Consensus report of the 8 and 9th Weinman Symposia on Gene x Environment Interaction in carcinogenesis: novel opportunities for precision medicine

Abstract

The relative contribution of intrinsic genetic factors and extrinsic environmental ones to cancer aetiology and natural history is a lengthy and debated issue. Gene-environment interactions (G x E) arise when the combined presence of both a germline genetic variant and a known environmental factor modulates the risk of disease more than either one alone. A panel of experts discussed our current understanding of cancer aetiology, known examples of G × E interactions in cancer, and the expanded concept of G × E interactions to include somatic cancer mutations and iatrogenic environmental factors such as anti-cancer treatment. Specific genetic polymorphisms and genetic mutations increase susceptibility to certain carcinogens and may be targeted in the near future for prevention and treatment of cancer patients with novel molecularly based therapies. There was general consensus that a better understanding of the complexity and numerosity of G × E interactions, supported by adequate technological, epidemiological, modelling and statistical resources, will further promote our understanding of cancer and lead to novel preventive and therapeutic approaches.

Fig. 1

Gene–environment and cancer pathogenesis. Both genetics and environment interact to affect the microenvironment from which ultimately causes cancer to develop in the first place and then progress

Fig. 2

The complexity of gene–environment interactions. Including somatic cancer mutations and anti-cancer treatments further increases the layers of gene–environment interactions, providing us with the opportunity to increase our understand the of complexity of the cancer phenomenon

Fig. 3

Environmental pressure and cancer susceptibility. A number of extrinsic factors associated to lifestyle, early-life influence or pre-existing chronic conditions exerts pressure on cancer insurgence. The genetic background, including somatic mutations, germline mutations and single nucleotide polymorphism contributes to the outcome of the impact of these environmental factors on the organism. Some extrinsic factors can also promote alteration of the genetic information producing mutagenic events that trigger cancer

Fig. 4

Asbestos pathogenesis leads to mesothelioma. Asbestos fibers travel to pleura and cause human mesothelial cells (HM) to die of necrosis, leading to the release of HMGB1 into the extracellular space. HMGB1 induces macrophages and other inflammatory cells to accumulate and triggers the inflammatory response and leads to the secretion of cytokines such as TNF-α and IL-1β, which stimulate survival signalling pathways that increase survival of asbestos-damaged HM. This allows key genetic alterations to accumulate within HM that sustain asbestos-induced DNA damage that over time may lead to HM transformation and mesothelioma development

Fig. 5

Ca²⁺ transfer from ER to mitochondria at the MAM sites. Ca²⁺ released from ER through IP₃Rs flows into mitochondria matrix through VDAC in the outer mitochondrial membranes and MCU in the inner mitochondrial membranes. Optimal levels of Ca²⁺ transfer to mitochondria is necessary for mitochondrial metabolism and energy production (left). Excessive Ca²⁺ flux into mitochondria results release of pro-apoptotic proteins into cytosol, and results in apoptosis (middle). Suppression of basal mitochondrial Ca²⁺ uptake induces reduction in ATP production and autophagy in normal cells. Autophagy is not enough for survival of cancer cells (right) [155]

Fig. 6

Obesity and hyperinsulinemia influence cancer development and progression. Accumulation of adipose tissue in obesity systemically alters metabolic homeostasis, affecting endocrine signalling between organs and leading to condition such as chronic hyperinsulinemia. Insulin activates signalling pathways, including PI3-K and MAPK, which are generally required to sustain cancer cells. Overall these mechanisms might both contribute to reduction of physiological barriers against tumour ormation and promote cancer progression