BRCA and Beyond: The Genetics of Inherited Cancers

Our DNA, the intricate loom of life, weaves a complex genetic code forming a tapestry of traits. All cancers originate as a result of some aberration in this genetic code in our body. The genomic basis of the development and progression of cancer is a complex interplay between inherited genetic factors (germline variations) and acquired genetic factors (somatic variations). Somatic variations are genetic changes that occur after conception, typically during a person’s lifetime.

Somatic mutations are a normal part of aging and can occur in a person either spontaneously or as a result of environmental factors. If these occur in critical genes like tumour suppressors, they can disrupt the normal functioning of cells, leading to genomic instability and potentially, cancer. However, these changes are specific to certain cells or tissues in the body and will not be passed on to the next generations. 

Germline variations, in contrast, are echoes of our ancestors, woven into the very fabric of our being from conception. These are genetic changes in the DNA of an individual’s gametes. They can be inherited from one or both parents and are present in all cells of the resulting offspring. In some cases, germline mutations become more than mere alterations and if occurring in certain genes, can predispose an individual to developing certain cancers. For example, individuals with specific germline mutations in the BRCA1 and BRCA2 genes have a higher risk of developing breast and ovarian cancer.

While most cancers are sporadic, i.e. driven by somatic mutations, nearly 10% of cancers have germline causes. Because such pathogenic mutations can be passed on from generation to generation, they act as crucial warning bells, illuminating a heightened cancer risk not just for a single person, but for future generations woven from the same loom.

Hereditary cancer syndromes are intricate genetic tales, woven with mutations that cast shadows of predisposition to specific cancers. These mutations don’t guarantee cancer but increase its risk. Some genes are well known to be associated with certain inherited cancers. Mutations in BRCA1 and BRCA2 are known to significantly increase the risk of developing hereditary breast and ovarian cancer while inherited mutations in the PALB2 are also associated with an increased risk of breast cancer.

Mutations in DNA mismatch repair genes such as MLH1, MSH2, MSH6, PMS2, and EPCAM cause Lynch Syndrome, which significantly increases the risk of developing colon, endometrial, and other cancers. Peutz-Jeghers syndrome, caused by defects in the STK11 gene, is an inherited condition that increases the risk of developing certain cancers, including gastrointestinal cancers, breast cancer, and pancreatic cancer.

PTEN mutations causing hamartoma tumour syndrome increase the risk of breast, head, and neck squamous cell carcinoma, lung, and prostate cancers. WT1 gene changes cause Wilms tumour susceptibility syndromes that raise the risk of kidney cancer.

Li-Fraumeni Syndrome caused by mutations in the TP53 gene is another hereditary cancer predisposition syndrome characterised by a wide range of cancers occurring in affected families, particularly in children and young adults, and an increased risk of developing cancer across generations including bone cancer, soft tissue sarcoma, leukemia, breast cancer, brain cancer, and adrenal cortical tumours. RB gene mutations are linked to rare retinoblastoma eye cancers in children. RET gene mutations increase the risk of medullary thyroid carcinoma.