CASE STUDY. Germline Test for Mother and Follow up Testing for Daughter: Assessment of Hereditary Cancer Risk. Introduction.

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CASE STUDY Germline Test for Mother and Follow up Testing for Daughter: Assessment of Hereditary Cancer Risk Introduction Germline cancer risk assessment tests are well-prescribed tests from Strand

1 CASE STUDY Germline Test for Mother and Follow up Testing for Daughter: Assessment of Hereditary Cancer Risk Introduction Germline cancer risk assessment tests are well-prescribed tests from Strand Life Sciences. These lab-developed tests are designed to understand whether a person harbors mutated genes that can cause hereditary cancers. In India, there is a high proportion of hereditary breast and ovarian cancer (HBOC) cases, a fact that is evident from the high incidence of breast and ovarian cancers in women in their thirties (1,2). Hereditary cancers - about 10% of all cancer cases - develop at a young age and are typically more aggressive as well. One way to manage the disease efficiently is to understand one s own personal risk before the actual development and detection of cancer. Strand offers many germline tests to people who have been diagnosed with cancer. When such patients are found positive for an inherited mutation, Strand also offers Mutation-Specific Tests (MST) or follow up testing to first degree relatives (siblings, children and parents) or other affected members in the family to understand if they are carriers of the same inherited cancer-causing gene. MSTs are convenient because the turnaround is rapid and consequently, the cost of the test is also low. Patient Profile Adira Joseph*, a 55-year-old high school math teacher from Mumbai was diagnosed with ovarian cancer in Adira was shocked, naturally, upon receiving this diagnosis. She never imagined that cancer would become a part of her life, just when life was running smoothly on the home as well as career front. She had always been careful with health management and led an active lifestyle complemented with a good diet and moderate alcohol consumption. Adira was advised standard chemotherapy for ovarian cancer, as well as genetic testing to understand the cause of her ovarian cancer. Gender: Female, proband (mother) plus daughter Age: 44 years and 26 years Location: Mumbai, Maharashtra Diagnosis: Ovarian Cancer, Hereditary BOC syndrome suspected Strand Test: Strand Germline Cancer Test Conclusion: BRCA1 mutation identified in proband Eligibility for PARP inhibitor therapy established Prevalence of HBOC in family confirmed MST offered to proband s daughter Daughter is negative for the heritable BRCA1 mutation Adira had received chemotherapy for her ovarian cancer, in several rounds, for nearly eleven years. Her cancer would respond to the treatment initially, but would re-emerge a few months later. Since the cancer was persistent, her oncologist advised her to undergo genetic testing to identify the genetic cause of her ovarian cancer. Family History Adira s mother had been diagnosed with ovarian cancer at the age of 55 years. Her mother s sister had also suffered from ovarian cancer (age of diagnosis, 55 years). Adira s maternal uncle had battled throat cancer. Adira s sister had been diagnosed with blood cancer, at the age of 22 years. Adira s daughter was 28 years old and was unaffected, when Adira took the germline test. Given this family history of various cancers, inheritance of a cancer-causing gene mutation was strongly suspected. Accordingly, the Strand Hereditary Cancer Test for hereditary predisposition towards breast and ovarian cancer was prescribed to Adira. * Name changed to protect patient privacy

2 Family Tree - Pre-Test Genetic Counselling Adira was found to be Positive for a heterozygous 'pathogenic' variant, detected in an essential splice donor site at the junction of exon 16-intron 16 of the BRCA1 gene. BRCA1 chr17: c>t c.507+1g>a

Key Findings A pathogenic mutation in the BRCA1 gene was detected in Adira s genome. This mutation was at the splice site between exon 16 and intron 16 in the BRCA1 gene.

3 Key Findings A pathogenic mutation in the BRCA1 gene was detected in Adira s genome. This mutation was at the splice site between exon 16 and intron 16 in the BRCA1 gene. Incorrect splicing of the BRCA1 mrna, owing to this mutation, was expected to create a frameshift mutation, leading to premature termination of the protein. The resultant BRCA1 protein would lack the BRCT2 domain that is engaged in DNA repair. Therefore, this loss-of-function variant of BRCA1 is the most probable genetic cause of Adira s ovarian cancer. Treatment Plan Generic chemotherapy would have been the therapy of choice for targeting Adira s ovarian cancer, if the germline analysis had not been done. However, the identification of the BRCA1 mutation in her DNA makes her eligible to receive PARP inhibitor therapy as well. Treatment of ovarian cancer patients with PARP inhibitors results in longer periods of progression-free survival in patients (3,4). Mutation-Specific Testing Adira was adamant that her 26-year-old daughter Pearl* be tested for the presence of the same BRCA1 mutation as well. Strand s genetic counsellor had explained the inheritance pattern of autosomal dominant mutations in genes such as BRCA1 and BRCA2 to her. She was aware that Pearl had a 50% chance of bearing the same mutation in her genome. Moreover, the counselor had stressed upon the fact that early identification of a woman s genetic status can lead to better health surveillance and better planning of motherhood. Also, Strand s MST tests are highly economical and simple. A small blood sample was all that Pearl had to provide to get her genome analyzed. MST was advised to Adira s younger daughters, aged 24 and 22 years, respectively, as well. The timing of the MST is just right for them since their BRCA status, if they are positive, can be leveraged to manage their decisions for having children. They can have children and then undergo risk-reduction surgery (removal of ovaries) that has a protective effect against ovarian cancer (5 7). Results of Mutation-Specific Testing The genetic variant identified in Adira s genome was NOT detected in Pearl s genome. Figure 1: Sanger sequencing data (electropherogram) from the individual showing the reference nucleotide 'G' at position c in the BRCA1 gene (RefSeq id:nm_007294). This finding was confirmed by sequencing with forward primer in two independent experiments. Therefore, Pearl is unlikely to suffer from hereditary breast and ovarian cancer, resulting from the hereditary mutation that Adira, her mother and presumably her aunt, also bear in their genomes. Pearl s risk for suffering from other cancers that can result as a function of having a BRCA1 mutation is also low (8,9).

4 Conclusions Adira, a 44-year-old woman from Mumbai, was diagnosed with ovarian cancer and was advised genetic testing. Adira s family history indicated a strong likelihood of hereditary breast and ovarian cancer in the family. The Strand Hereditary Cancer Test facilitated the identification of a BRCA1 mutation- chr17: c>t c g>a in Adira s DNA. Identification of this mutation indicates her eligibility to receive PARP inhibitor therapy instead of standard chemotherapy. Mutation-specific testing of Adira s daughter Pearl led to the confirmation that she had NOT inherited this pathogenic mutation. Adira and Pearl were counseled about their risks for developing other cancers (apart from breast and ovarian cancer) in their lifetime. Germline (proband) + MST (first degree relatives) tests are a good combination to rapidly assess the prevalence of hereditary cancer syndromes in families. Strand Hereditary Cancer Test The Strand Hereditary Cancer Test is designed to identify mutations in 19 genes that are involved in several inherited cancers. The following genes are analyzed in samples from breast and ovarian cancer patients, as per international genetic testing guidelines. ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, TP53

References 1 2 3 4 5 6 7 8 9 Mannan AU, Singh J, Lakshmikeshava R, Thota N, Singh S, Sowmya TS, et al.

5 References Mannan AU, Singh J, Lakshmikeshava R, Thota N, Singh S, Sowmya TS, et al. Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: implications of embracing a multi-gene panel in molecular diagnosis in India. J Hum Genet [Internet]. 2016;61(6): Available from: Malvia S, Bagadi SA, Dubey US, Saxena S. Epidemiology of breast cancer in Indian women. Asia Pac J Clin Oncol [Internet] Aug [cited 2017 Aug 16];13(4): Available from: Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med [Internet] Dec [cited 2017 Jan 16];375(22): Available from: Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol [Internet] Jan [cited 2017 Jan 21];18(1): Available from: Ricciardi E, Tomao F, Aletti G, Bazzurini L, Bocciolone L, Boveri S, et al. Risk-reducing Salpingo Oophorectomy in Women at Higher Risk of Ovarian and Breast Cancer: A Single Institution Prospective Series. Anticancer Res [Internet] Sep 6 [cited 2017 Sep 12];37(9): Available from: Zakhour M, Danovitch Y, Lester J, Rimel BJ, Walsh CS, Li AJ, et al. Occult and subsequent cancer incidence following risk-reducing surgery in BRCA mutation carriers. Gynecol Oncol [Internet] Nov [cited 2017 Sep 12];143(2): Available from: Lee YJ, Lee SW, Kim KR, Jung KH, Lee JW, Kim YM. Pathologic findings at risk-reducing salpingo-oophorectomy (RRSO) in germline BRCA mutation carriers with breast cancer: significance of bilateral RRSO at the optimal age in germline BRCA mutation carriers. J Gynecol Oncol [Internet] Jan [cited 2017 May 7];28(1):e3. Available from: Lee M V., Katabathina VS, Bowerson ML, Mityul MI, Shetty AS, Elsayes KM, et al. BRCA -associated Cancers: Role of Imaging in Screening, Diagnosis, and Management. RadioGraphics [Internet] May 26 [cited 2017 Jul 10]; Available from: van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, Hoogerbrugge N, Verhoef S, Vasen HFA, et al. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet [Internet] Sep [cited 2017 Jul 11];42(9): Available from: Strand Life Sciences Pvt. Ltd. 5th Floor, Kirloskar Business Park, Bellary Road, Hebbal, Bangalore Phone: , support.strandx@strandls.com, Strand is accredited by # Certificate No. MC Strand Patient ID: GC Strand Life Sciences

CASE STUDY. Mutation-Specific Testing: Eligibility for PARP Inhibitor Therapy Established. Introduction. Patient Profile.

CASE STUDY. Mutation-Specific Testing: Eligibility for PARP Inhibitor Therapy Established. Introduction. Patient Profile. CASE STUDY Mutation-Specific Testing: Eligibility for PARP Introduction Genetic testing is an emergent diagnostic technique that can provide specific and actionable inputs to the management of cancer therapy.