Gene Overlap and Breast Cancer

By Priyanka Varma, Barbara Guido

BURLINGAME, Calif. Dec 14th, 2021

Gene panel tests serve as tools to better understand genomic profiling of multiple cancers as well as assess the inherited risk of cancer. There are several companies in the market currently which employ multigene panel testing for genes up to 100 or more [1]. They can be utilized for simultaneous screening of several genes and can be customized for specific cancers. The advent of Next Generation Sequencing with advanced technology incorporates targeted enrichment of selected genes followed by parallel sequencing. Such new age technologies have improved the accuracy and made the panel testing efficient and cost effective than single gene testing [2].

Some gene mutations can predispose to an increased risk of both breast and ovarian cancer. BRCA1 and BRCA2 confer elevated risks of both breast and ovarian cancer [3]. Other genes with good evidence for increased risk of both breast and ovarian cancer include ATM, PALB2 (sometimes referred to as BRCA3) and STK11, as well as MALAT1, MUC16, FOXP1, WWOX, XIST, among others [4, 5]. Other genes such as BRIP1, RAD51C, and RAD51D have an increased risk for ovarian cancer and there is limited evidence for a potential increase in risk of breast cancer [6].

Lynch Syndrome or Hereditary Non Polyposis Colon Cancer is associated with mutations in several genes: MLH1, MSH2, MSH6, PMS2, and EPCAM. Some data shows that women have mutations in some Lynch Syndrome genes such as MSH6 and PMS2 may have an increased risk of breast cancer, in addition to colon cancer. The increase in the risk of breast cancer varies based on the mutation. With PMS2 mutation, the risk increases by 27%, versus other genes like MLH1, MSH2, and MSH6, where the risk is 3%, 4%, and 9% respectively. However, there are no current guidelines for management or enhanced screening for breast cancer for this increased risk [7, 8].

Gene mutations in BARD1, BRIP1, NBN, RAD51C, and RAD51D may confer slightly increased risk of developing breast cancer. This may not warrant changing screening for breast cancer, but enhanced screening may be recommended based on a family history of the disease. Mutations in ATM, CDH1, CHEK2, NF1, PTEN, and STK11 moderately elevate the risk of breast cancer and other cancers. The guidelines recommend enhanced breast cancer screening for women with these mutations. In the majority of families with inherited cancer syndromes, there is a significant family history of cancers in multiple generations. However, in small families or those with a limited number of females, there may not be a significant family history of breast or ovarian cancer. Testing for multiple genes may be considered when the family history is not well known, or when there are limited females in the family.

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New clinical guidance issued for people at increased cancer risk due to PALB2 gene variance | VUMC Reporter | Vanderbilt University
Inherited breast and ovarian cancer - Macmillan Cancer Support
MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer | Genetics in Medicine (nature.com)
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