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by Piri Welcsh, PhD
Patients with multiple primary cancers should consider genetic counseling and testing.
Rates of inherited mutations in genes other than BRCA1 and BRCA2 are twice as high in breast cancer patients who have a second primary cancer compared to those who only have a single primary breast cancer.
Kara Maxwell from the University of Pennsylvania presented a study that looked at breast cancer patients who did not have a BRCA1 or BRCA2 mutation who were tested with a 15-gene panel test. Researchers compared panel test results between patients who had a second primary breast cancer and patients who had only a single primary breast cancer.
“Our data show that patients who have had multiple primary cancers should undergo genetic testing, and likely this holds true for a number of other types of second cancer,” Maxwell said. “However, the overall numbers are still low, which shows the level of uncertainty that still exists and highlights the need for further research.”
Some inherited lung cancers can be explained by mutations in BRCA1, BRCA2, CHEK2 and other genes.
Most of the heritability for lung cancer nearly 20% of all cases is unknown. To better understand this, researchers used the FDA-approved Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) panel test for somatic mutations in 468 genes. (Somatic mutations are defects that occur within a person's lifetime that can cause cancer in cells. In contrast, germline mutations are inherited.)
The study compared samples of lung cancer tumors and normal tissue from patients with a family history of other cancers, early age at onset or multiple cancer diagnoses to unselected lung cancer patients-those who had no family history of cancer, early age at onset or multiple cancers. For this study 2,687 patients consented to sequencing their tumor tissue and normal tissue to identify DNA changes in their tumors. It is also possible to detect germline (inherited) mutations which will be present in normal tissue as well as tumor tissue.
Among all lung cancer patients, approximately 8% (210) had a pathogenic germline mutation in one of 27 genes. Of these, the most common were BRCA1 (16), BRCA2 (19) and CHEK2 (25).
Of the 42 patients who opted to receive germline test results, 24% had early onset lung cancer and 52% multiple cancers. 31% had inherited a mutation known to cause cancer in one of 10 genes (3 BRCA2, 2 MEN1, 1 APC, 1 ATM, 1 BAP1, 1 BLM, 1 CHEK2, 1 FH, 1 FLCN, and 1 RAD51D)
These results show that patients with lung cancer who have either a family history of other cancers, early age at onset or multiple cancer diagnoses, are more likely to have a germline mutation as compared to unselected lung cancer patients.
Certain tumor features in many types of cancers can reveal who should be tested for Lynch syndrome.
Lynch Syndrome is associated with mutations in the genes of the mismatch repair system. When the Lynch syndrome genes are defective, DNA repair does not happen efficiently, many additional mutations can occur in a cell and the cell is more likely to become cancerous. People with Lynch syndrome have a higher frequency of colon cancer. Because of this, NCCN guidelines recommend that all patients who are diagnosed with colon cancer be tested for Lynch Syndrome mutations. These guidelines also endorse that all endometrial tumors be tested for defects in DNA mismatch repair (MMR) in the tumor to identify which patients should consider testing for Lynch Syndrome.
Microsatellites short, repeated, sequences of DNA-naturally occur all over the genome. One measure of defective mismatch repair is changes in length of microsatellites. Sometimes cancer cells have an increased number of copies of these microsatellites (ie longer length of DNA sequence). Cancer cells with microsatellites that grow beyond their natural length are said to be “microsatellite instability high” (MSI-H); these cells may be unable to correct mistakes that occur when DNA is copied in the cell. Similar defective behavior can occur in cells that have many DNA mutations that can lead to cancer; these cells are said to be “mismatch repair deficient” (MMR-D).
Recently, immunotherapy (therapy that triggers a patient’s own immune system to fight disease) has been used successfully to treat MSI-H and/or MMR-D tumors. As a result, many advanced solid tumors are routinely tested for these features. However, the frequency of Lynch syndrome gene mutations in MSI-H/MMR-D tumors is unknown.
Alicia Latham Schwark, MD, from Memorial Sloan Kettering presented results of a study that looked at whether individual tumor characteristics (such as MSI-H and MMR-D states) can indicate which patients should be screened for Lynch syndrome gene mutations. She and her colleagues screened 15,045 tumors, including 50 different types of cancers, for microsatellite instability. Of these tumore, 2.2% were MSI-H. Germline mutations were identified in tumors that were MSI-stable (MSS-S) or intermediate (MSS-I), however germline mutations were significantly more common in the MSI-H group-16.3% (53 of 326 tumors).
Of all 1,025 MSI-H/MSI-I tumors reviewed, 25% were colorectal or endometrial cancers. In contrast ,among the MSI-H/MSI-I tumors that came from Lynch syndrome patients, 50% (33 of 66) were cancer types that were less commonly or not previously associated with Lynch syndrome (mesothelioma, sarcoma, adrenocortical, melanoma, ovarian germ cell).
Lynch syndrome patients with MSI-H/MSI-I non-colorectal/endometrial tumors only met standard genetic testing criteria for evaluating Lynch syndrome genes in 63.6% of cases. Of Lynch syndrome patients with non-MSI/I tumors, 78% had mutations in the MSH6 or PMS2 genes, but 71% of Lynch syndrome patients with MSI-H/MSI-I tumors had mutations in the MLH1, MSH2, or EPCAM genes.
MSI-H/MMR-D in many tumor types is predictive of Lynch syndrome. This suggests that there are more types of tumors associated with Lynch syndrome than previously suspected. In this study, nearly 40% of Lynch syndrome patients with MSI-H/MMR-D non-colorectal/non-endometrial tumors did not meet clinical criteria for genetic testing. This suggests that any tumor with MSI-H/MMR-D, regardless of cancer type or family history, should prompt germline testing for Lynch syndrome.