Inherited Malignancy

Screening the human genome for breast-cancer susceptibility factors has led to the identification of novel genetic variants, and ongoing studies and further technical progress will certainly lead to additional significant findings. But the challenge today is to dig out the clinical relevance of these findings and translate them into daily health care.

HANNOVER , GERMANY – Breast cancer is among the most life-threatening of malignancies, affecting about one in ten women in the Western world. Taking the family history of 100 healthy women, at least one affected first-degree relative can be found in up to 15 of them.

Indeed, investigations have shown that the risk of developing breast cancer is roughly doubled in females with a family history of breast cancer. In 1994-1995, the human genes BRCA1 and BRCA2 were identified as major culprits. Dozens of their mutations are associated with an increased risk of hereditary breast and ovarian cancer. Women who have an abnormal BRCA1 or BRCA2 gene run a lifetime risk of up to 85% of developing breast cancer, while the increased risk of developing ovarian cancer is about 55% for women with BRCA1 mutations and about 25% for women with BRCA2 mutations. Most recently, huge studies analyzing effects of single nucleotide variations in genomic DNA, so-called single nucleotide polymorphisms (SNP), on breast cancer risk of BRCA1/BRCA2 mutation carriers have identified so-called modifier SNP that can decrease or increase the individual lifetime risk.

We have also learned that only 20-40% of the breast cancers that cluster in families come from BRCA1 or BRCA2 germline mutations – genetic alterations that are present from birth in every cell of the body and can be transmitted to the offspring. Increased breast cancer risk is also known to be associated with several inherited syndromes, such as Li-Fraumeni syndrome, a condition that is further associated with childhood onset of multiple malignancies including soft tissue sarcomas, leukemias, and brain tumors. In most cases of familial breast cancer, however, genetic predisposition remains elusive. Indeed, no further genes have been found whose mutations are associated with high lifetime risks of developing breast cancer.