Multi-gene Hereditary Cancer Panel Testing Research Articles

Cancer Risk Associated With PTEN Pathogenic Variants Identified Using Multigene Hereditary Cancer Panel Testing.

PTEN-associated clinical syndromes such as Cowden syndrome (CS) increase cancer risk and have historically been diagnosed based upon phenotypic criteria. Because not all patients clinically diagnosed with CS have PTEN pathogenic variants (PVs), and not all patients with PTEN PVs have been clinically diagnosed with CS, the cancer risk conferred by PTEN PVs calculated from cohorts of patients with clinical diagnoses of CS/CS-like phenotypes may be inaccurate. We assessed a consecutive cohort of 727,091 individuals tested clinically for hereditary cancer risk, with a multigene panel between September 2013 and February 2022. Multivariable logistic regression models accounting for personal and family cancer history, age, sex, and ancestry were used to quantify disease risks associated with PTEN PVs. PTEN PVs were detected in 0.027% (193/727,091) of the study population, and were associated with a high risk of female breast cancer (odds ratio [OR], 7.88; 95% CI, 5.57 to 11.16; P = 2.3 × 10-31), endometrial cancer (OR, 13.51; 95% CI, 8.77 to 20.83; P = 4.2 × 10-32), thyroid cancer (OR, 4.88; 95% CI, 2.64 to 9.01; P = 4.0 × 10-7), and colon polyposis (OR, 31.60; CI, 15.60 to 64.02; P = 9.0 × 10-22). We observed modest evidence suggesting that PTEN PVs may be associated with ovarian cancer risk (OR, 3.77; 95% CI, 1.71 to 8.32; P = 9.9 × 10-4). Among patients with similar personal/family history and ancestry, every 5-year increase in age of diagnosis decreased the likelihood of detecting a PTEN PV by roughly 60%. We demonstrate that PTEN PVs are associated with significantly increased risk for a range of cancers. Together with the observation that PTEN PV carriers had earlier disease onset relative to otherwise comparable noncarriers, our results may guide screening protocols, inform risk-management strategies, and warrant enhanced surveillance approaches that improve clinical outcomes for PTEN PV carriers, regardless of their clinical presentation.

Ancestry-specific hereditary cancer panel yields: Moving toward more personalized risk assessment.

Healthcare disparities in genomic medicine are well described. Despite some improvements, we continue to see fewer individuals of African American, Asian, and Hispanic ancestry undergo genetic counseling and testing compared to those of European ancestry. It is well established that variant of uncertain significance (VUS) rates are higher among non-European ancestral groups undergoing multi-gene hereditary cancer panel testing. However, pathogenic variant (PV) yields, and genomic data in general, are often reported in aggregate and derived from cohorts largely comprised of individuals of European ancestry. We performed a retrospective review of clinical and ancestral data for individuals undergoing multi-gene hereditary cancer panel testing to determine ancestry-specific PV and VUS rates. An ancestry other than European was reported in 29,042/104,851 (27.7%) of individuals. Compared to Europeans (9.4%), individuals of Middle Eastern ancestry were more likely to test positive for one or more pathogenic variants (12.1%, p=.0025), while African Americans were less likely (7.9%, p<.0001). Asian and Middle Eastern individuals were most likely (34.8% and 33.2%, respectively) to receive a report with an overall classification of VUS, while individuals of Ashkenazi Jewish and European ancestry were least likely (17.1% and 20.4%, respectively). These data suggest that in addition to higher VUS rates, there may be ancestry-specific PV yields. Providing aggregate data derived from cohorts saturated with European individuals does not adequately reflect genetic testing outcomes in minority groups, and interrogation of ancestry-specific data is a step toward a more personalized risk assessment.

Abstract P5-09-08: Germline variants in non-BRCA homologous recombination genes detected in HER2-negative breast cancer patients

Abstract Background: PARP inhibitors (PARPi) are FDA approved for a subset of metastatic human epidermal growth factor receptor 2-negative (H2N) breast cancer patients who harbor a germline pathogenic or likely pathogenic variant (PV) in BRCA1/2, two of the most well-described breast cancer susceptibility genes in the homologous recombination (HR) pathway. While the NCCN guidelines recommend consideration of BRCA1/2 testing for patients with H2N disease that are eligible for single-agent therapy, there are currently clinical trials available for women with advanced H2N breast cancer who have PVs in HR genes beyond BRCA1/2 to investigate outcomes of receiving PARPi. The yield of germline PVs in other HR genes in the H2N population is not well-described. Methods: Clinical histories and test results were reviewed for women with a diagnosis of H2N breast cancer who underwent multi-gene hereditary cancer panel testing that included a minimum of 10 homologous recombination (HR) genes in addition to BRCA1/2 (ATM, BARD1, BRIP1, CHEK2, FANCC, NBN, PALB2, PTEN, RAD51C, RAD51D). Those with prior BRCA1/2 testing were excluded. We assessed the yield of PVs in non-BRCA1/2 HR genes in the H2N breast cancer population. In addition, we compared the yield of PVs in non-BRCA1/2 HR genes in a “low risk” population (probands with H2N breast cancer with no reported personal history of ovarian or pancreatic cancer and no reported family history of breast, ovarian, pancreatic, or prostate cancer) to a “high risk” population (probands with H2N breast cancer who also have a personal history of ovarian or pancreatic cancer and/or a reported family history of breast, ovarian, pancreatic, or prostate cancer) via a two-tailed Fisher's exact test. Results: A total of 6179 women with H2N breast cancer were identified. Of these, BRCA1/2 PVs were identified in 4.8% (299/6179), while 5.7% (351/6179) carried PVs in HR genes other than BRCA1/2. These included CHEK2 (145), ATM (62), PALB2 (59), BRIP1 (26), FANCC (18), BARD1 (17), RAD51C (12), NBN (11), RAD51D (6), and PTEN (2). No statistically significant difference in the likelihood to harbor a PV in one of the 10 non-BRCA1/2 HR genes was observed between those with a “low risk” presentation (4.8% (53/1096) as compared to those with a “high risk” presentation (5.9% (298/5083)) (p=0.1956). Conclusions: Our findings show that the yield of PVs in HR genes other than BRCA1/2 is appreciable in the H2N breast cancer population. As such, it may be beneficial to include all HR genes when testing H2N breast cancer patients, regardless of other personal or family history, if and/or when a patient develops metastatic disease. Citation Format: Vogel Postula KJ, McGill AK, Sutcliffe E, Murphy PD, Klein RT, Hruska KS. Germline variants in non-BRCA homologous recombination genes detected in HER2-negative breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-08.

Women with breast and uterine cancer are more likely to harbor germline mutations than women with breast or uterine cancer alone: A case for expanded gene testing

ObjectiveWe explored the germline mutation spectrum and prevalence among 1650 women with breast and uterine cancer (BUC) who underwent multi-gene hereditary cancer panel testing at a single commercial laboratory. MethodsThe combined frequency of mutations in 23 BC and/or UC genes was compared between BUC cases and control groups with (1) no personal cancer history; (2) BC only; and (3) UC only using logistic regression. ResultsFourteen percent (n = 231) of BUC cases tested positive for mutations in BC and/or UC genes and were significantly more likely to test positive than individuals with BC only (P < 0.001), UC only (P < 0.01), or unaffected controls (P < 0.001). Analysis of gene-specific mutation frequencies revealed that MSH6, CHEK2, BRCA1, BRCA2, ATM, PMS2, PALB2 and MSH2 were most frequently mutated among BUC cases. Compared to BC only, BRCA1, MLH1, MSH2, MSH6, PMS2 and PTEN mutations were more frequent among BUC; however, only ATM mutations were more frequent among BUC compared to UC only. All of the more commonly mutated genes have published management guidelines to guide clinical care. Of patients with a single mutation in a gene with established testing criteria (n = 152), only 81.6% met their respective criteria, and 65.8% met criteria for multiple syndromes. ConclusionsWomen with BUC are more likely to carry hereditary cancer gene mutations than women with breast or uterine cancer alone, potentially warranting expanded genetic testing for these women. Most mutations found via multi-gene panel testing in women with BUC have accompanying published management guidelines and significant implications for clinical care.

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.

Utility of Expedited Hereditary Cancer Testing in the Surgical Management of Patients with a New Breast Cancer Diagnosis.

Knowledge of a germline pathogenic/likely pathogenic variant (PV) may inform breast cancer management. BRCA1/2 PV often impact surgical decisions, but data for multi-gene panel testing are lacking. Expedited genetic testing reduces turn-around times based on request for treatment-related decision making. This report aims to describe the clinical utility of expedited multi-gene panel testing for patients with newly diagnosed breast cancer. Clinical and demographic information were reviewed for patients with newly diagnosed female breast cancer undergoing expedited panel testing between 2013 and 2017. The National Comprehensive Cancer Network guidelines (NCCN, version 1.2018) were evaluated in terms of published management recommendations for the genes in which PVs wereidentified. The overall PV yield was 9.5% (678/7127) for women undergoing expedited panel testing, with 700 PVs identified among 678 women. PVs were identified in genes other than BRCA1/2 in 55.9% (391/700) of cases. The NCCN guidelines recommend management for the genes in which 96.6% (676/700) of PVs are identified. The NCCN guidelines also recommend risk-reducing mastectomy for 46.0% (322/700) of PVs identified. An additional 45.6% (319/700) of PVs were identified in genes for which NCCN recommends mastectomy based on family history. In addition, 49.9% (349/700) of PVs were in genes with NCCN guidelines recommending prophylactic surgery for tissues other than breast. A majority of the patients with newly diagnosed breast cancer were candidates for surgical intervention according to the NCCN guidelines, and half of these patients would have been missed if only BRCA1/2 testing had been ordered. Expedited multi-gene hereditary cancer panel testing should be considered as a first-line approach to provide comprehensive information for breast cancer management.

Triple-Negative Breast Cancer Risk Genes Identified by Multigene Hereditary Cancer Panel Testing.

BackgroundGermline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor–negative, progesterone receptor–negative, human epidermal growth factor receptor–negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of this study was to define the cancer panel genes associated with increased risk of TNBC.MethodsMultigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium (TNBCC) of research studies. Associations between deleterious mutations in cancer predisposition genes and TNBC were evaluated using results from TNBC patients and reference controls.ResultsGermline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20% lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of TNBC. Similar trends were observed for the African American population. Pathogenic variants in these TNBC genes were detected in 12.0% (3.7% non-BRCA1/2) of all participants.ConclusionsMultigene hereditary cancer panel testing can identify women with elevated risk of TNBC due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D. These women can potentially benefit from improved screening, risk management, and cancer prevention strategies. Patients with mutations may also benefit from specific targeted therapeutic strategies.

Mosaic TP53 pathogenic variants on multi-gene hereditary cancer panel testing: Clinical characteristics and follow-up testing.

1580Background: Li-Fraumeni Syndrome (LFS) is an autosomal dominant cancer susceptibility syndrome due to germline pathogenic variants in TP53 and is associated with a significant risk for sarcomas...

MP28-18 INHERITED PATHOGENIC VARIANTS IDENTIFIED IN PATIENTS WITH RENAL CANCER

You have accessJournal of UrologyKidney Cancer: Epidemiology & Evaluation/Staging I1 Apr 2018MP28-18 INHERITED PATHOGENIC VARIANTS IDENTIFIED IN PATIENTS WITH RENAL CANCER Maegan Roberts, Megan Marshall, Natalie Carter, Kevin Arvai, Lance Grau, Shirley Yao, Ying Wang, Rachel Klein, and Kathleen Hruska Maegan RobertsMaegan Roberts More articles by this author , Megan MarshallMegan Marshall More articles by this author , Natalie CarterNatalie Carter More articles by this author , Kevin ArvaiKevin Arvai More articles by this author , Lance GrauLance Grau More articles by this author , Shirley YaoShirley Yao More articles by this author , Ying WangYing Wang More articles by this author , Rachel KleinRachel Klein More articles by this author , and Kathleen HruskaKathleen Hruska More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.918AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES It is estimated that 3-5% of all renal cancers are due to a hereditary predisposition. Additionally, hereditary renal cancers have been reported to develop at earlier ages and are more likely to present as multifocal or bilateral disease. We describe clinical features of probands with renal cancer with a pathogenic or likely pathogenic variant (collectively, PV) identified via multi-gene hereditary cancer panel testing. METHODS We performed a retrospective review of clinical and molecular data for all individuals diagnosed with renal cancer undergoing multi-gene panel testing at our clinical diagnostic laboratory (N=945). Individuals with cancer of the renal pelvis were excluded. Student′s t-test with two-sided p-value of 0.05 was used to compare age at diagnosis. RESULTS Of the 945 individuals reporting a personal history of renal cancer, 93 PVs were identified in 89 individuals (9.4%). Thirty-nine individuals (4.1%) were identified as having a PV in a gene previously associated with hereditary renal cancer. While 50 individuals (5.3%) were found to have a PV in a gene not previously associated with hereditary renal cancer, 39 (78%) reported a history of a second non-renal primary tumor. A personal history of >1 renal cancer was reported for 98 (10.4%) individuals. Among these, 12 (12.2%) were found to have a PV in ATM, BAP1, CHEK2, FH (3), MET, MITF, WT1, SDHA, TSC1, and VHL. Individuals with >1 renal cancer who tested positive (41.2 yrs) tended to be diagnosed at a younger age compared to those who tested negative (49.8 yrs) (p=0.085). Among those reporting a single primary renal cancer, the yield was 7.4% (21/284), and the average age at diagnosis was not significantly different between those testing positive (42.0 yrs) and those testing negative (44.2 yrs) (p=0.544). When assessing family history, 178 (18.8%) reported a family history of renal cancer; 20 (11.2%) were found to have a PV. CONCLUSIONS The overall PV yield observed in this cohort was 9.4%. When limiting to genes known to be associated with a hereditary predisposition to renal cancer, the yield was 4.1%, consistent with published estimates. The highest PV yield (12.2%) was observed in individuals with >1 renal tumor followed by those reporting a family history of renal cancer (11.2%). Age at diagnosis was not significantly different with regards to PV yield in either group evaluated. Overall, individuals with >1 renal tumor or a family history of renal cancer have the highest yield for PVs. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e363-e364 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Maegan Roberts More articles by this author Megan Marshall More articles by this author Natalie Carter More articles by this author Kevin Arvai More articles by this author Lance Grau More articles by this author Shirley Yao More articles by this author Ying Wang More articles by this author Rachel Klein More articles by this author Kathleen Hruska More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Germline pathogenic variants in patients with pheochromocytoma.

668 Background: Approximately 25% of pheochromocytomas (PCC) have a hereditary basis, and germline variants in the SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 genes have been associated with a predisposition to PCC and paraganglioma (PGL). Multi-gene hereditary cancer panel testing for PCC has become increasingly more common than single-gene testing algorithms. Identification of a pathogenic or likely pathogenic variant (PV/LPV) in one of these genes has important implications for surveillance in patients and their family members. Here we describe the spectrum of PV/LPV variants identified in individuals with PCC. Methods: We performed a retrospective review of clinical and molecular data for all individuals diagnosed with PCC who underwent panel testing through BioReference Laboratories that included at least SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 between January 2016 and February 2017. Results: Seventy-nine individuals underwent testing due to a personal (n = 76) or family (n = 3) history of PCC. The positive yield was 14% (11/79). The majority of PV/LPV were in SDHB (n = 4; 36%), followed by RET (n = 2, 18%), with the remaining variants being identified in SDHA (1), SDHC (1), VHL (1), TMEM127 (1), and MAX (1). Approximately half (6/11) of those with a PV/LPV had a non-syndromic presentation of a unilateral PCC with no reported family history of PCC or PGL. The average age at tumor diagnosis was lower for probands testing positive than those without PV/LPV (34y±14 vs 44y±16). Conclusions: Our data support previous recommendations that patients with apparently sporadic, non-syndromic PCC be considered for genetic testing. Panel testing is a useful tool for identifying individuals with hereditary PCC.

Abstract PD7-11: The role of multi-gene hereditary cancer panels in male patients with breast cancer

Abstract Background/Statement of Purpose: The role of cancer susceptibility genes in the male breast cancer population beyond BRCA1 and BRCA2 (BRCA) is not well defined. While breast cancer has been documented in men with pathogenic variants in a number of other breast cancer susceptibility genes (e.g. CHEK2, PALB2, PTEN), the yield of testing is not well documented nor are predictive clinical features of those likely to harbor causative variants. This study assesses the yield of pathogenic/likely pathogenic variants (collectively, PV) in male breast cancer patients who underwent multi-gene hereditary cancer panel testing. In addition, we aim to examine predictors of identifying a PV in this population. Methods: Clinical histories and test results were reviewed for men with a diagnosis of breast cancer who underwent panel testing that included a minimum of eight well-described breast cancer susceptibility genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, TP53) and up to 24 additional genes. Using t-test and two-tailed Fisher's exact test, we assessed whether age at diagnosis, family history of breast cancer, or the presence of selected second primary cancers (second breast, prostate, pancreatic, colon, or melanoma cancers) were associated with a greater likelihood of identifying a PV. Results: The clinical histories and test results of 381 men with breast cancer were reviewed, of whom 12.1% had at least one PV (46/381). When we limited our assessment to men who had not had prior negative BRCA testing, 13.3% had at least one PV (42/315). Variants were most commonly detected in BRCA2 (21) and CHEK2 (17), followed by PALB2 (4), BRCA1 (4), and ATM (2). A two sample t-test showed no significant difference (p=0.39) in the average age of diagnosis for those with a PV (62.5y, n=47) compared to those without a PV (60.9y, n=334). Two-tailed Fisher's exact test showed no association between having a PV and a history of a selected second primary (SP) cancer [10.8% (7/65) w/SP vs 12.3% (39/316) w/out SP; p=0.84]. Lastly, two-tailed Fisher's exact test showed those with a family history of breast cancer (fhx br) were more likely to have a PV [15.1% (32/212) fhx br vs. 8.3% (14/169) no fhx br], although this did not reach statistical significance (p=0.06). Conclusions: While BRCA2 remains the most common gene in which PVs are identified in men with breast cancer, a significant proportion of patients will have a PV in another well-described breast cancer susceptibility gene, particularly CHEK2, PALB2, and ATM. Therefore, it is reasonable to utilize a panel that is inclusive of these genes when testing male breast cancer patients. As the likelihood to harbor a PV was not significantly associated with age of onset, family history of breast cancer, or presence of a second primary, all men with breast cancer could consider genetic testing. Further study is warranted as the current sample size may limit the power to detect associations. Citation Format: Vogel Postula KJ, Andolina LM, Theobald K, McGill AK, Sutcliffe E, Arvai KJ, Murphy PD, Klein RT, Hruska KS. The role of multi-gene hereditary cancer panels in male patients with breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD7-11.

High prevalence of pathogenic variants in individuals with colorectal cancer ≤ age 35.

576 Background: Young age at onset is a hallmark feature of an inherited predisposition to cancer. Recent evidence suggests that the incidence of pathogenic/likely pathogenic variants (PV) in cancer predisposition genes among individuals diagnosed with colorectal cancer (CRC) ≤ age 35 is high, but few studies have examined the frequency identified by multi-gene hereditary cancer panel testing. We report on PV yield and clinical presentation of individuals diagnosed with CRC ≤ 35 years (y). Methods: We retrospectively reviewed test requisition forms and provided pathology reports for 4,727 individuals with CRC who underwent panel testing of, at a minimum, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, and MUTYH. Two-tailed Fisher’s exact tests were used to determine statistically significant differences between groups. Results: Of the 691 individuals diagnosed with CRC ≤35y, 137 PV were identified in 126 individuals (126/691, 18.2%), including 72 with Lynch syndrome, 16 with familial adenomatous polyposis (FAP), five with MUTYH-associated polyposis, four with constitutional mismatch repair deficiency, one with juvenile polyposis syndrome, and one with Peutz-Jeghers syndrome. Thirty-eight additional PVs were identified in other non-CRC genes. Microsatellite instability (MSI) and immunohistochemistry (IHC) results were reported for 277 individuals and were reportedly abnormal in 63. The yield of PV in individuals with abnormal tumor studies was 52.4% (33/63); PV in genes other than the Lynch syndrome-associated genes were identified, commonly in the MSI-H group. While statistical significance was not observed, the positive rate was higher for individuals with non-rectal cancers (colon cancer: 104/534, 19.5%; rectal cancer: 22/157, 14.0%, p = 0.13). Conclusions: In our cohort, 18.2% of individuals diagnosed with CRC ≤35y were found to harbor a PV. Yield increased in those with abnormal MSI/IHC as well as non-rectal tumor location. Hereditary predispositions in patients diagnosed with very early-onset CRC are not limited to Lynch syndrome and FAP. Therefore, individuals with very early-onset CRC may benefit from multi-gene panel testing rather than syndromic-based testing.

Multigene hereditary cancer panel testing for patients with pancreatic cancer.

244 Background: Pancreatic ductal adenocarcinoma (PC) is associated with multiple hereditary cancer syndromes. Genes implicated in hereditary PC include ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2 and PMS2. The advent of multi-gene hereditary cancer panel testing streamlines diagnoses and medical management for clinicians and patients. Our objective was to assess the yield of pathogenic/likely pathogenic variants (PV/LPV) in individuals with PC undergoing panel testing as an initial test at GeneDx. Methods: We retrospectively reviewed panel test results of 605 individuals reporting a personal history of PC. Panel testing evaluated up to 32 genes associated with hereditary cancer. Individuals reporting neuroendocrine pathology or previous BRCA1/BRCA2 testing were excluded. Results: In this cohort, 61 PV/LPV were detected in 57 individuals in the following genes: ATM (17), BRCA2 (14), BRCA1 (5), CDKN2A (5), PALB2 (5), CHEK2 (4), MLH1 (2), MUTYH (2), PMS2 (2), BARD1 (1), FANCC (1), MSH2 (1), RAD51D (1) and TP53 (1), corresponding to a positive yield of 9.4% (57/605). Fifty-one of 61 PV/LPV were detected in genes associated with PC (84%) while 10 PV/LPV (16%) were identified in other genes including BARD1, CHEK2, FANCC, MUTYH, and RAD51D. The diagnostic yield among those reporting a family history of PC (33/294, 11.2%) was not statistically different from those without a reported family history (24/311, 7.7%). However, PV/LPV in ATM were detected more often in individuals reporting a family history of PC compared to those without a family history (4.1% vs. 1.6%, p=0.018). Conclusions: In total, 9.4% of patients with PC tested positive for PV/LPV in 14 different genes by panel testing. Although the majority of PV/LPV were identified in known PC genes, 16% of positive findings occurred in genes not typically associated with PC. ATM was most commonly implicated and more frequently reported in patients reporting family histories of PC. Assessing whether these genes are indeed causally related to PC and/or are possibly associated with other cancer types requires further investigation. Based on our results we conclude multi-gene panel testing may be considered as a first option for patients with PC regardless of their family history.

Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort

AbstractHereditary endometrial carcinoma is associated with germline mutations in Lynch syndrome genes. The role of other cancer predisposition genes is unclear. We aimed to determine the prevalence of cancer predisposition gene mutations in an unselected endometrial carcinoma patient cohort. Mutations in 25 genes were identified using a next-generation sequencing-based panel applied in 381 endometrial carcinoma patients who had undergone tumor testing to screen for Lynch syndrome. Thirty-five patients (9.2%) had a deleterious mutation: 22 (5.8%) in Lynch syndrome genes (three MLH1, five MSH2, two EPCAM-MSH2, six MSH6, and six PMS2) and 13 (3.4%) in 10 non-Lynch syndrome genes (four CHEK2, one each in APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, NBN, PTEN, and RAD51C). Of 21 patients with deleterious mutations in Lynch syndrome genes with tumor testing, 2 (9.5%) had tumor testing results suggestive of sporadic cancer. Of 12 patients with deleterious mutations in MSH6 and PMS2, 10 were diagnosed at age >50 and 8 did not have a family history of Lynch syndrome-associated cancers. Patients with deleterious mutations in non-Lynch syndrome genes were more likely to have serous tumor histology (23.1 vs 6.4%, P=0.02). The three patients with non-Lynch syndrome deleterious mutations and serous histology had mutations in BRCA2, BRIP1, and RAD51C. Current clinical criteria fail to identify a portion of actionable mutations in Lynch syndrome and other hereditary cancer syndromes. Performance characteristics of tumor testing are sufficiently robust to implement universal tumor testing to identify patients with Lynch syndrome. Germline multi-gene panel testing is feasible and informative, leading to the identification of additional actionable mutations.

An Individual with Both MUTYH-Associated Polyposis and Lynch Syndrome Identified by Multi-Gene Hereditary Cancer Panel Testing: A Case Report.

The utilization of next-generation sequencing technology to interrogate multiple genes simultaneously is being utilized more frequently in hereditary cancer testing. While this has benefits of reducing cost and allowing clinicians to cast a wide net in the elucidation of their patient's cancer, panel testing has the potential to reveal unexpected information. We report on a proband with pathogenic variants resulting in two different hereditary colon cancer syndromes. A 39-year-old male with a history of colon cancer, more than 20 colon polyps and a family history of colon cancer presented for genetic counseling. Testing with a 7-gene high-risk hereditary colon cancer panel identified a homozygous pathogenic variant, c.1187G>A (p.Gly396Asp) in MUTYH, and a likely pathogenic duplication of exon 7 in MSH2. Since this test result, the proband's mother was diagnosed with colon cancer; subsequent genetic testing confirmed she also carries the likely pathogenic duplication in the MSH2 gene. Although the cancer risk in individuals who carry multiple pathogenic variants has not been established for combined biallelic MUTYH-associated polyposis and Lynch syndrome, the identification of multiple pathogenic variants does allow for screening for cancers associated with both syndromes and has implications for cancer risk for family members. In particular, this has significant impact on those who test negative for a known familial pathogenic variant, yet could be still be at risk for cancer due to a second pathogenic variant in a family. More information is needed on the frequency of occurrence of multiple pathogenic variants, as well as the phenotypic spectrum when multiple pathogenic variants are present.

Abstract 14: Identification of probands with multiple mutations in cancer susceptibility genes using a multigene panel approach

Abstract The multi-gene hereditary cancer panel testing approach allows for the identification of probands carrying multiple mutations in hereditary cancer predisposition genes. The purpose of this study is to assess the frequency and phenotypes of individuals in our hereditary cancer panel cohort carrying multiple mutations in hereditary cancer predisposition genes. From March 2012 through October 2013, results were reported for 4382 individuals who underwent hereditary cancer panel testing at our laboratory. Panels included comprehensive analysis of 14-24 genes, depending on the panel ordered. Genes analyzed on each panel included both genes associated with defined hereditary cancer syndromes and genes not yet associated with a defined hereditary cancer syndrome, with moderate to high penetrance estimates. Panel results were reviewed to determine the number of probands carrying multiple pathogenic mutations or likely pathogenic variants in the genes analyzed, and retrospective test requisition form review was used to obtain clinician-reported clinical history information. Biallelic MUTYH mutation carriers were not counted as multiple mutation cases, nor were individuals carrying a monoallelic MUTYH mutation in combination with a mutation in a different gene. Nine probands (0.2%) were identified to carry two cancer-predisposing mutations. Mutations included 7 small insertions/deletions, 1 nonsense, 4 missense, 3 splicing, and 3 gross deletions. Five individuals carried two mutations in moderately-penetrant cancer susceptibility genes not associated with a defined hereditary cancer syndrome. Mutated gene combinations included CHEK2/CHEK2 (confirmed to be in trans), ATM/RAD50, ATM/CHEK2 (identified in two probands), and MRE11A/PALB2. Two individuals carried one mutation in a moderately-penetrant gene and one mutation in a highly-penetrant gene associated with a defined hereditary cancer syndrome (ATM/MSH6 and MLH1/CHEK2). The remaining two individuals carried two mutations in highly-penetrant genes (MSH6/MSH6 (phase unknown) and MSH2/MSH6). The average age at first primary cancer diagnosis was 42 years (range 16-66 years). All probands had a history of cancer, including six of the nine probands with a reported history of more than one primary cancer diagnosis. Results from this study indicate that a minority of probands undergoing hereditary cancer panel testing are identified to carry multiple mutations in cancer susceptibility genes. This data highlights the need for further research to determine the clinical implications of carrying multiple mutations in cancer susceptibility genes, particularly for those with mutations in moderately-penetrant genes. Detailed pedigree analysis, co-segregation analysis, and longitudinal follow-up will be helpful in clarifying cancer risks in these probands and the significance of multiple mutations in cancer susceptibility genes. Citation Format: Chia-Ling Gau, Holly LaDuca, Hong Lu, AJ Stuenkel, Tina Pesaran, Elaine Chen, Jill Siegfried, Sharon Mexal, Robert Hoiness, Jill Cook, John Copenhaver, Elizabeth Chao. Identification of probands with multiple mutations in cancer susceptibility genes using a multigene panel approach. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 14. doi:10.1158/1538-7445.CANSUSC14-14