印度遗传性乳腺癌和卵巢癌队列的突变图谱表明需要识别特定人群的基因和生物标志物用于筛查。
Mutational Landscape for Indian Hereditary Breast and Ovarian Cancer Cohort Suggests Need for Identifying Population Specific Genes and Biomarkers for Screening.
作者信息
Kadri Mohammed Shaad N, Patel Komal M, Bhargava Poonam A, Shah Franky D, Badgujar Nutan V, Tarapara Bhoomi V, Patel Prabhudas S, Shaikh Mohammed Inayatullah, Shah Krati, Patel Apurva, Pandya Shashank, Vora Hemangini, Joshi Chaitanya G, Joshi Madhvi N
机构信息
Gujarat Biotechnology Research Centre, Department of Science and Technology, Government of Gujarat, Gandhinagar, India.
Gujarat Cancer Research Institute, Civil Hospital, Ahmedabad, India.
出版信息
Front Oncol. 2021 Jan 21;10:568786. doi: 10.3389/fonc.2020.568786. eCollection 2020.
BACKGROUND
Breast and ovarian cancers are the most prevalent cancers and one of the leading causes of death in Indian women. The healthcare burden of breast and ovarian cancers and the rise in mortality rate are worrying and stress the need for early detection and treatment.
METHODS
We performed amplicon sequencing of 144 cases who had breast/ovarian cancer disease (total 137 cases are patients and seven are tested for BRCA1/2 carrier) Using our custom designed gene panel consisting of 14 genes, that are associated with high to moderate risk of breast and ovarian cancers. Variants were called using Torrent Variant Caller and were annotated using ThermoFisher's Ion Reporter software. Classification of variants and their clinical significance were identified by searching the variants against ClinVar database.
RESULTS
From a total of 144 cases, we were able to detect 42 pathogenic mutations in [40/144] cases. Majority of pathogenic mutations (30/41) were detected in BRCA1 gene, while (7/41) pathogenic mutations were detected in BRCA2 gene, whereas, (2/41) pathogenic mutations were detected in TP53 gene and BRIP1, PALB2, and ATM genes respectively. So, BRCA genes contributed 88.09% of pathogenic mutations, whereas non-BRCA genes contributed 11.91% of pathogenic mutations. We were also able to detect 25 VUS which were predicted to be damaging by prediction tools.
CONCLUSION
Early detection of cancers in the Indian population can be done by genetic screening using customized multi-gene panels. Indications of our findings show that in the Indian population, apart from the common BRCA genes, there are other genes that are also responsible for the disease. High frequency mutations detected in the study and variants of uncertain significance predicted to be damaging by pathogenicity prediction tools can be potential biomarkers of hereditary breast and ovarian cancer in Indian HBOC patients.
背景
乳腺癌和卵巢癌是印度女性中最常见的癌症，也是主要死因之一。乳腺癌和卵巢癌的医疗负担以及死亡率的上升令人担忧，凸显了早期检测和治疗的必要性。
方法
我们对144例患有乳腺癌/卵巢癌的病例进行了扩增子测序（其中137例为患者，7例检测BRCA1/2携带者状态），使用我们定制设计的包含14个基因的基因panel，这些基因与乳腺癌和卵巢癌的高到中度风险相关。使用Torrent Variant Caller调用变异，并使用ThermoFisher的Ion Reporter软件进行注释。通过在ClinVar数据库中搜索变异来确定变异的分类及其临床意义。
结果
在总共144例病例中，我们在[40/144]例中检测到42个致病突变。大多数致病突变（30/41）在BRCA1基因中检测到，而（7/41）个致病突变在BRCA2基因中检测到，（2/41）个致病突变分别在TP53基因以及BRIP1、PALB2和ATM基因中检测到。因此，BRCA基因贡献了88.09%的致病突变，而非BRCA基因贡献了11.91%的致病突变。我们还检测到25个意义未明的变异，预测工具预计它们具有损害性。
结论
印度人群中的癌症早期检测可以通过使用定制的多基因panel进行基因筛查来实现。我们的研究结果表明，在印度人群中，除了常见的BRCA基因外，还有其他基因也与该疾病有关。研究中检测到的高频突变以及致病性预测工具预计具有损害性的意义未明变异可能是印度遗传性乳腺癌和卵巢癌患者遗传性乳腺癌和卵巢癌的潜在生物标志物。
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