Aminian Solaleh, Al-Alloosh Fawaz, Yadegari Fatemeh, Zarinfam Shiva, Al-Abedi Haider Hamza, Majidzadeh-A Keivan
Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
Warith International Cancer Institute, Karbala, Iraq.
Case Rep Genet. 2024 Jun 6;2024:5591237. doi: 10.1155/2024/5591237. eCollection 2024.
Multiple primary cancers (MPCs) are defined as the presence of more than one cancer in an individual that is not due to recurrence, metastasis, or local spread. Different factors such as copathogenic genetic mutations, environmental factors, lifestyle, and first cancer treatment increase the possible occurrence of subsequent malignancies. In recent years, the risk of MPCs has increased due to improved treatment; however, quadruple primary malignancies are still rare and require further investigation and treatment of the underlying cause. Here, we present a 64-year-old man with a 40-year history of cigarette smoking who developed quadruple primary malignancies of the epiglottis, kidney, pancreas, and lung. To investigate the possible genetic cause, we performed WES, and a variant of c.580G > A (Ala194Thr) was discovered in exon 5 of the Krebs cycle enzyme gene, fumarate hydratase (FH). This substitution was classified as VUS in Clinvar and likely pathogenic by Varsome and Franklin software. The structural analysis showed that the variation found was localized in a highly conserved alpha helix in the D2 domain near the FH hinge region (<6 Å), suggesting that enzyme activity was affected by a perturbation in protein quaternary structure. Because of the well-established role of FH mutations in renal cancer risk, it was possible that the FH mutation could have led to the development of renal cell carcinoma in this case. The biological mechanisms of MPCs suggest that subsequent primary malignancies are triggered by the combined effects of environmental factors, such as smoking and genetics.
多原发性癌症（MPCs）被定义为个体中存在一种以上并非由复发、转移或局部扩散引起的癌症。诸如共同致病基因突变、环境因素、生活方式和首次癌症治疗等不同因素会增加后续恶性肿瘤发生的可能性。近年来，由于治疗水平的提高，MPCs的风险有所增加；然而，四重原发性恶性肿瘤仍然罕见，需要对潜在病因进行进一步调查和治疗。在此，我们报告一名64岁男性，有40年吸烟史，发生了会厌、肾脏、胰腺和肺部的四重原发性恶性肿瘤。为了调查可能的遗传原因，我们进行了全外显子组测序（WES），并在三羧酸循环酶基因富马酸水合酶（FH）的第5外显子中发现了一个c.580G＞A（Ala194Thr）的变异。该替代在Clinvar中被分类为意义未明的变异（VUS），而在Varsome和Franklin软件中可能具有致病性。结构分析表明，发现的变异位于FH铰链区附近D2结构域高度保守的α螺旋中（<6Å），这表明酶活性受到蛋白质四级结构扰动的影响。由于FH突变在肾癌风险中已明确的作用，在这种情况下，FH突变有可能导致了肾细胞癌的发生。MPCs的生物学机制表明，后续原发性恶性肿瘤是由吸烟等环境因素和遗传学的综合作用引发的。
