The Role of Selection for Function in Aging and Chronic Diseases: A Novel Evolutionary Perspective.

Aging, and by extension age-related diseases, has traditionally been understood through classical evolutionary genetic models, such as the mutation accumulation and antagonistic pleiotropy theories. However, these frameworks primarily focus on the declining efficacy of organismal-level selection against mutations with deleterious effects in late life. Here, we propose a novel hypothesis: many chronic diseases associated with aging may emerge, at least in part, as a result of selection acting at lower organizational levels, including non-replicative biological entities, enabled by the relaxation of selective pressures that constrained within-organism evolutionary processes in early life.

Increasing incidence of breast cancer in young women over time.

The incidence of early-onset breast cancer (EOBC) has recently been shown to be increasing over time in the US and the UK. Using national cancer registries data including 229,352 BC cases, we show that the incidence rate of EOBC in France increased steadily from 1990 to 2023, rising from 16.1 (95 % CI: 14.

Reverse genotyping: unveiling Alu element insertion as a new cause of Kabuki syndrome using DNA methylation signature.

Kabuki syndrome type 1 (KS1) is a monogenic disorder arising from pathogenic variants within KMT2D and characterized by syndromic neurodevelopmental delay. We report the retrospective identification of a causative AluY insertion within KMT2D in a genetically unsolved individual with typical KS1 features, after identification of a DNA methylation signature. This is the first documentation of Alu insertion as a molecular mechanism responsible for KS1.

Screening Mammography and Breast Cancer: Variation in Risk with Rare Deleterious or Predicted Deleterious Variants in DNA Repair Genes.

Background: Women with a familial predisposition to breast cancer (BC) are offered screening at earlier ages and more frequently than women from the general population.

Methods: We evaluated the effect of screening mammography in 1552 BC cases with a hereditary predisposition to BC unexplained by or and 1363 unrelated controls. Participants reported their lifetime mammography exposures in a detailed questionnaire.

Li-Fraumeni syndrome: a germline splice variant reveals a novel physiological alternative transcript.

Background: Li-Fraumeni syndrome (LFS) predisposes individuals to a wide range of cancers from childhood onwards, underscoring the crucial need for accurate interpretation of germline variants for optimal clinical management of patients and families. Several unclassified variants, particularly those potentially affecting splicing, require specialised testing. One such example is the NM_000546.

Homologous recombination deficiency in ovarian cancer: Global expert consensus on testing and a comparison of companion diagnostics.

Background: Poly (ADP ribose) polymerase inhibitors (PARPis) are a treatment option for patients with advanced high-grade serous or endometrioid ovarian carcinoma (OC). Recent guidelines have clarified how homologous recombination deficiency (HRD) may influence treatment decision-making in this setting. As a result, numerous companion diagnostic assays (CDx) have been developed to identify HRD.

When Do Tumours Develop? Neoplastic Processes Across Different Timescales: Age, Season and Round the Circadian Clock.

While it is recognised that most, if not all, multicellular organisms harbour neoplastic processes within their bodies, the timing of when these undesirable cell proliferations are most likely to occur and progress throughout the organism's lifetime remains only partially documented. Due to the different mechanisms implicated in tumourigenesis, it is highly unlikely that this probability remains constant at all times and stages of life. In this article, we summarise what is known about this variation, considering the roles of age, season and circadian rhythm.

Characterizing intragenic duplication breakpoints in a triple-negative breast cancer case using long-read sequencing.

Introduction: Accurate identification and characterization of Large Genomic Rearrangements (LGR), especially duplications, are crucial for precise diagnosis and risk assessment. In this report, we characterized an intragenic duplication breakpoint of to determine its pathogenicity significance.

Methods: A 52-year-old female with triple-negative breast cancer was diagnosed with a novel LGR.

Recommandations francophones pour la pratique clinique concernant la prise en charge des cancers du sein de Saint-Paul-de-Vence 2022-2023.

With more than 60,000 new cases of breast cancer in mainland France in 2023 and 8% of all cancer deaths, breast cancer is the leading cancer in women in terms of incidence and mortality. While the number of new cases has almost doubled in 30 years, the percentage of patients at all stages alive at 5 years (87%) and 10 years (76%) testifies to the major progress made in terms of screening, characterisation and treatment. However, this progress, rapid as it is, needs to be evaluated and integrated into an overall strategy, taking into account the characteristics of the disease (stage and biology), as well as those of the patients being treated.

The effect of placentation type, litter size, lactation and gestation length on cancer risk in mammals.

Reproduction is a central activity for all living organisms but is also associated with a diversity of costs that are detrimental for survival. Until recently, the cost of cancer as a selective force has been poorly considered. Considering 191 mammal species, we found cancer mortality was more likely to be detected in species having large, rather than low, litter sizes and long lactation lengths regardless of the placentation types.

No evidence that spice consumption is a cancer prevention mechanism in human populations.

Background: Why humans historically began to incorporate spices into their diets is still a matter of unresolved debate. For example, a recent study (Bromham et al. There is little evidence that spicy food in hot countries is an adaptation to reducing infection risk.

Association and performance of polygenic risk scores for breast cancer among French women presenting or not a familial predisposition to the disease.

Background: Three partially overlapping breast cancer polygenic risk scores (PRS) comprising 77, 179 and 313 SNPs have been proposed for European-ancestry women by the Breast Cancer Association Consortium (BCAC) for improving risk prediction in the general population. However, the effect of these SNPs may vary from one country to another and within a country because of other factors.

Objective: To assess their associated risk and predictive performance in French women from (1) the CECILE population-based case-control study, (2) BRCA1 or BRCA2 (BRCA1/2) pathogenic variant (PV) carriers from the GEMO study, and (3) familial breast cancer cases with no BRCA1/2 PV and unrelated controls from the GENESIS study.

PARP Inhibitors: A Major Therapeutic Option in Endocrine-Receptor Positive Breast Cancers.

Recently, OlympiAD and EMBRACA trials demonstrated the favorable efficacy/toxicity ratio of PARPi, compared to chemotherapy, in patients with HER2-negative metastatic breast cancers (mBC) carrying a germline BRCA mutation. PARPi have been largely adopted in triple-negative metastatic breast cancer, but their place has been less clearly defined in endocrine-receptor positive, HER2 negative (ER+/ HER2-) mBC. The present narrative review aims at addressing this question by identifying the patients that are more likely benefit from PARPi.

On the need for integrating cancer into the One Health perspective.

Recent pandemics have highlighted the urgency to connect disciplines studying animal, human, and environment health, that is, the "One Health" concept. The One Health approach takes a holistic view of health, but it has largely focused on zoonotic diseases while not addressing oncogenic processes. We argue that cancers should be an additional key focus in the One Health approach based on three factors that add to the well-documented impact of humans on the natural environment and its implications on cancer emergence.

No Association of Early-Onset Breast or Ovarian Cancer with Early-Onset Cancer in Relatives in or Mutation Families.

According to clinical guidelines, the occurrence of very early-onset breast cancer (VEO-BC) (diagnosed ≤ age 30 years) or VEO ovarian cancer (VEO-OC) (diagnosed ≤ age 40 years) in families with or mutation () prompts advancing the age of risk-reducing strategies in relatives. This study aimed to assess the relation between the occurrence of VEO-BC or VEO-OC in families with and age at BC or OC diagnosis in relatives. We conducted a retrospective multicenter study of 448 consecutive families with from 2003 to 2018.

Diagnostic chest X-rays and breast cancer risk among women with a hereditary predisposition to breast cancer unexplained by a BRCA1 or BRCA2 mutation.

Background: Diagnostic ionizing radiation is a risk factor for breast cancer (BC). BC risk increases with increased dose to the chest and decreases with increased age at exposure, with possible effect modification related to familial or genetic predisposition. While chest X-rays increase the BC risk of BRCA1/2 mutation carriers compared to non-carriers, little is known for women with a hereditary predisposition to BC but who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation.

Identifying key questions in the ecology and evolution of cancer.

The application of evolutionary and ecological principles to cancer prevention and treatment, as well as recognizing cancer as a selection force in nature, has gained impetus over the last 50 years. Following the initial theoretical approaches that combined knowledge from interdisciplinary fields, it became clear that using the eco-evolutionary framework is of key importance to understand cancer. We are now at a pivotal point where accumulating evidence starts to steer the future directions of the discipline and allows us to underpin the key challenges that remain to be addressed.

Conditional Probability of Survival and Prognostic Factors in Long-Term Survivors of High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancers (HGSOC) are heterogeneous, often diagnosed at an advanced stage, and associated with poor overall survival (OS, 39% at five years). There are few data about the prognostic factors of late relapses in HGSOC patients who survived ≥five years, long-term survivors (LTS). The aim of our study is to assess the probability of survival according to the already survived time from diagnosis.

Calibration of Pathogenicity Due to Variant-Induced Leaky Splicing Defects by Using Exon 3 as a Model System.

is a clinically actionable gene implicated in breast and ovarian cancer predisposition that has become a high priority target for improving the classification of variants of unknown significance (VUS). Among all VUS, those causing partial/leaky splicing defects are the most challenging to classify because the minimal level of full-length (FL) transcripts required for normal function remains to be established. Here, we explored exon 3 (e3) as a model for calibrating variant-induced spliceogenicity and estimating thresholds for haploinsufficiency.