Clinical Cancer Genomics Community Research Research Articles

Genetic Gastric Cancer Susceptibility in the International Clinical Cancer Genomics Community Research Network

Few susceptibility genes for gastric cancer have been identified. We sought to identify germline susceptibility genes from participants with gastric cancer from an international hereditary cancer research network. Adults with gastric cancer of any histology, and with a germline DNA sample (n = 51), were retrospectively selected. For those without previously identified germline mutations (n = 43), sequencing was performed for 706 candidate genes. Twenty pathogenic or likely pathogenic variants were identified among 18 participants. Eight of the 18 participants had previous positive clinical testing, including six with CDH1 pathogenic or likely pathogenic variants, and two with pathogenic MSH2 and TP53 variants. Of the remaining 10, six were in BRCA1 DNA damage response pathway genes (ATM, ATR, BRCA2, BRIP1, FANCC, TP53), other variants were identified in CTNNA1, FLCN, SBDS, and GNAS. Participants identified with pathogenic or likely pathogenic variants were younger at gastric cancer diagnosis than those without, 39.1 versus 48.0 years, and over 50% had a close family member with gastric cancer (p-values < 0.0001). In conclusion, many participants were identified with mutations in clinically-actionable genes. Age of onset and family history of gastric cancer were mutation status predictors. Our findings support multigene panels in identifying gastric cancer predisposition.

Abstract 4273: Variant reclassifications in hereditary cancer genetics and their implications for clinical care

Abstract BACKGROUND: Clinicians who provide genetic cancer risk assessment (GCRA) are dependent on laboratory reporting of germline results to inform cancer screening and treatment recommendations. Efforts to enhance variant classification and harmonization, such as ClinVar, will lead to an increase in the number of variants being reclassified. Given that the impact of variant reclassification on care is unknown, we evaluated the frequency and clinical impact of variant reclassification on individuals seen for GCRA. METHODS: We retrospectively evaluated data on 7,356 participants enrolled through the Clinical Cancer Genomics Community Research Network (CCGCRN) at City of Hope and Olive View Medical Center from September 1996- October 2016. RESULTS: 4,969 commercial genetic tests yielded a total of 1,610 variants of any category, of which 181 unique variants in 20 genes were reclassified. BRCA1 and BRCA2 (BRCA) and mismatch repair genes comprised 73.5% and 5.5% of the genes reclassified, respectively. Reclassification impacted 225 individuals (97% women) from 217 families; 89% of these individuals (n=201) had a personal history of cancer. The interval between initial report and variant reclassification averaged 3 years (17 days- 13 years). Minorities had higher reclassification rates as compared to non-Hispanic white participants (P = 0.0149). Of the 181 unique reclassifications, 164 (90.6%) of variants were downgraded. Sixteen reclassifications led to changes in clinical care. Thirteen variants carried by 15 individuals were upgraded from a variant of uncertain significance (VUS) to likely pathogenic or pathogenic (10 BRCA, 3 MLH1 or MSH2). These reclassifications prompted additional prophylactic surgical interventions (i.e., bilateral salpingo-oophorectomy), specialist referrals, and surveillance recommendations for at risk patients and family members. Three variants (NBN p.Arg215Trp, PTEN p.Ala79Thr, and MET c.1200+2T&amp;gt;C) were downgraded from likely pathogenic or pathogenic to VUS. Prior to downgrade to VUS, 2 cases had unnecessary surveillance procedures. CONCLUSIONS: Since many genomic variants will be reclassified over time, it is critical that laboratories deliver prompt notification of reclassifications, and that providers involved in GCRA discuss the possibility of variant reclassification with patients and family members and collect patient/proxy information during informed consent so that re-contact is possible. Given the non-trivial effort required for variant reclassification and patient/participant re-contact, system-level interventions are needed to facilitate genomic reinterpretation and the return of results to individuals over time. Citation Format: Thomas P. Slavin, Stacy W. Gray, Lily R. Van Tongeren, Ilana Solomon, Christina Rybak, Bita Nehoray, Lili Kuzmich, Mariana Niell-Swiller, Kathleen R. Blazer, Kai Yang, Julie Culver, Sharon Sand, Danielle Castillo, Josef Herzog, Jeffrey N. Weitzel. Variant reclassifications in hereditary cancer genetics and their implications for clinical care [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4273. doi:10.1158/1538-7445.AM2017-4273

Germline cancer susceptibility mutations in older women with breast cancer (BC).

e13030 Background: Older women with BC are less likely to undergo genetic cancer risk assessment since a hallmark of hereditary BC is younger age at onset. Hence there are limited data regarding genetic risk assessment findings in older women with BC. We analyzed the clinical characteristics and germline variant profiles of women with history of BC referred for genetic counseling at age ≥ 65 years, enrolled in the Clinical Cancer Genomics Community Research Network registry. Methods: Women age ≥ 65 with a history of BC (invasive or ductal carcinoma in situ) who underwent genetic testing from 1997 to 2016 were included. The profile of those found to have BC-related pathogenic variants was analyzed. Demographic and clinical characteristics for those with and without germline variants were compared using Fisher’s test and x2statistics. Results: 1372 women age ≥ 65 with BC were identified. Genetic testing was performed in 75% (n = 1035), among whom 10.4% (n = 108) had a germline variant in a BC-associated gene. High risk gene variants accounted for 85.1% (n = 92): BRCA2 (41.6%, n = 45), BRCA1 (37%, n = 40), PALB2 (5.5%, n = 6) and TP53 ( &lt; 1%, n = 1). Moderate risk gene variants were identified in 16.6% (n = 18): CHEK2 (13.8%, n = 15), ATM (1.8%, n = 2) and NF1 ( &lt; 1%, n = 1). Mean age at BC diagnosis was 56.4 (range 29 - 84) for women with variants and 60.9 (range 20 - 90) for those without (p &lt; .001). 25.9% of women with variants (n = 28) had their first BC diagnosed ≥ age 65, of which 60.7% (n = 17) were BRCA2 and 21.4% (n = 6) were BRCA1 mutations ( BRCA2 was significantly higher in women diagnosed with BC age ≥ 65 [p &lt; .001]). There was no difference in the mean number of 1st, 2nd and 3rd degree relatives with BC (2.4 [range 0-10] vs 2.2 [range 0-15]) for women with and without variants, respectively, and no difference in stage at diagnosis (Stage I-II in 95% vs 89.5%, p = .4). Women with variants were less likely to have ER/PR positive tumors than those without (66% vs 81.6%, p = .01). Conclusions: BC related susceptibility variants, particularly in BRCA2, are found in a significant number of older women undergoing genetic testing for a first diagnosis of BC ≥ 65. Older women with a clinical suspicion of hereditary BC should not be excluded from genetic testing and counseling based on chronological age alone.

Genetic, clinical and pathological characteristics of BRCA-associated breast cancer (BC) in Hispanic patients in the United States (US) and Latin America (LatAm).

1539 Background: Hispanic women with BC present at a younger age, have a higher frequency of BRCA mutations and show a worse incidence-to-mortality ratio than non-Hispanic women. Information regarding the characteristics of BRCA-associated BC in Hispanics is limited. Here, we assess differences in BRCA-associated BC between Hispanic patients in the US and in LatAm. Methods: Hispanic patients from the US and LatAm (Mexico, Colombia, Peru, and Puerto Rico) with a history of BRCA-associated BC enrolled in the Clinical Cancer Genomics Community Research Network registry were included. We compared the genetic, demographic, clinical and pathologic characteristics between Hispanics from the US and LatAm using Fisher’s exact test and x2statistics. Results: Between 1997 and 2016, 3670 Hispanic patients with a history of BC from LatAm (n = 1341) and the US (n = 2329) were identified, of which 490 (13.3%) had a deleterious BRCA mutation. The frequency of BRCA mutations was similar in Hispanics from LatAm (13.8%, n = 185) and the US (13.1%, n = 305). No significant differences were found in the frequency of BRCA1 vs BRCA2 mutations between patients from LatAm (BRCA1 68%, BRCA2 31.8%) and the US (BRCA1 61.3%, BRCA2 39%) (p = .12). The most frequent mutations found in BRCA1 were: ex 9-12del (LatAm n = 24, US n = 15), 185delAG (LatAm n = 13, US n = 18) and 943ins10 (LatAm n = 3, US n = 8), and in BRCA2 3492insT (LatAm n = 3, US n = 28). Mean age at BC diagnosis was 39.1 (SD 9.5) in LatAm and 41.7 (SD 10.6) in the US (p = 0.01). US patients were significantly more likely to present with Stage 0-II BC than those from LatAm (77.1% vs. 47.6%, p &lt; .001). We found no differences in the proportion of hormone receptor positive tumors between patients from LatAm (45%) and the US (47%) (p = .78). Conclusions: The frequency of BRCA-associated BC was similar between Hispanics in LatAm and the US. Women from LatAm with BRCA mutations present at a younger age, as seen for sporadic BC; the causes for this finding warrant further research. Women with BRCA-associated BC in LatAm are more likely to have advanced BC at presentation, which may be a reflection of disparities and barriers in access to care.

Abstract 2551: Identifying hereditary gastric cancer predisposition in the clinical cancer genomics community research network

Abstract Genetic Cancer Risk Assessment (GCRA) clinical referral and testing guidelines are limited for individuals and families with gastric cancer. In part, this is due to a lack of knowledge regarding hereditary gastric cancer susceptibility. The Clinical Cancer Genomics Community Research Network registry includes over 15,000 families seen for GCRA at City of Hope and 45 other collaborating sites. The purpose of this research was to identify variants conferring inherited gastric cancer susceptibility for individuals and families in our registry without previously known genetic predisposition. Adult research participants from our IRB-approved registry with a DNA sample and a personal history of gastric cancer were selected. Those with a previously identified genetic predisposition were excluded (n = 8). In families with more than one eligible individual, the individual with earliest onset of disease was selected. All histologies were included (i.e., intestinal and diffuse adenocarcinomas, as well as, gastrointestinal stromal tumors). Of 47 eligible participants, 22 had previously uninformative clinical testing. Germline sequencing was completed using a novel 706 candidate cancer gene panel, which included genes involved in DNA damage response, cell cycle regulation, apoptosis, and the Fanconi anemia, mTOR, JAK-STAT, and RAS-MAPK pathways; known cancer susceptibility genes; and genes frequently mutated in gastric tumors (data from the Catalog of Somatic Variants in Cancer database). Based on 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology Standards and Guidelines, 18 out of 47 research participants had pathogenic or likely pathogenic germline variants. Of the 18, 11 had a first- or second-degree relative with gastric cancer. Variants were identified in established cancer susceptibility genes, such as BRCA2, BRIP1, RAD51C, ATM, FLCN, as well as in genes from rare autosomal recessive conditions, such as FANCC. In conclusion, using a 706 gene panel to test a GCRA cohort, we were able to identify potentially pathogenic variants in 38% of participants with gastric cancer, with nearly half of these variants in clinically actionable genes. The variants identified in this study will need to be further evaluated using segregation studies, tumor studies, and in larger cohorts to establish causality. Citation Format: Thomas P. Slavin, Kai Yang, Sharon Sand, Tanya Chavez, Danielle Castillo, Joseph Herzog, Ilana Solomon, Christina Rybak, Mariana Niell-Swiller, Bita Nehoray, Aaron Adamson, Kathleen Blazer, Susan Neuhausen, Jeffrey Weitzel, Clinical Cancer Genomics Community Research Network. Identifying hereditary gastric cancer predisposition in the clinical cancer genomics community research network. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2551.