Marie-Gabrielle Dondon

Second primary malignancies in thyroid cancer patients

The late health effects associated with radioiodine (131I) given as treatment for thyroid cancer are difficult to assess since the number of thyroid cancer patients treated at each centre is limited. The risk of second primary malignancies (SPMs) was evaluated in a European cohort of thyroid cancer patients. A common database was obtained by pooling the 2-year survivors of the three major Swedish, Italian, and French cohorts of papillary and follicular thyroid cancer patients. A time-dependent analysis using external comparison was performed. The study concerned 6841 thyroid cancer patients, diagnosed during the period 1934–1995, at a mean age of 44 years. In all, 17% were treated with external radiotherapy and 62% received 131I. In total, 576 patients were diagnosed with a SPM. Compared to the general population of each of the three countries, an overall significantly increased risk of SPM of 27% (95% CI: 15–40) was seen in the European cohort. An increased risk of both solid tumours and leukaemias was found with increasing cumulative activity of 131I administered, with an excess absolute risk of 14.4 solid cancers and of 0.8 leukaemias per GBq of 131I and 105 person-years of follow-up. A relationship was found between 131I administration and occurrence of bone and soft tissue, colorectal, and salivary gland cancers. These results strongly highlight the necessity to delineate the indications of 131I treatment in thyroid cancer patients in order to restrict its use to patients in whom clinical benefits are expected.

Radiation dose, chemotherapy and risk of soft tissue sarcoma after solid tumours during childhood.

Soft tissue sarcoma (STS) is one of the most frequent second primary cancer that occurs during the first 20 years following treatment for a solid cancer in childhood. Our aim was to quantify the risk of STS as a second malignant neoplasm and to investigate its relationship with radiotherapy and chemotherapy. A cohort study of 4,400 3‐year survivors of a first solid cancer diagnosed during childhood in France or the United Kingdom, between 1942 and 1985, was followed 15 years on average. In a partially nested case‐control study, we matched 25 cases of STS and 121 controls for sex, type of first cancer, age at first cancer and duration of follow‐up. Sixteen STS occurred in the cohort, as compared to 0.3 expected from the general population (Standardized Incidence Radio, SIR = 54 (95%CI: 34–89)). The SIR was 113 (95% CI: 62–185) after chemotherapy plus radiotherapy (13 STS), whereas it was 28 (95%CI: 2–125) after chemotherapy alone (1 STS) and 19 (95%CI: 3–60) after radiotherapy alone (2 STS). After adjustment for treatment, there was no evidence of variation in the annual excess of incidence or in the SIR with either age at first cancer or time since 1st cancer. In the case‐control study, the risk of a STS was increased with the square of the dose of radiation to the site of STS development and with the administration of Procarbazine. The increased risk of soft tissue sarcoma that occurred after childhood cancer is independently related to exposure to radiotherapy and Procarbazine. A closer surveillance of children treated with this treatment combination is strongly recommended.

Increased risk of breast cancer among female relatives of patients with ataxia-telangiectasia: a causal relationship?

Increased risk of breast cancer among female relatives of patients with ataxia-telangiectasia: a causal relationship?

Radiotherapy as a risk factor for malignant melanoma after childhood skin hemangioma

The aim of this study was to determine therapy-related risk factors for the development of melanoma after hemangioma. A cohort study was conducted among 4620 patients treated before 16 years of age for skin hemangioma in France. A nested case–control study was also conducted on 13 patients who developed a melanoma (cases) matched with five controls in cohort according to sex, age at the hemangioma diagnostic, the calendar year of occurrence of the hemangioma, and follow-up. The radiation dose received at the site of the melanoma and at the same site in controls was estimated, and named ‘local dose’. A total of 13 melanomas were registered during an average follow-up of overall 35 years, the risk of developing melanoma after a hemangioma treatment was 2.5-fold higher [95% confidence interval (CI): 1.4–4.1] compared with that of the general population, this ratio being only 0.8 (95% CI: 0.05–3.6) in 896 patients who did not receive radiotherapy, but 3.0 (95% CI: 1.6–5.1) after radiotherapy. When adjusting on sex, age, and year of the treatment and follow-up duration, melanoma risk was 11.9 (95% CI: 1.4–123) times higher in patients treated with ytrium 90 than in the ones who did not received radiotherapy. In the case–control study, the risk of melanoma was not linked to the local radiation dose. Indeed, the increase in melanoma risk was observed even for very low local doses. Compared with the corresponding skin areas in patients who did not receive radiotherapy, the ones having received less than 0.001 Gy had a melanoma risk of 3.9 (95% CI: 0.5–32) and those who received more than 0.01 Gy had a risk of 6.9 (0.5–99). This study suggests that radiation therapy of skin hemangioma increases the risk of further melanoma, but we were not able to evidence a relation with the local dose. Nevertheless, childhood treated for hemangioma should be considered at risk for developing melanoma and suspicious pigmented lesions should be carefully evaluated even far from treated areas.

Telomere length, ATM mutation status and cancer risk in Ataxia-Telangiectasia families.

Both telomere length (TL) and ATM mutations have been associated with cancer susceptibility and ATM participates in the signaling of telomere erosion. We wondered whether carriage of an ATM mutation influences age-related TL shortening and cancer risk in ataxia-telangiectasia families.

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3′- untranslated regions (3′-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1- and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3′-UTR and one in BRCA2 3′-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3′-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3′-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.

Familial breast cancer and DNA repair genes: insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing: Contribution of DNA repair genes in familial breast cancer

Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost‐effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of our study was to assess the contribution of rare, deleterious‐predicted variants in DNA repair genes in familial breast cancer (BC) in a well‐characterized and homogeneous population. We analyzed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC (N = 1,207), and general population controls (N = 1,199). Sequencing data were filtered for rare loss‐of‐function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2, ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI, MAST1, POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (ORLoF = 17.4 vs. ORMV = 1.6; p Het = 0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious‐predicted variants in PALB2, ATM and CHEK2 and to add MAST1, POLH, RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates.