Details

Autor(en) / Beteiligte

• Laitman, Yael
• Nielsen, Sarah M.
• Bernstein-Molho, Rinat
• Heald, Brandie
• Hatchell, Kathryn E.
• Esplin, Edward D.
• Friedman, Eitan

Titel

Cancer risks associated with heterozygous ATM loss of function and missense pathogenic variants based on multigene panel analysis

Ist Teil von

• Breast cancer research and treatment, 2022-11, Vol.196 (2), p.355-361

Ort / Verlag

New York: Springer US

Erscheinungsjahr

2022

Quelle

SpringerLink

Beschreibungen/Notizen

• Purpose Cancer risks conferred by germline, heterozygous, ATM pathogenic/likely pathogenic variants (PSVs) are yet to be consistently determined. The current study assessed these risks by analysis of a large dataset of ATM heterozygote loss of function (LOF) and missense PSV carriers tested with a multigene panel (MGP). Methods De-identified data of all individuals who underwent ATM sequencing as part of MGP between October 2015 and February 2020 were reviewed. In cancer cases, rates for the six most prevalent variants and for all LOF and missense PSV combined were compared with rates of the same PSV in ethnically matched, healthy population controls. Statistical analysis included Chi-square tests and odds ratios calculations. Results For female breast cancer cases, LOF )1794/219,269) and missense (301/219,269) ATM PSVs were seen at higher rates compared to gnomAD non-cancer controls ( n  = 157/56,001 and n  = 27/61,208; p  < 0.00001, respectively). Notably, the rate of the c.103C > T variant was higher in controls than in breast cancer cases [ p  = 0.001; OR 0.31 (95% CI 0.1–0.6)]. For all cancer cases combined, compared with non-cancer population controls, LOF ( n  = 143) and missense ( n  = 15) PSVs reported in both datasets were significantly more prevalent in cancer cases [OR LOF 1.7 (95% 1.5–1.9) OR missense 3.0 (95% CI 2.3–4); p  = 0.0001]. Conclusion Both LOF and missense heterozygous ATM PSVs are more frequently detected in cases of several cancer types (breast, ovarian, prostate, lung, pancreatic) compared with healthy population controls. However, not all ATM PSVs confer an increased cancer risk (e.g., breast).