Ovarian Clear Cell Carcinoma in Cowden Syndrome.

Cowden syndrome (CS) is an autosomal dominant mendelian disease related to germline pathogenic variants affecting the PTEN-gene. CS is characterized by macrocephaly, mucocutaneous lesions, and an increased risk of breast and thyroid cancers. Rare ovarian cancer cases (mostly embryonic tumors) associated with PTEN have been described in the literature, but no current CS guidelines are available for ovarian cancer risk management. We report on a woman diagnosed with ovarian clear cell carcinoma (OCCC) at 28 years of age. The patient displayed macrocephaly, trichilemmomas, oral papillomatosis, and acral keratosis. A family history of multiple cancer cases within the PTEN-related tumor spectrum was identified. In addition, PET scan and fine-needle biopsy results led to a diagnosis of thyroid follicular neoplasia. PTEN sequencing revealed that she carried a germline inherited pathogenic variant in exon 5 c.388C>T, p.(Arg130*) (NM_000314). Somatic mismatch repair immunohistochemistry analysis showed normal expression, and germline BRCA1/2 sequencing did not reveal pathogenic or likely pathogenic variants. An ovarian cell immunohistochemistry analysis reported total loss of PTEN expression, which strongly suggested the role of PTEN in the oncogenesis of this cancer. Hence, a total thyroid resection was performed instead of thyroid lobectomy and a risk-reducing bilateral mastectomy was discussed. Co-occurrence of this pathogenic germline mutation in PTEN in this patient, early development of OCCC at age 28 years, and total loss of PTEN expression in the tumor might support the involvement of PTEN in the carcinogenesis of her ovarian cancer. We describe a new ovarian cancer case with an atypical histologic type-clear cell carcinoma-in CS. This observation might be the first indication of the need to expand the PTEN-related tumor spectrum to incorporate OCCC. The CS diagnosis significantly changed the therapeutic outcome of this patient.

Early onset breast cancer: differences in risk factors, tumor phenotype, and genotype between North African and South European women.

PURPOSE: This report compares the risk factors, the tumor phenotypes, and the BRCA1/BRCA2 genotype of early onset breast cancer (EOBC) patients between Southern Europe and North Africa. METHODS: Four hundred and fifty six women with invasive EOBC (≤40 years) were prospectively included from four centers in France (n = 270) and four centers in North Africa (Algeria, Egypt, Morocco, Tunisia; n = 186). Life style, tumor phenotype, familial history, BRCA1/BRCA2 genotype were compared between the two populations. RESULTS: We found an older age at menarche, a higher number of childbearing, a more frequent breastfeeding, a higher body mass index, a lower use of oral contraceptives in North African women compared to French women. TNM stage at diagnosis was higher in North African women than in French women. North African women had a lower incidence of triple negative and proliferative (Ki 67 index > 20%) tumors. There was a lower rate of BRCA1 mutation in North Africa (7 vs. 15%, P = 0.02). Three putative BRCA1/2 founder mutations were identified in North Africa. CONCLUSIONS: In EOBC, we found significant differences in risk factors, phenotype and a higher incidence of BRCA1 mutations in Southern Europe as compared to North Africa. The worst prognosis previously reported for EOBC in North Africa is more likely due to a higher stage at diagnosis than to a more aggressive phenotype, since triple negative tumors are more common in Southern Europe and advanced tumors in North Africa.

No Association of Early-Onset Breast or Ovarian Cancer with Early-Onset Cancer in Relatives in BRCA1 or BRCA2 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 BRCA1 or BRCA2 mutation (BRCAm) 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 BRCAm and age at BC or OC diagnosis in relatives. We conducted a retrospective multicenter study of 448 consecutive families with BRCAm from 2003 to 2018. Mean age and 5-year-span distribution of age at BC or OC in relatives were compared in families with or without VEO-BC or VEO-OC. Conditional probability calculation and Cochran-Mantel-Haenszel chi-square tests were used to investigate early-onset cancer occurrence in relatives of VEO-BC and VEO-OC cases. Overall, 15% (19/245) of families with BRCA1m and 9% (19/203) with BRCA2m featured at least one case of VEO-BC; 8% (37/245) and 2% (2/203) featured at least one case of VEO-OC, respectively. The cumulative prevalence of VEO-BC was 5.1% (95% CI 3.6-6.6) and 2.5% (95% CI 1.4-3.6) for families with BRCA1m and BRCA2m, respectively. The distribution of age and mean age at BC diagnosis in relatives did not differ by occurrence of VEO-BC for families with BRCA1m or BRCA2m. Conditional probability calculations did not show an increase of early-onset BC in VEO-BC families with BRCA1m or BRCA2m. Conversely, the probability of VEO-BC was not increased in families with early-onset BC. VEO-BC or VEO-OC occurrence may not be related to young age at BC or OC onset in relatives in families with BRCAm. This finding-together with a relatively high VEO-BC risk for women with BRCAm-advocates for MRI breast screening from age 25 regardless of family history.

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing.

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices.

Role of the general practitioner in the care of BRCA1 and BRCA2 mutation carriers: General practitioner and patient perspectives.

BACKGROUND: General practitioners (GPs) have an increasing role in referring patients with putative mutation in BRCA1/2 genes for genetics consultation and for long-term follow-up of mutation carriers. METHODS: We compared the expectations of the GPs' role according to BRCA1/2 mutation carriers and to GPs themselves. RESULTS: Overall, 38% (58/152) of eligible GPs and 70% (176/252) of eligible patients were surveyed. Although 81% of GPs collected the family history, only 24% considered that they know criteria indicating genetics consultation and 39% sufficient knowledge of BRCA1/2 guidelines to answer patients' questions. Twelve% of GPs were aware of the French national guidelines. Among unsatisfied patients, 40% felt that their GP was able to answer (moderately, sufficiently, or completely) specific questions about BRCA1/2 care as compared with 81% in satisfied patients. Only 33% of GPs reported being informed directly by the geneticist about the patients' results. GPs' main expectations for their role in BRCA1/2 carrier care were psychological support and informing relatives about screening (72% and 71%, respectively), which contrasts with the perceptions of patients, who mainly requested medical advice for BRCA1/2-related care (51%). CONCLUSION: There is an important need for GP training and enhancing interactions between GPs and geneticists to improve the GP's role in BRCA1/2 screening and management.

Guidelines for reporting secondary findings of genome sequencing in cancer genes: the SFMPP recommendations.

In oncology, the expanding use of multi-gene panels to explore familial cancer predisposition and tumor genome analysis has led to increased secondary findings discoveries (SFs) and has given rise to important medical, ethical, and legal issues. The American College of Medical Genetics and Genomics published a policy statement for managing SFs for a list of genes, including 25 cancer-related genes. Currently, there are few recommendations in Europe. From June 2016 to May 2017, the French Society of Predictive and Personalized Medicine (SFMPP) established a working group of 47 experts to elaborate guidelines for managing information given on the SFs for genes related to cancers. A subgroup of ethicists, lawyers, patients' representatives, and psychologists provided ethical reflection, information guidelines, and materials (written consent form and video). A subgroup with medical expertise, including oncologists and clinical and molecular geneticists, provided independent evaluation and classification of 60 genes. The main criteria were the "actionability" of the genes (available screening or prevention strategies), the risk evaluation (severity, penetrance, and age of disease onset), and the level of evidence from published data. Genes were divided into three classes: for class 1 genes (n = 36), delivering the information on SFs was recommended; for class 2 genes (n = 5), delivering the information remained questionable because of insufficient data from the literature and/or level of evidence; and for class 3 genes (n = 19), delivering the information on SFs was not recommended. These guidelines for managing SFs for cancer-predisposing genes provide new insights for clinicians and laboratories to standardize clinical practices.

Uptake of a randomized breast cancer prevention trial comparing letrozole to placebo in BRCA1/2 mutations carriers: the LIBER trial.

Women with germline BRCA1 or BRCA2 (BRCA1/2) mutations are considered as an extreme risk population for developing breast cancer. Prophylactic mastectomy provides a valid option to reduce such risk, impacting however, the quality of life. Medical prevention by aromatase inhibitor that has also recently shown to have preventive effect may thus be considered as an alternative. LIBER is an ongoing double-blind, randomized phase III trial to evaluate the efficacy of 5-year letrozole versus placebo to decrease breast cancer incidence in post-menopausal BRCA1/2 mutation carriers (NCT00673335). We present data on the uptake of this trial. We compared characteristics of women in the LIBER trial (n = 113) to those of women enrolled in the prospective ongoing national GENEPSO cohort (n = 1,505). Uptake was evaluated through a survey sent to all active centres, with responses obtained from 17 to the 20 (85%) centres. According to the characteristics of the women enrolled in the GENEPSO cohort and the survey, approximately one-third of BRCA1/2 mutation carriers were eligible for the trial. Five hundred and thirty-four women eligible from chart review have been informed by mail about the prevention trial and were invited to an oral information by participating centres. Forty-four percentage of them came to the dedicated medical visit. Uptake of drug prevention trial was 32% among women informed orally and 15% of all the eligible women. The main reasons of refusal were: potential side effects, probability to receive the placebo and lack of support from their physicians. Additionally, we noticed that prior prophylactic oophorectomy and previous unilateral breast cancer were more frequent in women enrolled in the LIBER trial than in the French cohort (93% vs. 60% and 50% vs. 39%, respectively). Based on an overall 15% uptake among all eligible subjects, greater and wider information of the trial should be offered to women with BRCA1/2 mutation to improve recruitment. Women with previous unilateral breast cancer or prior prophylactic oophorectomy are more likely to enter a medical prevention trial.

Sterol-dependent regulation of sphingolipid metabolism in Saccharomyces cerevisiae.

We had previously isolated the temperature-sensitive erg26-1 mutant and characterized the sterol defects in erg26-1 cells (Baudry, K., Swain, E., Rahier, A., Germann, M., Batta, A., Rondet, S., Mandala, S., Henry, K., Tint, G. S., Edlind, T., Kurtz, M., and Nickels, J. T., Jr. (2001) J. Biol. Chem. 276, 12702-12711). We have now determined the defects in sphingolipid metabolism in erg26-1 cells, examined their effects on cell growth, and initiated studies designed to elucidate how might changes in sterol levels coordinately regulate sphingolipid metabolism in Saccharomyces cerevisiae. Using [(3)H]inositol radiolabeling studies, we found that the biosynthetic rate and steady-state levels of specific hydroxylated forms of inositolphosphorylceramides were decreased in erg26-1 cells when compared with wild type cells. [(3)H]Dihydrosphingosine radiolabeling studies demonstrated that erg26-1 cells had decreased levels of the phytosphingosine-derived ceramides that are the direct precursors of the specific hydroxylated inositol phosphorylceramides found to be lower in these cells. Gene dosage experiments using the sphingolipid long chain sphingoid base (LCB) hydroxylase gene, SUR2, suggest that erg26-1 cells may accumulate LCB, thus placing one point of sterol regulation of sphingolipid synthesis possibly at the level of ceramide metabolism. The results from additional genetic studies using the sphingolipid hydroxylase and copper transporter genes, SCS7 and CCC2, respectively, suggest a second possible point of sterol regulation at the level of complex sphingolipid hydroxylation. In addition, [(3)H]inositol radiolabeling of sterol biosynthesis inhibitor-treated wild type cells and late sterol pathway mutants showed that additional blocks in sterol biosynthesis have profound effects on sphingolipid metabolism, particularly sphingolipid hydroxylation state. Finally, our genetic studies in erg26-1 cells using the LCB phosphate phosphatase gene, LBP1, suggest that increasing the levels of the LCB sphingoid base phosphate can remediate the temperature-sensitive phenotype of erg26-1 cells.