During the past several decades, genetic testing for germline and somatic mutations has been incorporated into routine clinical practice for many different cancer types. Germline mutations, contained within the heritable genome, and somatic mutations, acquired de novo by cancer cells, have historically been considered as separate entities. Until recently, each had unique clinical applications and implications for patient care.
As the use of next-generation sequencing (NGS) has become more widespread, the lines between the 2 types of mutations have increasingly become blurred. Researchers are seeking to make sense of unprecedented amounts of genetic information; for example, investigators conducting a pan-cancer analysis across 12 cancer types identified distinct patterns of aberrations in 51 genes due to germline and somatic mutations.1
Many challenges remain to the optimal interpretation of genetic test results and the effective translation of these data into improved diagnostic, prognostic, and therapeutic capabilities. Nevertheless, there are signs of change. In December 2016, the FDA approved the PARP inhibitor rucaparib (Rubraca) for the treatment of patients with BRCA-mutated ovarian cancer, regardless of whether the alterations stemmed from germline or somatic changes.2
A Genomic Disease
For decades, the prevailing paradigm in oncology research has been that cancer is driven predominantly by the accumulation of mutations in the genetic material as a result of DNA-damaging chemical or environmental assaults on the cell. Anywhere from 2 to 8, potentially as many as 20 mutations, are required for the development of a cancer.3,4
In most cases, cancers are sporadic, driven by acquired somatic mutations. These mutations are unique to tumor cells and occur in genes encoding proteins that play a central role in the hallmark processes that dictate malignant growth. Sometimes, however, the mutations found in cancer cells are present in all cells of the body and represent genetic variations inherited from a parent. These are germline mutations that were present in the germ cells that created the sperm or egg from which the fetus developed.
Germline mutations increase the likelihood that an individual will develop cancer in his or her lifetime. Since most cancers result from multiple “hits” to a gene or to several different types of genes, individuals with germline mutations already have the first hit present from birth. In approximately 5% to 10% of cases, hereditary cancer ensues and family members can develop the same type of cancer or multiple types of primary cancer. An additional 10% to 15% of cases are referred to as familial, in which an inherited gene is suspected but has not been identified (Figure).5
Figure. Origins of Mutations in Cancer5
In some genes, germline mutations have been linked to the development of certain types of cancers and form the genetic basis of several wellknown hereditary cancer syndromes (Table 1).6
Table. Hereditary Cancer Syndromes6
The best characterized of these likely are hereditary breast and ovarian cancers (HBOCs), caused by germline mutations in the breast cancer susceptibility genes BRCA1
. It is estimated that approximately 1% of the general population carries germline BRCA1/2
mutations. Their presence increases the risk of developing ovarian cancer from about 1.3% to 39% (BRCA1) and 11% to 17% (BRCA2
); for breast cancer, the increased risk ranges from 12% to 55% or 65% (BRCA1
) and up to 45% (BRCA2
mutations have also been implicated in several other tumor types, including prostate and pancreatic cancer.