Hereditary cancer: 97% of all carriers remain unidentified

In the Swedish healthcare system, families must fulfill specific criteria to be offered genetic testing for hereditary cancer. One such criteria is the occurrence of several related cancer types in the same family, such as breast and ovarian cancer. Alternatively, someone could have been diagnosed at a young age. This is called the family-history model. A recently published review article shows that the family-history model is ineffective, resource intensive, and associated with underutilization of genetic testing. Over 50% of all carriers of a pathogenic variant are missed by the family-history model.

The family-history model contributes to healthcare disparities as it requires healthy individuals to be aware of their family history of cancer across several generations (both maternal and paternal). Healthcare providers must then be able to interpret this information, which requires an understanding of genetic inheritance and hereditary cancers. Awareness of clinical genetic testing is greater in higher socio-economic groups and this group is therefore overrepresented in clinical genetic testing. Small family units or families with adoption lack the opportunity to identify this clustering and are therefore at a disadvantage. In the case of genetic variants that increase the risk of female cancers, male predominance and paternal inheritance may conceal its visibility through generations. Similarly, those who have a new (de novo) variant will also lack an indicative family history. Consequently, 97% of all carriers remain unidentified, resulting in several missed opportunities for cancer prevention or early detection for a better prognosis.

As a result, researchers are looking into whether the population-based model could be an alternative to the family-history model. In the population-based model, genetic screening for pathogenic variants contributing to certain diseases or disorders are made available to unselected individuals in the general population regardless of family history. One such available example is PKU-testing, in which parents may choose to test their newborn babies for 25 different diseases that can be prevented when detected early.

According to the authors of the recent review article, population-based genetic testing has the potential to overcome the limitations of the family-history model, which in turn makes preventive measures available to more people.

In another recent article, researchers evaluated whether population-based screening could efficiently identify carriers of pathogenic variants in genes associated with breast and ovarian cancer (BRCA1, BRCA2) and colorectal cancer (MLH1, MSH2, MSH6, and PMS2) by screening almost 27 000 individuals. A pathogenic or likely pathogenic variant in BRCA1 or BRCA2 was identified in 178 individuals. Such variants in MLH1, MSH2, MSH6, or PMS2 were identified in 80 individuals. 91 individuals with a variant in BRCA1 or BRCA2, did not fulfill the testing criteria according to the family-history model. As many as 51 individuals with a pathogenic variant in MLH1, MSH2, MSH6, or PMS2 did not fulfill the same criteria. The authors conclude that population-based genetic testing for the above-mentioned genes potentially could identify 90% of previously unidentified individuals with a high risk of developing cancer.

Population-based testing of BRCA1 and BRCA2 in women ≥ 30 years of age is cost-effective and cost-saving (especially in high-income countries) when compared to the family based model according to a study from 2020. As compared to present methods, population-based screening could prevent between 2319 and 2666 additional breast cancer cases and between 327 and 449 additional ovarian cancer cases per one million women.

Anna Hellquist, Genetic Counselor at iCellate Medical AB, PhD Cell and Microbiology