Twenty-one-gene recurrence score (RS) in germline (g)CHEK2 mutation-associated versus sporadic breast cancers (BC): A multi-site case-control study.

10531 Background: Genomic assays, such as RS, are used to determine chemotherapy benefit in early-stage, estrogen receptor (ER)- and/or progesterone receptor (PR)-positive, HER2 negative BC patients (pts). Currently, guidelines to use pts’ germline genetic testing results to guide adjuvant therapy are lacking. Several reports have indicated worse outcomes for BC pts with g CHEK2 pathogenic variants (PV). We investigated whether PV in CHEK2 were associated with increased RS. Methods: Patient-level clinical data and RS were derived from electronic medical records of seven medical centers between years 2013-17. Confirmation of RS using the Genomic Health provider portal was performed. 38 pts with germline PV in CHEK2 (15 pts/39.5% with c.1100delC mutation) and RS score (cases) were matched with BC pts whose genetic testing did not identify PV (controls) using a 1:2 matching schema. Pts were matched based on age at diagnosis and lymph node (LN) status. LN negative pts were further matched based on T-stage. A multivariate random intercept linear mixed model of CHEK2 mutation status on RS was performed, adjusting for PR. A secondary ordinal univariate analysis was conducted that categorized RS into low, intermediate and high risk ( < 18, 18-30, and > 30, respectively). P-values were reported based on a null hypothesis of no effect against a two-sided alternative. Results: The median RS for cases was 19.5 (interquartile range [IQR]: 15 to 25) and the median RS for controls was 18 (IQR: 12 to 22). A greater proportion of cases were categorized as high risk (10.5%) compared to controls (5.6%), and a smaller proportion of cases were categorized as low risk (36.8%) compared to controls (49.3%). Cases had higher grade and increased proportion of PR-negative BC as compared with controls (grade 1: 12.1% of cases versus 32.4% of controls; PR-negative: 7.9% of cases versus 5.6% of controls). The variables used to match cases and controls (age, lymph node status, and T-stage) had similar summary statistics. The RS was 1.97-point higher in pts with g CHEK2 PV compared to controls, after adjusting for PR (95% confidence interval [CI]: 1.02-point lower to 4.96-point higher; p = 0.194). The secondary analysis of CHEK2 mutation status on an ordinal RS risk group yielded comparable results; on average, the odds of being high risk compared to the combined intermediate/low risk groups was 1.72 times higher in cases compared to controls (95% CI: 0.77 to 3.80; p = 0.181), but these differences were not significant. Conclusions: Our case-control study did not show a statistically higher RS for BC that develops in pts with g CHEK2 PV. Further studies are warranted to evaluate the association between type of CHEK2 PV (frameshift versus missense) and other modifying genetic variables and RS.

The somatic mutation landscape of germline CHEK2-altered prostate cancer.

5084 Background: The intersection between germline and somatic genomics is an evolving field in which germline mutations may predispose to unique patterns of subsequent somatic mutations in cancer. Germline mutations in CHEK2, involved in cell cycle regulation and DNA damage response, are associated with an increased risk of prostate cancer (PCa), while somatic-only CHEK2 alterations in PCa are rare. The association of germline CHEK2 (g CHEK2)-altered PCa with somatic mutations is unknown, and may inform hypotheses about the etiology of these cancers. Methods: Germline DNA sequencing of 1,042 consecutive PCa patients (pts) from the public SignalDB database (www.signaldb.org) was analyzed for prevalence of pathogenic g CHEK2 mutations and was compared to individuals from the general population estimated by the ExAC database (containing 53,105 germline exomes). A separate cohort of 33 PCa pts from Johns Hopkins (JH) with known g CHEK2 mutations and available somatic tumor DNA sequencing (from primary prostatic tissue) was used to assess the association of g CHEK2 mutations with somatic mutations in genes that are recurrently altered in PCa ( TP53, RB1, PTEN, ATM, BRCA1/2, and CDK12); the prevalence of these somatic alterations was compared to those in 333 unselected PCa pts from the TCGA cohort. Somatic biallelic inactivation of CHEK2 was analyzed in a subset of pts. After uncovering a potential link between g CHEK2 and somatic CDK12 mutations, we studied a cohort of 69 pts with somatic CDK12 mutations where germline data were also available. Results: 28 of 1,042 (2.7%) PCa pts from SignalDB had a pathogenic g CHEK2 mutation, compared to a population prevalence (in ExAC) of 1.4% (750 of 53,105) (RR 1.9, 95%CI 1.3–2.8, P< 0.001). Strikingly, only 23.8% of pts from SignalDB with g CHEK2 mutations had biallelic inactivation in the tumor . Furthermore, none of the 33 g CHEK2 pts from the JH cohort had evidence of somatic LOH. There were no differences in mutation prevalences involving TP53, RB1, PTEN, ATM, and BRCA1/2 between g CHEK2-altered and non-altered PCa pts. Unexpectedly, 5 of 33 (15%) g CHEK2-altered pts from the JH cohort had a somatic CDK12 mutation, compared to only 3 of 333 CDK12 mutations (1%) in unselected PCa pts from the TCGA cohort (RR 16.8, 95%CI 4.2–67, P< 0.001). Conversely, 11 of 69 (16%) pts with a somatic CDK12 mutation harbored a pathogenic g CHEK2 mutation, compared to 28 of 1,042 (2.7%) unselected PCa pts from SignalDB (RR 5.9, 95%CI 3.1–11.4, P< 0.001). Conclusions: Prostate cancers from g CHEK2-altered pts are infrequently characterized by biallelic CHEK2 inactivation and may be enriched for somatic CDK12 mutations, suggesting a unique mechanism of carcinogenesis that is different from g BRCA2-altered pts. Conversely, somatic CDK12-mutated cancers may be enriched for g CHEK2 mutations. The co-occurrence of CHEK2 and CDK12 mutations suggests a synergistic role in promoting cancer growth.

Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers

The most common breast cancer (BC) susceptibility genes beyond BRCA1/2 are ATM and CHEK2. For the purpose of exploring the clinicopathologic characteristics of BC developed by ATM or CHEK2 mutation carriers, we reviewed the archive of our Family Cancer Clinic. Since 2018, 1185 multi-gene panel tests have been performed. Nineteen ATM and 17 CHEK2 mutation carriers affected by 46 different BCs were identified. A high rate of bilateral tumors was observed in ATM (26.3%) and CHEK2 mutation carriers (41.2%). While 64.3% of CHEK2 tumors were luminal A-like, 56.2% of ATM tumors were luminal B-like/HER2-negative. Moreover, 21.4% of CHEK2-related invasive tumors showed a lobular histotype. About a quarter of all ATM-related BCs and a third of CHEK2 BCs were in situ carcinomas and more than half of ATM and CHEK2-related BCs were diagnosed at stage I-II. Finally, 63.2% of ATM mutation carriers and 64.7% of CHEK2 mutation carriers presented a positive BC family history. The biological and clinical characteristics of ATM and CHEK2-related tumors may help improve diagnosis, prognostication and targeted therapeutic approaches. Contralateral mastectomy should be considered and discussed with ATM and CHEK2 mutation carriers at the first diagnosis of BC.

The clinical and molecular characteristics of patients with personal or family history of gastrointestinal malignancies/polyposis and checkpoint kinase 2 (CHEK2) mutations.

44 Background: Checkpoint Kinase 2 (CHEK 2) encodes the protein CHK2, a serine/threonine kinase involved in pathways that conduct DNA repair as well as apoptosis in response to initial DNA damage. Germline mutations in the CHEK2 gene are associated with several malignancies such as colon, breast, stomach, prostate, kidney, thyroid and soft tissue cancers. Here, we describe the clinical and molecular characteristics of patients with personal or family history of gastrointestinal (GI) malignancies/polyposis and CHEK2 gene mutations. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a germline CHEK2 mutation were identified (N = 16). Patients with a CHEK2 mutation and personal and family history of GI malignancies/polyposis were further explored and their clinical and molecualr characteristics are summarized. Results: The reasons for referral to the Cancer Genetics Counseling Services in patients with pathogenic CHEK2 mutations were personal history of colon cancer (N = 3) and family history of colon cancer (N = 4). One patient with the CHEK2 c.1100delC mutation had a personal history of juvenile polyposis syndrome and a family history of colon cancer. In our cohort, 11 out of 16 (69%) patients had a CHEK2 mutation and personal or family history of GI malignancies/polyposis. The median age was 57 years old (25-80). Six (55%) patients were males. All (100%) patients were Caucasians. Seven (64%) patients had a pathogenic germline CHEK2 mutation and 4 (36%) patients had a variant of unknown significance (VUS). Among patients with pathogenic germline CHEK2 mutations (N = 7), 5 (72%) patients had CHEK2 c.1100delC mutation, 1 (14%) patient had CHEK2 c.190G > A mutation and 1 (14%) patient had CHEK2 c.470T > C mutation. The CHEK2 VUS mutations seen in our cohort were CHEK2 c.539G > A, CHEK2 p.V395L, CHEK2 gain of exons 3-15 and CHEK2 c.1421G > A mutations. Conclusions: All patients in our cohort with CHEK2 mutations were Caucasians. The majority of our patients (69%) had an underlying personal or family history of GI malignancies/polyposis. In patients with personal or family history of GI malignancies/polyposis and CHEK2 mutation, 64% were found to have pathogenic CHEK2 mutations. The most common diagnosed CHEK2 mutation in our cohort was CHEK2 c.1100delC mutation.

A first Japanese Case of Intraductal Cancer of the Prostate with CHEK2 Mutation

The authors have requested that this preprint be withdrawn due to erroneous posting.