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A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and ova). [1] Mutations in these cells are the only mutations that can be passed on to offspring, when either a mutated sperm or oocyte come together to form a zygote . [ 2 ]
The germline genome considers inter-individual inherited genetic variations, and the tumour genome considers any somatic mutations that accrue as a cancer evolves. [5] The accumulation of somatic mutations within the tumour genome represents variation in disease, and plays a major role in understanding how individuals will respond to treatments.
Such germline mutations are shown in a box at the left of the figure, with an indication of their contribution to DNA repair deficiency. However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about one percent of cancers. [25] The majority of cancers are called non-hereditary or "sporadic cancers".
Women with deleterious mutations in either the BRCA1 or BRCA2 genes have a high risk of developing breast and/or ovarian cancer.Because different studies look at different populations, and because different types of mutations have somewhat different risks, the risk is best expressed as a range, rather than a single number.
In 2010, J. William Harbour and colleagues published a landmark article in Science, in which they used exome sequencing of patient tumor samples and identified inactivating mutations in BAP1 in 47% of uveal melanomas. They were also the first to show germline BAP1 mutations, and that BAP1 mutation was strongly associated with metastasis. [14]
Mono- and biallelic germline mutations of MBD4 have been identified in acute myeloid leukemias, uveal melanomas, and glioblastomas. [ 13 ] [ 14 ] [ 15 ] and monoallelic MBD4 germline mutations have been shown to predispose to uveal melanomas. [ 16 ]
Analysis of mutations that occur with high frequency also permits the study of their clinical expression. [46] A striking example of a founder mutation is found in Iceland, where a single BRCA2 (999del5) mutation accounts for virtually all breast/ovarian cancer families. [47] [48] This frame-shift mutation leads to a highly truncated protein ...
In whole genome sequencing of different types of cancers, large numbers of mutations were found in two breast cancers (about 20,000 point mutations [43]), 25 melanomas (9,000 to 333,000 point mutations [44]) and a lung cancer (50,000 point mutations and 54,000 small additions and deletions [45]). Genome instability is also referred to as an ...