MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer.

PURPOSE: An association of Lynch syndrome (LS) with breast cancer has been long suspected; however, there have been insufficient data to address this question for each of the LS genes individually. METHODS: We conducted a retrospective review of personal and family history in 423 women with pathogenic or likely pathogenic germ-line variants in MLH1 (N = 65), MSH2 (N = 94), MSH6 (N = 140), or PMS2 (N = 124) identified via clinical multigene hereditary cancer testing. Standard incidence ratios (SIRs) of breast cancer were calculated by comparing breast cancer frequencies in our study population with those in the general population (Surveillance, Epidemiology, and End Results 18 data). RESULTS: When evaluating by gene, the age-standardized breast cancer risks for MSH6 (SIR = 2.11; 95% confidence interval (CI), 1.56-2.86) and PMS2 (SIR = 2.92; 95% CI, 2.17-3.92) were associated with a statistically significant risk for breast cancer whereas no association was observed for MLH1 (SIR = 0.87; 95% CI, 0.42-1.83) or MSH2 (SIR = 1.22; 95% CI, 0.72-2.06). CONCLUSION: Our data demonstrate that two LS genes, MSH6 and PMS2, are associated with an increased risk for breast cancer and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.

Overlap of Juvenile polyposis syndrome and Cowden syndrome due to de novo chromosome 10 deletion involving BMPR1A and PTEN: implications for treatment and surveillance.

We describe a patient with a severe juvenile polyposis phenotype, due to a de novo deletion of chromosome 10q22.3-q24.1. He was initially diagnosed with Juvenile polyposis syndrome (JPS) at age four after presenting with hematochezia due to multiple colonic juvenile polyps. He then re-presented at 23 years with recurrent hematochezia from juvenile polyps in his ileoanal pouch. He is one of the earliest reported cases of JPS associated with a large deletion of chromosome 10. Since his initial diagnosis of JPS further studies have confirmed an association between JPS and mutations in BMPR1A in chromosome band 10q23.2, which is in close proximity to PTEN. Mutations in PTEN cause Cowden syndrome (CS) and other PTEN hamartoma tumor syndromes. Due to the chromosome 10 deletion involving contiguous portions of BMPR1A and PTEN in our patient, he may be at risk for CS associated cancers and features, in addition to the polyps associated with JPS. This case presents new challenges in developing appropriate surveillance algorithms to account for the risks associated with each syndrome and highlights the importance of longitudinal follow-up and transitional care between pediatric and adult gastroenterology for patients with hereditary polyposis syndromes.

Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing.

PURPOSE: Although CHEK2 is a well-established cancer gene, questions remain including whether risks vary substantially between different variants and whether biallelic carriers have higher risks than heterozygotes. We report on a cohort of individuals with CHEK2 pathogenic and likely pathogenic variants (collectively, PV) in order to better characterize this gene. METHODS: We retrospectively queried samples submitted for multi-gene hereditary cancer testing to identify individuals with CHEK2 PVs and assessed differences in phenotypes among various genotypes. RESULTS: CHEK2 PVs were identified in 2508 individuals, including 32 individuals with biallelic CHEK2 PVs. Breast (female, 59.9% and male, 11.8%), prostate (20.1%), and colorectal (3.5%), were among the most frequently reported cancers. Select missense PVs showed similar cancer prevalence to truncating PVs while some others showed lower prevalence. No significant differences were observed between biallelic carriers and heterozygotes. CONCLUSIONS: Our data support that some, but not all, CHEK2 missense PVs demonstrate lower cancer prevalence; further studies are needed to continue characterizing possible variant specific risks. In addition, biallelic CHEK2 PVs do not appear to be associated with a more severe phenotype than single CHEK2 PVs. Furthermore, co-occurrences with PVs in other cancer risk genes are common among CHEK2 heterozygotes and often warrant additional management.

Apparently Heterozygous TP53 Pathogenic Variants May Be Blood Limited in Patients Undergoing Hereditary Cancer Panel Testing.

Heterozygous (HET) TP53 pathogenic variants (PVs) are associated with Li-Fraumeni syndrome (LFS), a dominantly inherited condition causing high risk for sarcoma, breast, and other cancers. Recent reports describe patients without features of LFS and apparently HET TP53 PVs in blood cells but not fibroblasts (FBs), suggesting the variant occurred sporadically during hematopoiesis and rose to high allele fraction through clonal expansion. To explore possible clonal hematopoiesis in patients undergoing hereditary cancer testing, FB testing was performed for patients with apparently HET or mosaic TP53 PVs identified in blood, oral rinse, or buccal specimens via next-generation sequencing panels. Among 291 individuals with TP53 PVs, 146 (50.2%) appeared HET and 145 (49.8%) were mosaic. Twenty-eight HET cases were proven constitutional through familial testing. FB testing was completed for 17 apparently HET and 36 mosaic patients. FB testing was positive in 11 of 17 (64.7%) apparently HET patients, only one of whom met Chompret criteria. Of 36 mosaic patients, 5 (13.9%) were also mosaic in FBs, indicating constitutional mosaicism. Breast cancers in patients with constitutional TP53 PVs were diagnosed at younger ages (P < 0.0001) and more likely to demonstrate human epidermal growth factor receptor 2 overexpression (P = 0.0003). These results demonstrate the utility of cultured FB testing to clarify constitutional status for TP53 PVs identified on next-generation sequencing panels, particularly for patients not meeting LFS or Chompret criteria.

Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis.

Biallelic pathogenic variants (PVs) in MUTYH cause MUTYH-Associated Polyposis (MAP), which displays phenotypic overlap with other hereditary colorectal cancer (CRC) syndromes including Familial Adenomatous Polyposis (FAP) and Lynch syndrome. We report the phenotypic spectrum of MAP in the context of multi-gene hereditary cancer panel testing. Genetic testing results and clinical histories were reviewed for individuals with biallelic MUTYH PVs detected by panel testing at a single commercial molecular diagnostic laboratory. Biallelic MUTYH PVs were identified in 82 individuals (representing 0.2% of tested individuals) with most (75/82; 91.5%) reporting a personal history of CRC and/or polyps. Ten percent (6/61) of individuals reporting polyp number reported fewer than 10 polyps and therefore did not meet current MAP testing criteria. Extracolonic cancers (21/82; 25.6%), multiple primaries (19/82; 23.2%), Lynch-like (17/82; 20.7%) and FAP-like phenotypes (16/82; 19.5%) were observed, including individuals with mismatch repair-deficient tumors (3/82; 3.7%), sebaceous neoplasms (2/82; 2.4%), or congenital hypertrophy of the retinal pigment epithelium (CHRPE) (2/82; 2.4%). We report what is to our knowledge the first cohort of individuals with MAP identified by panel testing. The phenotypic spectrum of MAP observed in this cohort aligns with the published literature. In addition to standard indications for MUTYH testing, our data provide evidence to support consideration of MAP in the differential diagnosis for some individuals with fewer than 10 polyps, depending on other personal and/or family history, as well as for individuals suspected to have Lynch syndrome or FAP.