Hiroyuki Matsubayashi

Factors affecting the implementation of cascade testing of patients with BRCA1 or BRCA2 pathogenic germline variants in Japan

AbstractIn clinical management for hereditary cancer patients, risk assessment is needed not only for patients but also for their blood relatives. In people with Hereditary Breast and Ovarian Cancer syndrome (HBOC), benefits are demonstrated by identifying relatives with BRCA1 and BRCA2 pathogenic germline variants (PGV) and implementing clinical surveillance and risk‐reduction surgeries for the at‐risk organs. To date, the uptake of cascade testing has been reported to be insufficient, but only a limited number of studies have analyzed the barriers to cascade testing. The current study aimed to analyze the uptake of cascade testing in the relatives of Japanese HBOC probands and clarify the factors that promote cascade testing uptake. This retrospective study included 125 probands carrying BRCA1 or BRCA2 PGV and 425 of their first‐degree relatives (FDRs). Individual clinicodemographic data were collected from medical records, and comparisons were made between those who did and did not undergo cascade testing. Ninety‐two (21.6%) FDRs of HBOC probands underwent cascade testing. Approximately 70% of the relatives underwent testing within 6 months of the proband's genetic testing. Independent predictors of cascade testing of 425 FDRs were: being present at the proband's genetic counseling session [odds ratio (OR): 8.3, 95% CI 4.2–16.1], cost‐free testing (OR: 2.4, 95% CI 1.4–4.2), being the child of a proband (OR: 1.9, 95% CI 1.1–3.2), and female sex (OR: 1.8, 95% CI 1.0–3.0). The cascade testing uptake rate of FDRs in this study was similar to or lower than other countries. cascade testing uptake can be improved in HBOC families by encouraging relatives (children, siblings, and parents) to attend genetic counseling with the proband. Further prospective studies are needed to pursue the reasons for accepting cascade testing, including an evaluation of intrafamily communication processes.

Genetic medicine of familial and hereditary pancreatic cancer: Recent update in the era of precision cancer medicine

AbstractIn Japan, 5 years have passed since the initiation of precision cancer medicine, and recent data accumulation in familial pancreatic cancer (FPC) and hereditary pancreatic cancer is outstanding. Multigene germline panel tests (MGPTs) have revealed that 7%–18% of patients with pancreatic cancer (PC) harbor pathogenic germline variants (PGVs), almost equal to the levels of breast, ovarian, endometrial, and colorectal cancers, with a higher incidence in FPC (14%–26%). The majority of PGVs seen in PC patients are clinically actionable and associated with homologous recombination (HR) pathways (6%–10%, particularly BRCA1/2 in 5%–6%), and the clinical guidelines recommend or propose genetic testing for all PC patients. Consensus guidelines have been established for most of the hereditary syndromes associated with PC risks, and surveillances of the pancreas and other at‐risk organs are recommended for PGV carriers. Hereditary breast and ovarian cancer (HBOC) is the commonest hereditary cancer syndrome that has moderately increasing life‐time risks of PC (3%–7% in Western countries); however, recent Japanese research demonstrated a higher risk level (BRCA1: 16%, BRCA2: 14%). Moreover, recent evidence has suggested a risk linkage between PC and ovarian cancer in HBOC pedigrees. High scores of homologous recombination deficiency suggest biallelic dysfunction of BRCA or other HR‐related genes, and the likely effectiveness of platinum agents and PARP inhibitors against PCs. Remote counseling and testing are possible option in the future genetic medicine. As PC ranks in the second commonest target of precision cancer medicine in Japan, we must treat the patients and manage their at‐risk relatives efficiently.

Four cancer cases with pathological germline variant RAD51D c.270_271dup

Abstract Pathological germline variants (PGVs) of RAD51D increase the risk of breast and ovarian cancer. In East Asia, c.270_271dup is the most frequently detected PGV of RAD51D ; however, only a few cases have been reported in Japan. We report four cancer cases with a germline RAD51D c.270_271dup PGV. Three of them (lung cancer: 2, oral cancer: 1) were incidentally identified by whole genome sequencing in patients negative for the associated cancer histories, homologous recombination (HR) deficiency, or a second hit of RAD51D in the cancer DNA. For genetic counseling, we provided information on surveillance and cascade testing based on Western guidelines. The PGVs of moderate‐risk HR‐related genes are difficult to detect based on phenotype, especially in male‐predominant pedigrees. The current spread of cancer genomic analysis will increase opportunities for incidental variant identification. The establishment of Japanese guidelines is expected to aid in the management of PGV carriers of moderate‐risk genes.

A Japanese case of ovarian mucinous adenocarcinoma with germline double variants of MSH2 and BRCA2

Germline double heterozygosity (GDH) is rarely reported in cases of inherited cancer syndromes, and GDH of a mismatch repair gene and BRCA has never been reported in Japan. Nonetheless, the current report demonstrates a case of ovarian mucinous adenocarcinoma with initiated Lynch syndrome (LS)-related surveillance because of a known germline MSH2 variant. Six and a half years after oophorectomy, multiple tumors developed in the patient's lungs, bones, and lymph nodes, and histology results confirmed mucinous adenocarcinoma. Systemic chemotherapy including an anti-PD-L1 antibody was effective for >1 year, but brain metastases developed. Pathology of the brain tumors showed mucinous adenocarcinoma without expression of MSH2 and MSH6, while multi-gene panel testing demonstrated not only high microsatellite instability and a high tumor mutation burden, but also germline BRCA2 variants. Further, germline testing in relatives confirmed both variants were from the paternal line, from which many LS-related cancers develop, but not BRCA-related cancer.

Clinical risk management of breast, ovarian, pancreatic, and prostatic cancers for BRCA1/2 variant carriers in Japan

Opportunities for genetic counseling and germline BRCA1/2 (BRCA) testing are increasing in Japan owing to cancer genomic profiling testing and companion diagnostics being covered by national health insurance for patients with BRCA-related cancers. These tests are useful not only to judge whether platinum agents and PARP inhibitors are indicated but also to reveal an autosomal-dominant inherited cancer syndrome: hereditary breast and ovarian cancer. In individuals with germline BRCA variants, risk of cancers of the breast, ovary, pancreas, and prostate is significantly increased at various ages of onset, but the stomach, uterus, biliary tract, and skin might also be at risk. For women with pathogenic BRCA variants, breast awareness and image analyses should be initiated in their 20s, and risk-reducing procedures such as mastectomy are recommended starting in their 30s, with salpingo-oophorectomy in their late 30s. For male BRCA pathogenic variant carriers, prostatic surveillance should be applied using serum prostate-specific antigen starting in their 40s. For both sexes, image examinations ideally using endoscopic ultrasound and magnetic resonance cholangiopancreatography and blood testing should begin in their 50s for pancreatic surveillance. Homologous recombination pathway-associated genes are also causative candidates. Variant pathogenicity needs to be evaluated every 6-12 months when results are uncertain for clinical significance. Genetic counseling needs to be offered to the blood relatives of the pathogenic variant carriers with suitable timing. We review the recommended cross-organ BRCA risk management in Japan.

Genetic medicine in companion diagnostics of germline BRCA testing of Japanese pancreatic cancer patients

In 2021, Japan's national health insurance made germline BRCA (g.BRCA) testing available to unresectable pancreatic cancer (PC) patients as a companion diagnostic (CD) of the PARP inhibitor. This study investigated the incidence of the g.BRCA variant (g.BRCAv.) and the status of the genetic medicine associated with its testing. A total of 110 PC patients underwent the testing, five of whom (4.5%) had a deleterious g.BRCA2v. (all truncations) but no g.BRCA1v. The turnaround time (TAT) to the doctors was 13 days, and to the patients, 17 days. A higher incidence of a BRCA-related family history and a shorter TAT were seen in the g.BRCAv. patients, but they were insignificant (p = 0.085 and p = 0.059, respectively). Genetic counseling was not performed for three g.BRCA2v. patients because two of them had no accessible relatives and one died of the cancer before the genetic report was completed. Two families underwent generic counseling and testing based on the patient's genetic data. g.BRCAv. is recognized in a small fraction of PC cases, and the following genetic counseling is done more for the relatives than for the patients. TAT was constant and did not affect much on the genetic counseling, but the earlier testing is expected for patients with a deadly cancer.