Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement

Abstract

The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an "average sex "or a pathogenic variant in an "average Lynch syndrome gene" and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.

Fig. 1

Cumulative incidences of cancers in male and female carriers subjected to colonoscopy stratified by gene, and sex and age (50 and 75 y.o.a.), ordered by incidence in path_MLH1 carriers. The graphs are based on figures given in [14]

Fig. 2

Median ages of onset of cancers in male and female carriers subjected to colonoscopy, by gene and sex, ordered by median ages in path_MMR carriers. The graphs are based on figures given in [14]

Fig. 3

10-year survival following cancer in different organs in path_MMR carriers subjected to early diagnosis and treatment including colonoscopy. The graph is based on figures given in [14]. While there was no difference in survival between carriers of path_MMR variants by gene, cancer in path_MSH6 and path_PMS2 carriers were not frequent enough to measure survival apart from after endometrial cancer in path_MSH6 carriers

Fig. 4

Cumulative incidence of death at 75 years of age following cancer in male and female carriers subjected to colonoscopy, by gene. The graphs are based on figures given in [14]