AMP case report: Identification of multiple germline cancer predisposing gene variants in a single patient during tumor sequencing analysis

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With patients who harbor potential germline variants, we follow institution-specific guidelines. These guidelines include VAF-independent referrals, given that genetic changes like loss of heterozygosity in tumors can alter VAF, and referrals for genes that may or may not be involved in the somatic indication for sequencing. Some referrals may be age based, including those for APC, RB1, NF1, and TP53 in individuals with cancer diagnosed under the age of 30. Known germline founder variants are automatically referred. In addition, referrals may be based on phasing of mutations, for example, only referring biallelic MUTYH. Lastly, referrals often depend on prior treatments, including only referring EGFR T790M in the setting of EGFR-treatment naïve patients.

After identifying these potentially actionable germline variants and obtaining the results of homologous recombination deficiency testing, the patient was deemed a candidate for PARP inhibitors as adjunctive therapy for ovarian cancer. Due to the strong relationship of CDKN2A variants with familial melanoma and pancreatic cancer syndromes, the benefit of predictive genetic testing in relatives was discussed with the patient, as the patient has two nephews with melanoma but without known variants. While the patient has no offspring, she has one full sibling for whom predictive genetic testing was recommended. She was referred for consideration of pancreatic cancer screening studies through contrast-enhanced MRI/magnetic resonance cholangiopancreatography and/or endoscopic ultrasound and will continue with semiannual skin exams with dermatology. She will also continue with annual mammograms for breast screening. Multiple commercial genetic testing labs currently classify the detected RAD51C variant as a variant of uncertain significance, although there is conflicting data for pathogenicity. In addition, the germline status and clinical implications of the ERCC4 variant is still unknown. Providers who are familiar with hereditary cancer syndromes will provide the follow-up care because current knowledge surrounding these germline variants continues to evolve and may have an impact on future management.

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Dr. Israelyan is a third-year pathology resident in clinical pathology, Dylane Wineland is a genetic counselor, Dr. Priore is assistant professor of clinical pathology and laboratory medicine, and Dr. Roth is assistant professor of clinical pathology and laboratory medicine—all at the Hospital of the University of Pennsylvania and the Perelman School of Medicine, Philadelphia.

Test yourself

Here are three questions taken from the case report. Answers are online now at www.amp.org/casereports and will be published next month in CAP TODAY.

1. Which of the following biomarker descriptor terms best defines the role of homologous recombination deficiency testing in hereditary breast and ovarian cancer syndromes?
a. Diagnostic
b. Prognostic
c. Predictive
d. Diagnostic and prognostic
e. Prognostic and predictive

2. Germline alterations in CDKN2A are associated with predisposition to which of the following hereditary cancer syndromes?
a. Hereditary breast and ovarian cancer syndrome
b. Lynch syndrome (hereditary nonpolyposis colorectal cancer)
c. Melanoma-pancreatic cancer syndrome
d. Li-Fraumeni syndrome
e. Cowden syndrome

3. Which of the following suggestions are good practices with regard to genetic counseling referrals in patients with incidentally found germline variants on somatic-only testing?
a. Refer only if variant allele frequency is close to 50 percent
b. Refer regardless of whether germline mutation is related to somatic testing indication
c. Refer for APC, RB1, NF1, or TP53 variants regardless of patient age
d. Founder mutations do not need to be automatically referred
e. Refer MUTYH variants regardless of phasing

‘Test yourself’ answers

In the September 2023 issue was a case report, “Lung micropapillary adenocarcinomas revisited: A tale of antithesis with yearslong accumulative genetic alterations,” written by members of the Association for Molecular Pathology. Here are answers (in bold) to the three “test yourself ” questions that followed that case report.

1. Which of the following is the most common mutated gene in lung cancers?
a. KRAS
b. TP53
c. BRAF
d. EGFR

2. Which of the following statements about lung adenocarcinomas is false?
a. Micropapillary pattern of adenocarcinomas (MPC) are not considered aggressive variants of lung adenocarcinomas.
b. The presence of a micropapillary component of greater than five percent is an independent risk factor for recurrence.
c. The adverse prognosis of MPC is directly proportional to the percentage of micropapillary component.
d. Patients with MPC have lower five-year survival in stage-matched patients compared with other morphological variants.

3. Which of the following statements about lung carcinomas is false?
a. MPC is not the result of expanded growth of the papillary component.
b. TTF-1 immunohistochemistry positivity is seen in lung adenocarcinomas.
c. The most frequent EGFR gene mutations are targetable for therapy.
d. Newer mutations are acquired during tumor evolution.