The authors respond:

Radhia M’kacher, Ph.D.1*, Catherine Yardin Ph.D.-M.D. 2, Eric Jeandidier M.D.3, M.D., Bruno Colicchio, Ph.D.4, Steffen Junker, D.Phil.5, Philippe Voisin, Sc.D. 1, Michael Grynberg Ph.D.-M.D. 6, Michael Fenech, Ph.D.7, Annelise Bennaceur-Griscelli, Ph.D.-M.D.8, Patrice Carde M.D.9

1Cell Environment, DNA damage R&D, Paris, France,

2Service de Cytogénétique, Génétique Médicale, et Biologie de la Reproduction Hôpital de la Mère et de l’Enfant, CHU Dupuytren, 87042 LIMOGES, France,

3Service de génétique Groupe Hospitalier de la Région de Mulhouse et Sud Alsace Mulhouse, France

4IRIMAS, Institut de Recherche en Informatique, Mathématiques, Automatique et Signal,
Université de Haute-Alsace, Mulhouse 68093 France,

5Institute of Biomedicine, University of Aarhus, Aarhus DK-8000, Denmark

6Department of Reproductive Medicine and Fertility Preservation, Hôpital Antoine Béclère, 92140 Clamart, France

7Genome Health Foundation, North Brighton, Australia

8APHP-Service d’hématologie-Oncohématologie moléculaire et Cytogénétique Hôpital Paul Brousse Université Paris Saclay/ Inserm UMR 935, Villejuif, France,

9Department of Hematology, Gustave Roussy Cancer Campus, Villejuif, France

We thank the authors of the Editorial and the Editor for giving us an opportunity to reply.

As indicated in the Editorial, telomere dysfunction and biology act as a surrogate biomarker of infertility women.

We agree that the current literature provides contradictory data, depending on the type of infertility, regarding telomere length (1). Long telomeres have been described in endometriosis and stromal cell carcinoma and short telomeres in premature ovarian insufficiency and multiform endometrial dysfunction. Thus, the role of telomere length in female infertility is still unclear.

However, as pointed out in the Editorial, telomere aberrations and telomere maintenance mechanisms have not been studied extensively. Indeed our study, recently published in “Fertility and Sterility” (2), demonstrates the presence of telomere aberrations in patients with infertility even in cases where karyotypes are described as normal.

Telomere aberrations such as telomere loss or excessive shortening, have been correlated to cancer and aging and are considered as driving forces for transformation into malignancy and chromosomal instability (3, 4).  In our article, we have chosen peripheral blood lymphocytes as a “surrogate” to identify potential biomarkers of infertility and sterility. For this purpose we have used the same slides that were prepared to establish the constitutional karyotype of the patients. Our approach combines global quantification of telomere length and detection of telomere aberrations that may help to explore the role of these aberrations in induction of chromosomal aberrations and progression of chromosomal instability during embryonic development (5).

This approach should be used to investigate telomere length and aberrations cut-offs in various subsets of female infertility that, as mentioned in the Editorial, are likely to be heterogeneous, and also the role of the different mechanisms of telomere maintenance (telomerase, ALT) in these pathologies.

More generally, the frequency of telomere aberrations should be included as a valid biomarker for infertility in the population. More data on telomere aberrations should be collected to establish cutoffs between normal populations and populations at risk. The contribution of parental genetic or acquired environmental or specific exposure to genotoxic agents and their potential impact on fertility remains the scope of this research. To this end, studying telomere length and aberrations in families with abnormal offspring may provide additional information.

Automation of this approach should enable the feasibility of prospective screening of large cohorts of women and men with regards to fertility assessment.

Reference:

1. Vasilopoulos E, Fragkiadaki P, Kalliora C, Fragou D, Docea AO, Vakonaki E, Tsoukalas D, Calina D, Buga AM, Georgiadis G, Mamoulakis C, Makrigiannakis A, Spandidos DA, Tsatsakis A. The association of female and male infertility with telomere length (Review). International journal of molecular medicine. 2019;44(2):375-89.


2. M’kacher R., Marquet V., Borie C., Najar W.,Hempel W.M. , Heidingsfelder L. , Oudrhiri N., Al Jawhari M. , Wilhelm-Murer N.,  Miguet M.,Dieterlen A., Deschênes G., Tabet A.,  Junker S.,  Grynberg M.,  Fenech M, Bennaceur-Griscelli A.,  Voisin P., Carde P.,  Jeandidier E.,  Yardin C. . Telomere aberrations, including telomere loss, doublets, and extreme shortening, are increased in infertility patients Fertility and Sterility. 2020.


3. M'Kacher R, Frenzel M, Al Jawhari M, Junker S, Cuceu C, Morat L, Bauchet AL, Stimmer L, Lenain A, Dechamps N, Hempel WM, Pottier G, Heidingsfelder L, Laplagne E, Borie C, Oudrhiri N, Jouni D, Bennaceur-Griscelli A., Colicchio B, Dieterlen A, Girinsky T, Boisgard R, Bourhis J, Bosq J, Mehrling T, Jeandidier E, Carde P. Establishment and Characterization of a Reliable Xenograft Model of Hodgkin Lymphoma Suitable for the Study of Tumor Origin and the Design of New Therapies2018;10(11). doi: 10.3390/cancers10110414. PubMed PMID: 30384446.


4. Cuceu C, Colicchio B, Jeandidier E., Junker S, Plassa F, Shim G, Mika J, Frenzel M, Al Jawhari M, Hempel WM, O'Brien G, Lenain A, Morat L, Girinsky T, Dieterlen A, Polanska J, Badie C, Carde P, M'Kacher R. Independent Mechanisms Lead to Genomic Instability in Hodgkin Lymphoma: Microsatellite or Chromosomal Instability 2018;10(7).


5. Scheffer JB, Scheffer BB, de Carvalho RF, Rodrigues J, Grynberg M, Mendez Lozano DH. Age as A Predictor of Embryo Quality Regardless of The Quantitative Ovarian Response. International journal of fertility & sterility. 2017;11(1):40-6.