Prevalence and spectrum of pathogenic variants among patients with multiple primary cancers evaluated by clinical characteristics

Bychkovsky, Brittany; Lo, Min‐Tzu; Yussuf, Amal; Horton, Carolyn; Richardson, Marcy E.; LaDuca, Holly; Garber, Judy E.; Rana, Huma Q.

doi:10.1002/cncr.34056

Cited by 12 publications

(6 citation statements)

References 37 publications

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“…While we have found eight PV carriers in HBOC genes and four carriers in LS genes (including a patient with co-occurrence of BRCA1 and MLH1 PV and diagnosed with EC, OC, and BC) in the group of 69 patients with EC and OC (11.6%), we have identified eight carriers of LS genes mutation and only one additional carrier of the CHEK2 gene mutation (a patient with EC, CRC, and melanoma) in the group of 34 patients with EC and CRC (26.5%). This suggests that the presence of double primary tumors could potentially represent a sole indication criterion for germline genetic testing, as indicated by previous studies ( 19 , 20 , 35 , 36 ).…”

Section: Discussionsupporting

confidence: 64%

Germline multigene panel testing of patients with endometrial cancer

Kral,

Jelinkova,

Zemankova

et al. 2023

Oncol Lett

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Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10 −17 ] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH ); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE / POLD1 ; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria.

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Section: Discussionsupporting

confidence: 64%

Germline multigene panel testing of patients with endometrial cancer

Kral,

Jelinkova,

Zemankova

et al. 2023

Oncol Lett

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“… 18 , 19 Bychkovsky et al’s analysis on 9714 multiple primary cancer patients showed the prevalence of germline pathogenic variants increased with the number of primary cancers (PCs): 13.1% with 2 PCs, 15.9% with 3 PCs, and 18.0% with ⩾4 PCs ( P = .00056). 20 In Win et al’s study over an average follow-up duration of 5 years, people with mismatch repair had an increased risk of colorectal cancer, bladder cancer, and urinary tract cancer. 21 Lynch syndrome (LS) is also a high-risk factor for multiple primary cancers.…”

Section: Discussionmentioning

confidence: 99%

One Patient With 4 Different Primary Cancers: A Case Report

Nguyen¹,

Nguyen²,

Phan³

et al. 2023

Clin Med Insights Case Rep

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Background: The development of medicine, especially in oncology, has been helping prolong the cancer patients’ survival, but also leads to increasing the possibility of getting multiple cancers. However, the possibility of getting 4 primary cancers in 4 different sites is extremely rare. Case presentation: A 63-year-old female patient was diagnosed with thyroid cancer in 2018, and then with right colon cancer in 2019. In 2020, this patient was diagnosed with left renal pelvis cancer, and most recently, in April 2022, she was hospitalized with bladder cancer diagnosis. Thanks to being closely and regularly followed-up, her malignancies had been detected early and treated suitably. Her health remains stable now and she is under following-up. Conclusion: Even though developing another primary cancer in a cancer survivor is not uncommon now and has the tendency to increase, a patient having 4 primary cancers in 4 different sites is still extremely rare and should be noticed, further followed up and investigated. Cancer patients and survivors need to be followed-up regularly, to early detect not only the progression or recurrence but also the second cancer (if it exists), to get timely and suitable treatment.

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“…The overall incidence of gHR mut in our cohort was 9.7% (51/527), which is in line with the results of previous reports (9.7–16.5%) [ 32 , 50 – 52 ]. The incidence of gHR mut in current study might be underestimated because patients with multiple primary cancers, who were more likely to harbor germline cancer susceptibility gene mutations, were excluded from initial study [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Germline mutations of homologous recombination genes and clinical outcomes in pancreatic cancer: a multicenter study in Taiwan

Cheng,

Su,

Chiang

et al. 2024

J Biomed Sci

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Background Cancer susceptibility germline mutations are associated with pancreatic ductal adenocarcinoma (PDAC). However, the hereditary status of PDAC and its impact on survival is largely unknown in the Asian population. Methods Exome sequencing was performed on 527 blood samples from PDAC individuals and analyzed for mutations in 80 oncogenic genes. Pathogenic and likely pathogenic (P/LP) germline variants were diagnosed according to the ACMG variant classification categories. The association between germline homologous recombination gene mutations (gHRmut, including BAP1, BRCA1, BRCA2, PALB2, ATM, BLM, BRIP1, CHEK2, NBN, MUTYH, FANCA and FANCC) and the treatment outcomes was explored in patients with stage III/IV diseases treated with first-line (1L) platinum-based versus platinum-free chemotherapy. Results Overall, 104 of 527 (19.7%) patients carried germline P/LP variants. The most common mutated genes were BRCA2 (3.60%), followed by ATR (2.66%) and ATM (1.9%). After a median follow-up duration of 38.3-months (95% confidence interval, 95% CI 35.0–43.7), the median overall survival (OS) was not significantly different among patients with gHRmut, non-HR germline mutations, or no mutation (P = 0.43). Among the 320 patients with stage III/IV disease who received 1L combination chemotherapy, 32 (10%) had gHRmut. Of them, patients receiving 1L platinum-based chemotherapy exhibited a significantly longer median OS compared to those with platinum-free chemotherapy, 26.1 months (95% CI 12.7–33.7) versus 9.6 months (95% CI 5.9–17.6), P = 0.001. However, the median OS of patients without gHRmut was 14.5 months (95% CI 13.2–16.9) and 12.6 months (95% CI 10.8–14.7) for patients receiving 1L platinum-based and platinum-free chemotherapy, respectively (P = 0.22). These results were consistent after adjusting for potential confounding factors including age, tumor stage, performance status, and baseline CA 19.9 in the multivariate Cox regression analysis. Conclusions Our study showed that nearly 20% of Taiwanese PDAC patients carried germline P/LP variants. The longer survival observed in gHRmut patients treated with 1L platinum-based chemotherapy highlights the importance of germline testing for all patients with advanced PDAC at diagnosis.

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Prevalence and spectrum of pathogenic variants among patients with multiple primary cancers evaluated by clinical characteristics

Cited by 12 publications

References 37 publications

Germline multigene panel testing of patients with endometrial cancer

Germline multigene panel testing of patients with endometrial cancer

One Patient With 4 Different Primary Cancers: A Case Report

Germline mutations of homologous recombination genes and clinical outcomes in pancreatic cancer: a multicenter study in Taiwan

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