Multigene Panel Testing Increases the Number of Loci Associated with Gastric Cancer Predisposition

The main gene involved in gastric cancer (GC) predisposition is CDH1, the pathogenic variants of which are associated with diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC). CDH1 only explains a fraction (10–50%) of patients suspected of DGC/LBC genetic predisposition. To identify novel susceptibility genes, thus improving the management of families at risk, we performed a multigene panel testing on selected patients. We searched for germline pathogenic variants in 94 cancer-related genes in 96 GC or LBC Italian patients with early-onset and/or family history of GC. We found CDH1 pathogenic variants in 10.4% of patients. In 11.5% of cases, we identified loss-of-function variants in BRCA1, BRCA2, PALB2, and ATM breast/ovarian cancer susceptibility genes, as well as in MSH2, PMS2, BMPR1A, PRF1, and BLM genes. In 78.1% of patients, we did not find any variants with clear-cut clinical significance; however, 37.3% of these cases harbored rare missense variants predicted to be damaging by bioinformatics tools. Multigene panel testing decreased the number of patients that would have otherwise remained genetically unexplained. Besides CDH1, our results demonstrated that GC pathogenic variants are distributed across a number of susceptibility genes and reinforced the emerging link between gastric and breast cancer predisposition.

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Germline pathogenic variants in cancer predisposition genes among women with invasive lobular cancer of breast.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10581 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10581-10581

Author(s):

Siddhartha Yadav ◽

Chunling Hu ◽

Susan M. Domchek ◽

Jeffrey N. Weitzel ◽

David Goldgar ◽

...

Keyword(s):

Breast Cancer ◽

Population Based ◽

Cancer Predisposition ◽

Clinical Cohort ◽

Breast Cancer Predisposition ◽

Panel Testing ◽

Pathogenic Variants ◽

Predisposition Genes ◽

Multigene Panel Testing ◽

Multigene Panel

10581 Background: The prevalence of germline pathogenic variants (PVs) in cancer predisposition genes among women with invasive lobular breast cancer (ILC) and the risk of ILC in PV carriers is not well-defined. Methods: The study included 2,999 women with ILC and 32,544 unaffected controls from a population-based cohort; 3,796 women with ILC and 20,323 women with invasive ductal carcinoma (IDC) undergoing clinical multigene panel testing (clinical cohort); and 125,748 exome sequences from unrelated women without a cancer diagnosis in the gnomAD 3.0 dataset. Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected controls in both cohorts and between women with ILC and IDC in the clinical cohort. Results: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analyses, CDH1 and BRCA2 PVs were associated with high risks of ILC (Odds ratio (OR) > 4), and CHEK2, ATM and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. PV frequencies in these genes in ILC and IDC were similar except for PV frequencies in BRCA1 and CDH1. Conclusions: The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2 and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. While, multigene panel testing may be appropriate for women with ILC, CDH1 should be specifically discussed in the context of low prevalence and attendant gastric cancer risk.

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Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

JCO Precision Oncology ◽

10.1200/po.21.00249 ◽

2021 ◽

pp. 1588-1602

Author(s):

Monica D. Levine ◽

Rachel Pearlman ◽

Heather Hampel ◽

Casey Cosgrove ◽

David Cohn ◽

...

Keyword(s):

Endometrial Cancer ◽

Cancer Susceptibility ◽

Susceptibility Genes ◽

Type Ii ◽

Newly Diagnosed ◽

Panel Testing ◽

Pathogenic Variants ◽

Cancer Susceptibility Genes ◽

Multigene Panel Testing ◽

Multigene Panel

PURPOSE Clinical utility of up-front multigene panel testing (MGPT) is directly related to the frequency of pathogenic variants (PVs) in the population screened and how genetic findings can be used to guide treatment decision making and cancer prevention efforts. The benefit of MGPT for many common malignancies remains to be determined. In this study, we evaluated up-front MGPT in unselected patients with endometrial cancer (EC) to determine the frequency of PVs in cancer susceptibility genes. METHODS Patients with EC were prospectively enrolled at nine Ohio institutions from October 1, 2017, to December 31, 2020. Nine hundred and sixty-one patients with newly diagnosed EC underwent clinical germline MGPT for 47 cancer susceptibility genes. In addition to estimating the prevalence of germline PVs, the number of individuals identified with Lynch syndrome (LS) was compared between MGPT and tumor-based screening. RESULTS Likely pathogenic variants or PVs were identified in 97 of 961 women (10.1%). LS was diagnosed in 29 of 961 patients (3%; 95% CI, 2.1 to 4.3), with PVs in PMS2 most frequent. MGPT revealed nine patients with LS in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 PVs were found in 1% (10 of 961; 95% CI, 0.6 to 1.9) of patients and that group was significantly enriched for type II ECs. CONCLUSION This prospective, multicenter study revealed potentially actionable germline variants in 10% of unselected women with newly diagnosed EC, supporting the use of up-front MGPT for all EC patients. The discovery that BRCA1 or BRCA2 heterozygotes frequently had type II cancers points to therapeutic opportunities for women with aggressive histologic EC subtypes.

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Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast

Journal of Clinical Oncology ◽

10.1200/jco.21.00640 ◽

2021 ◽

Author(s):

Siddhartha Yadav ◽

Chunling Hu ◽

Katherine L. Nathanson ◽

Jeffrey N. Weitzel ◽

David E. Goldgar ◽

...

Keyword(s):

Breast Cancer ◽

Lobular Carcinoma ◽

Population Based ◽

Cancer Predisposition ◽

Clinical Cohort ◽

Breast Cancer Predisposition ◽

Panel Testing ◽

Pathogenic Variants ◽

Predisposition Genes ◽

Multigene Panel

PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

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Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

International Journal of Cancer ◽

10.1002/ijc.31921 ◽

2018 ◽

Vol 144 (8) ◽

pp. 1962-1974 ◽

Cited By ~ 14

Author(s):

Elodie Girard ◽

Séverine Eon‐Marchais ◽

Robert Olaso ◽

Anne‐Laure Renault ◽

Francesca Damiola ◽

...

Keyword(s):

Breast Cancer ◽

Dna Repair ◽

Familial Breast Cancer ◽

Susceptibility Genes ◽

Dna Repair Genes ◽

Panel Testing ◽

Multigene Panel Testing ◽

Repair Genes ◽

Multigene Panel

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Patients’ Medical and Psychosocial Experiences After Detection of a CDH1 Variant With Multigene Panel Testing

JCO Precision Oncology ◽

10.1200/po.18.00300 ◽

2019 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Jada G. Hamilton ◽

Jessica M. Long ◽

Amanda C. Brandt ◽

Jamie Brower ◽

Heather Symecko ◽

...

Keyword(s):

Breast Cancer ◽

Gastric Cancer ◽

Self Report ◽

Diffuse Gastric Cancer ◽

Care Providers ◽

Cancer Risks ◽

Panel Testing ◽

Prophylactic Gastrectomy ◽

Multigene Panel Testing ◽

Multigene Panel

PURPOSE Germline CDH1 pathogenic variants (PV) are associated with hereditary diffuse gastric cancer and lobular breast cancer. Although prevalence of CDH1 PV is low in the general population, detection of these variants is increasing with the growing use of multigene panel testing. Little is known about the experiences of individuals tested for CDH1 variants in the multigene panel testing era. METHODS Participants recruited from the Prospective Registry of Multiplex Testing completed a cross-sectional self-report survey regarding CDH1 genetic testing experiences, medical management, and psychosocial adaptation. RESULTS Discordance existed in interpretations of CDH1 results; 13.3% of cases had disagreements in variant classifications among commercial laboratories, and 21.4% had disagreements between participant self-report and ClinVar classification. Survey data were available from 57 individuals reporting either PV (n = 16) or variants of uncertain significance (VUS; n = 41). Those with PV were more likely than those with VUS to report receiving a recommendation for prophylactic gastrectomy, although only 40.0% of those with PV received this recommendation. Participants with VUS were less satisfied with their health care providers’ knowledge and reported less CDH1 knowledge, distress, and worry about discrimination. Participants with PV perceived greater breast cancer risks, but similar gastric cancer risks, as those with VUS. CONCLUSION Few individuals with CDH1 PV report receiving recommendations for prophylactic gastrectomy, and no differences in perceived gastric cancer risk were observed based on participants’ CDH1 results, suggesting serious unmet informational needs.

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Inherited breast cancer predisposition in Asians: multigene panel testing outcomes from Singapore

npj Genomic Medicine ◽

10.1038/npjgenmed.2015.3 ◽

2016 ◽

Vol 1 (1) ◽

Cited By ~ 25

Author(s):

Edward S Y Wong ◽

Sandhya Shekar ◽

Marie Met-Domestici ◽

Claire Chan ◽

Melody Sze ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Predisposition ◽

Breast Cancer Predisposition ◽

Panel Testing ◽

Inherited Breast Cancer ◽

Multigene Panel Testing ◽

Multigene Panel

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Multigene Panel Testing Provides a New Perspective on Lynch Syndrome

Journal of Clinical Oncology ◽

10.1200/jco.2016.71.9260 ◽

2017 ◽

Vol 35 (22) ◽

pp. 2568-2575 ◽

Cited By ~ 68

Author(s):

Carin R. Espenschied ◽

Holly LaDuca ◽

Shuwei Li ◽

Rachel McFarland ◽

Chia-Ling Gau ◽

...

Keyword(s):

Breast Cancer ◽

Endometrial Cancer ◽

Lynch Syndrome ◽

Population Based ◽

Brca1 And Brca2 ◽

Panel Testing ◽

Multigene Panel Testing ◽

New Perspective ◽

Testing Criteria ◽

Multigene Panel

Purpose Most existing literature describes Lynch syndrome (LS) as a hereditary syndrome leading to high risks of colorectal cancer (CRC) and endometrial cancer mainly as a result of mutations in MLH1 and MSH2. Most of these studies were performed on cohorts with disease suggestive of hereditary CRC and population-based CRC and endometrial cancer cohorts, possibly biasing results. We aimed to describe a large cohort of mismatch repair (MMR) mutation carriers ascertained through multigene panel testing, evaluate their phenotype, and compare the results with those of previous studies. Methods We retrospectively reviewed clinical histories of patients who had multigene panel testing, including the MMR and EPCAM genes, between March 2012 and June 2015 (N = 34,981) and performed a series of statistical comparisons. Results Overall, MSH6 mutations were most frequent, followed by PMS2, MSH2, MLH1, and EPCAM mutations, respectively. Of 528 patients who had MMR mutations, 63 (11.9%) had breast cancer only and 144 (27.3%) had CRC only. When comparing those with breast cancer only to those with CRC only, MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations ( P = 2.3 × 10−5). Of the 528 patients, 22.2% met BRCA1 and BRCA2 ( BRCA1/2) testing criteria and not LS criteria, and 5.1% met neither BRCA1/2 nor LS testing criteria. MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations among patients who met BRCA1/2 testing criteria but did not meet LS testing criteria ( P = 4.3 × 10−7). Conclusion These results provide a new perspective on LS and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and ovarian cancer phenotype. These data also highlight the limitations of current testing criteria in identifying these patients, as well as the need for further investigation of cancer risks in patients with MMR mutations.

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