Abstract：
Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies.
Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n = 291).
In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n = 19), thyroid- (n = 19), and prostate (pre)malignancies (n = 12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared with females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins.
Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.
Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n = 291).
In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n = 19), thyroid- (n = 19), and prostate (pre)malignancies (n = 12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared with females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins.
Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.
摘要：
目的：具有双等位基因CHEK2种系致病变异体(gPV)的女性比具有单等位基因CHEK2gPV的个体更常发生多发性乳腺癌。这项研究旨在扩大对其他恶性肿瘤发生的认识。
方法：对发展为多种原发性恶性肿瘤的个体进行外显子组测序，鉴定出3名具有双等位基因状态的CHEK2（NM_007194.4）c.1100delp.（Thr367MetfsTer15）功能丧失gPV的个体。我们收集了另外一组具有CHEK2双等位基因gPV的个体的表型(n=291)。
结果：总计，157名个体（53.4%；157/294名个体）发展为≥1（前）恶性肿瘤。除乳腺癌外，最常见的（前）恶性肿瘤是结肠直肠-（n=19），甲状腺（n=19），和前列腺（前）恶性肿瘤（n=12）。与CHEK2c.470T>Cp.（Ile157Thr）错义变异的双等位基因女性相比，具有双等位基因CHEK2功能丧失gPV的女性更频繁地发展≥2（前）恶性肿瘤，并且年龄较早。此外，患有CHEK2双等位基因gPV的26名男性（31％；26/84名男性）发展出≥1（前）15种恶性肿瘤。
结论：我们的研究表明，CHEK2双等位基因gPV可能会增加各种组织中发生多种恶性肿瘤的易感性，无论是女性还是男性。然而,有相当比例的CHEK2双等位基因gPV患者可能被漏诊,因为CHEK2的诊断检测通常仅限于发生乳腺癌的患者.
方法：对发展为多种原发性恶性肿瘤的个体进行外显子组测序，鉴定出3名具有双等位基因状态的CHEK2（NM_007194.4）c.1100delp.（Thr367MetfsTer15）功能丧失gPV的个体。我们收集了另外一组具有CHEK2双等位基因gPV的个体的表型(n=291)。
结果：总计，157名个体（53.4%；157/294名个体）发展为≥1（前）恶性肿瘤。除乳腺癌外，最常见的（前）恶性肿瘤是结肠直肠-（n=19），甲状腺（n=19），和前列腺（前）恶性肿瘤（n=12）。与CHEK2c.470T>Cp.（Ile157Thr）错义变异的双等位基因女性相比，具有双等位基因CHEK2功能丧失gPV的女性更频繁地发展≥2（前）恶性肿瘤，并且年龄较早。此外，患有CHEK2双等位基因gPV的26名男性（31％；26/84名男性）发展出≥1（前）15种恶性肿瘤。
结论：我们的研究表明，CHEK2双等位基因gPV可能会增加各种组织中发生多种恶性肿瘤的易感性，无论是女性还是男性。然而,有相当比例的CHEK2双等位基因gPV患者可能被漏诊,因为CHEK2的诊断检测通常仅限于发生乳腺癌的患者.
