Germline Mutations and Their Clinical Applications in Cancer

Abstract

Over the past few decades, researchers have mainly focused on cancer somatic mutations, while germline mutations have been largely ignored. Cancer is a stochastic event that arises from acquiring multiple somatic mutations; therefore, the scientific rationale for targeting and characterizing these mutations is perfectly founded. However, while we do agree with this concept in a general sense, we believe it is partially incomplete. One of the major risk factors in cancer is family history (or hereditary germline mutations). Germline mutations inherited from previous generations act as predispositions in individuals, increasing their susceptibility to develop cancer. A multitude of studies have already linked various germline predispositions in many genes (BRCA1, BRCA2, PTEN, TP53, KRAS, APC, etc.), suggesting that germline mutations also impact tumor evolution [1-5]. Yet, still, many public databases, such as ICGC, have very little information concerning germline mutations (8857 germline profiles compared to 62329 somatic). Several years ago, we had proposed that pre-existing genetic variants could play important roles in shaping, or selecting, somatic mutations so that the selected mutated genes could work together with the pre-existing genetic variants to drive a transformation of a normal cell into a cancer cell [6]. Evidence from our most recent studies showed that inherited germline mutations not only increase cancer risk susceptibility but also act as modulators when shaping tumor evolution. We have shown that inheritably functional variants of breast cancer patients significantly predicted tumor recurrence [7,8], and the risk of developing breast, brain and other cancers [9]. Furthermore, we have shown that inheritably functional variants in natural killer cells (i.e., natural killer [NK] cells, an immune cell type) in cancer patients affected tumor-infiltrating lymphocytes (TILs) and survival [10]. These results bring a paradigm-shifting view about the roles of germline genomes in cancer. In the past decades, only a small fraction of cancer cases have been explained by germline dispositions; for example, a germline mutation in BRCA1/2 is found in only 5-10% of breast and ovarian cancer patients. As the penetrance of other germline genetic defects is very small, their role in cancer development and metastasis have been hard to study and eventually ignored. Taking a systems biology approach, we showed that germline genomes play a much more important role in cancer development and metastasis than what might have been estimated by the cancer community.