BRCA1 and 2 mutations are searched for by geneticists in sick women for whom there is a consistent suspicion of mutation)
• Women with prior history of breast cancer at the time of recruitment or within six months thereafter.

Health care workers with an employment relationship at IRCCS AOUBO Policlinico di S. Orsola and AOU "G. Martino" of Messina undergoing health surveillance, aged between 20 and 70 years at the time of recruitment (from January 1, 2000 until December 31, 2021).