Radiation-induced lung injury after breast cancer treatment: incidence in the CANTO-RT cohort and associated clinical and dosimetric risk factors.

Purpose: Radiation-induced lung injury (RILI) is strongly associated with various clinical conditions and dosimetric parameters. Former studies have led to reducing radiotherapy (RT) doses to the lung and have favored the discontinuation of tamoxifen during RT. However, the monocentric design and variability of dosimetric parameters chosen have limited further improvement. The aim of our study was to assess the incidence of RILI in current practice and to determine clinical and dosimetric risk factors associated with RILI occurrence. Material and methods: Data from 3 out of the 10 top recruiting centers in CANTO-RT, a subset of the CANTO prospective longitudinal cohort (NCT01993498), were retrospectively analyzed for RILI occurrence. This cohort, which recruited invasive cT0-3 cN0-3 M0 breast cancer patients from 2012 to 2018, prospectively recorded the occurrence of adverse events by questionnaires and medical visits at the end of, and up to 60 months after treatment. RILI adverse events were defined in all patients by the association of clinical symptoms and compatible medical imaging. Results: RILI was found in 38/1565 (2.4%) patients. Grade II RILI represented 15/38 events (39%) and grade III or IV 2/38 events (6%). There were no grade V events. The most frequently used technique for treatment was 3D conformational RT (96%). In univariable analyses, we confirmed the association of RILI occurrence with pulmonary medical history, absence of cardiovascular disease medical history, high pT and pN, chemotherapy use, nodal RT. All dosimetric parameters were highly correlated and had close predictive value. In the multivariable analysis adjusted for chemotherapy use and nodal involvement, pulmonary medical history (OR=3.05, p<0.01) and high V30 Gy (OR=1.06, p=0.04) remained statistically significant risk factors for RILI occurrence. V30 Gy >15% was significantly associated with RILI occurrence in a multivariable analysis (OR=3.07, p=0.03). Conclusion: Our study confirms the pulmonary safety of breast 3D RT in CANTO-RT. Further analyses with modern radiation therapy techniques such as IMRT are needed. Our results argue in favor of a dose constraint to the ipsilateral lung using V30 Gy not exceeding 15%, especially in patients presenting pulmonary medical history. Pulmonary disease records should be taken into account for RT planning.

A new frontier in Fanconi anemia: From DNA repair to ribosome biogenesis.

Described by Guido Fanconi almost 100 years ago, Fanconi anemia (FA) is a rare genetic disease characterized by developmental abnormalities, bone marrow failure (BMF) and cancer predisposition. The proteins encoded by FA-mutated genes (FANC proteins) and assembled in the so-called FANC/BRCA pathway have key functions in DNA repair and replication safeguarding, which loss leads to chromosome structural aberrancies. Therefore, since the 1980s, FA has been considered a genomic instability and chromosome fragility syndrome. However, recent findings have demonstrated new and unexpected roles of FANC proteins in nucleolar homeostasis and ribosome biogenesis, the alteration of which impacts cellular proteostasis. Here, we review the different cellular, biochemical and molecular anomalies associated with the loss of function of FANC proteins and discuss how these anomalies contribute to BMF by comparing FA to other major inherited BMF syndromes. Our aim is to determine the extent to which alterations in the DNA damage response in FA contribute to BMF compared to the consequences of the loss of function of the FANC/BRCA pathway on the other roles of the pathway.

Fanconi anemia A protein participates in nucleolar homeostasis maintenance and ribosome biogenesis.

Fanconi anemia (FA), the most common inherited bone marrow failure and leukemia predisposition syndrome, is generally attributed to alterations in DNA damage responses due to the loss of function of the DNA repair and replication rescue activities of the FANC pathway. Here, we report that FANCA deficiency, whose inactivation has been identified in two-thirds of FA patients, is associated with nucleolar homeostasis loss, mislocalization of key nucleolar proteins, including nucleolin (NCL) and nucleophosmin 1 (NPM1), as well as alterations in ribosome biogenesis and protein synthesis. FANCA coimmunoprecipitates with NCL and NPM1 in a FANCcore complex-independent manner and, unique among the FANCcore complex proteins, associates with ribosomal subunits, influencing the stoichiometry of the translational machineries. In conclusion, we have identified unexpected nucleolar and translational consequences specifically associated with FANCA deficiency that appears to be involved in both DNA damage and nucleolar stress responses, challenging current hypothesis on FA physiopathology.

A never-ending story: the steadily growing family of the FA and FA-like genes

Abstract Among the chromosome fragility-associated human syndromes that present cancer predisposition, Fanconi anemia (FA) is unique due to its large genetic heterogeneity. To date, mutations in 21 genes have been associated with an FA or an FA-like clinical and cellular phenotype, whose hallmarks are bone marrow failure, predisposition to acute myeloid leukemia and a cellular and chromosomal hypersensitivity to DNA crosslinking agents exposure. The goal of this review is to trace the history of the identification of FA genes, a history that started in the eighties and is not yet over, as indicated by the cloning of a twenty-first FA gene in 2016.

A never-ending story: the steadily growing family of the FA and FA-like genes.

Among the chromosome fragility-associated human syndromes that present cancer predisposition, Fanconi anemia (FA) is unique due to its large genetic heterogeneity. To date, mutations in 21 genes have been associated with an FA or an FA-like clinical and cellular phenotype, whose hallmarks are bone marrow failure, predisposition to acute myeloid leukemia and a cellular and chromosomal hypersensitivity to DNA crosslinking agents exposure. The goal of this review is to trace the history of the identification of FA genes, a history that started in the eighties and is not yet over, as indicated by the cloning of a twenty-first FA gene in 2016.