Childhood obesity and OC

Association between childhood adiposity and gynaecologic cancers: a mendelian randomisation analysis

https://tinyurl.com/mr2nah45

Obesity is a major health problem throughout the developed world. Previous studies have shown increased risks of cancer associated with obesity and being obese means worse survival for those affected.

Determining the level of risk is difficult because of multiple other factors which may mask the effect. This study using the UK genome-wide association study data, sought to determine the association between obesity for girls aged 10 or less with later development of gynaecological cancers of the ovary, endometrium, and cervix. This was achieved by a process known as mendelian randomisation which seeks to use genetic information in a non-biased randomised way, like an RCT.

Findings from the data showed increased risk of ovarian and endometrial cancer but not for cervical cancer. The latter finding is not surprising in that cervical cancer has been shown to be strongly associated with human papilloma virus infection.

The risk of developing ovarian cancer was increased by about 20% for those women who had been obese at the age of 10 or younger. It remains uncertain as to why this is so. However, childhood obesity is associated with early puberty and more lifetime menstrual cycles. Also, obesity causes inflammation. Both these factors are known to increase ovarian cancer risk.

Natural selection causing drug resistance

Tracking clonal evolution during treatment in ovarian cancer using cell-free DNA

https://tinyurl.com/2xtv64nx

Drug resistance is the major cause of death from ovarian cancer. Why this occurs is problematic and varies with individuals. This study looks at the evolving genetic mutations which cause previously effective chemo to lose its ability to control the cancer.

Using new sequence genetic profiling of circulating tumour DNA, this prospective study followed the course of disease for 18 women with ovarian cancer from diagnosis to recurrence. The main finding was that the genetic clones which disabled the chemo response were present at diagnosis for all these women. This suggests that evolutional preselection is occurring, whereby the environment of chemo promotes the increase in effectiveness of harmful genetic clones.

The authors suggest that understanding this evolutionary effect should lead to a change in management, alter the environment, and prevent the preselection. It seems that drug resistance is due to selective expansion of a small set of genetic clones with reduction of normal clone diversity. Early detection would allow personalisation of chemotherapy.

Recurrent OC subtypes

Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer

https://tinyurl.com/47mcxyde

Women unfortunate enough to develop a recurrence of ovarian cancer show a range of responses to repeat chemo. This study looks at the immune response to the cancer and the survival outcomes.

About half of these women show the presence of tumour infiltrating lymphocytes, (TIL), suggesting an active cell-mediated immune response. This is associated with better survival. Most of those women also display defective DNA repair with Homologous Recombination Deficiency (HRD). The immune response is stimulated by increased antigens such as PD-1, which suggest that immunotherapy with immune checkpoint inhibitors could be of benefit. However, in practice this has not seen to be true.

To understand why this is the case the authors reviewed the immune status of abut 600 patients with ovarian cancer using digital pathology. They subdivided the immune response into 4 groups from high to low.

In the presence of HRD, cell-mediated immunity is increased with inflammation. When treated with chemo and PARP inhibitors, prostaglandin E prevents TIL activity by cell death called ferroptosis. Using a mouse model the researchers were able to prevent this using ant-inflammatories and restore the immune response.