The importance to update the guidelines for the use of genetic testing in noncancer patients in Brazil

The Brazilian National Regulatory Agency for Private Health Insurance and Plans has recently published a technical note defining the criteria for the coverage of genetic testing to diagnose hereditary cancer. In this study we show the case of a patient with a breast lesion and an extensive history of cancer referred to a private service of genetic counseling. The patient met both criteria for hereditary breast and colorectal cancer syndrome screening. Her private insurance denied coverage for genetic testing because she lacks current or previous cancer diagnosis. After she appealed by lawsuit, the court was favorable and the test was performed using next-generation sequencing. A deletion of MLH1 exon 8 was found. We highlight the importance to offer genetic testing using multigene analysis for noncancer patients.

Since January 2014, the Agência Nacional de Saúde (ANS -Brazilian National Regulatory Agency for Private Health Insurance and Plans) has included 22 new guidelines (Anexo da Nota 876/GGRAS/DIPRO/ANS) concerning the utilization of DNA sequencing and of fluorescence in situ hybridization for microduplications and microdeletions to diagnose 29 genetic diseases. Herein we show a report of a patient that did not meet the ANS criteria to benefit from genetic testing, but did meet international guidelines, and was diagnosed with a MLH1 germline mutation. We highlight that the patient inclusion criteria and for molecular methodology of the ANS guidelines should be reviewed.
This article highlights the importance of discussing the criteria for molecular diagnosis in the Brazilian health care system.

CASE REPORT AND DISCUSSION
A 36-year-old patient was referred to a private genetic counseling service because, besides an extensive family history of cancer, she had a 2.0 cm lump detected in her right breast, as assessed by Magnetic Resonance Imaging, of Breast Imaging Reporting and Data System (BIRADS) category 4. The biopsy by fine needle aspiration showed a ductal proliferative breast lesion. The patient had a high risk for breast cancer and family history of cancer, with kindred diagnosed before the age of 50 years. The analysis of her pedigree showed an autosomal dominant disorder from her paternal side ( Figure) with early onset cases of colon adenocarcinoma, gastric, lung, prostate and pancreas cancer.
According to the ANS guideline, the patient did not meet the criteria to be tested for germline mutations INTRODUCTION because (i) she had no current or previous cancer diagnosis, (ii) she was not of Ashkenazi jewish origin, and (iii) there were no known mutations in her family. It is important to highlight that the patient was informed she was not the perfect index patient for family genetic counseling since she was not diagnosed with cancer; thus, her result was limited to individual genetic counseling, i.e., a negative result for presence of mutation would not mean the absence of mutation in her family.
Since Brazil lacks a specific guideline to screen hereditary cancer, the worldwide applied United States National Comprehensive Cancer Network (NCCN) is routinely used. It comprises recommendations on the prevention, diagnosis, and management of malignancies across the continuum of care. The NCCN Guidelines incorporate real-time updates in keeping with the rapid advancements in the field of cancer research and management. For hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome (LS), the patient should meet revised Amsterdam criteria 8 or revised Bethesda criteria. 7 Genetic counseling consultation is a health service that provides information and support to people who have or may be at risk for genetic disorders. It also addresses patients' specific questions and concerns. The consultation is held by a multidisciplinary team with a psychologist, a medical doctor and a geneticist. After careful medical data collection and considering the patient history, she met NCCN Genetic/Familial High-Risk Assessment criteria both for breast and ovarian and for colorectal cancer, contrary to the ANS guideline. She was considered eligible for genetic screening, and the genes implicated with hereditary breast and ovarian cancer and hereditary nonpolyposis colorectal cancer were chosen to be sequenced.    8 The Bethesda guidelines included testing for tumor marker microsatellite instability (MSI), and the revised Bethesda criteria 7 specified all cancers known at the time to be associated with the syndrome. Prostate cancer has also been shown to be part of the syndrome. 6 The clinical testing criteria for hereditary nonpolyposis colorectal cancer currently applied (based on personal and family history) meets revised Bethesda criteria or revised Amsterdam criteria, in which at least three relatives must have had a cancer associated with Lynch syndrome (colorectal, cancer of endometrium, small bowel, ureter or renal-pelvis); all of the following criteria should be present: • One must be a first-degree relative of the other two; • At least two successive generations must be affected; • At least one relative with cancer associated with LS should be diagnosed before the age of 50 years; • Familial adenomatous polyposis should be excluded in colorectal cancer cases (if any); • Tumors should be verified whenever possible. The molecular diagnosis of hereditary nonpolyposis colorectal cancer in the index patient had an important role in individual and familial follow-up. The patient had been monitored only by a breast surgeon; however, after the result, the gastrointestinal tract was the center of the problem and she looked for a proctologist and gastroenterologist. Her family was aware of the hereditary risk for colorectal cancer and for extracolonic cancers, especially endometrial cancer.
The impact of genetic counseling in this family highlights the importance to track individuals at risk for hereditary cancer, in spite of the patient lacking a previous or current diagnosis of cancer. The main objective of DNA sequencing to identify germline mutations is to offer early detection of cancer; nevertheless, in some cases, prophylactic surgery should be recommended. The earliest the cancer diagnosis is concluded, the better is the patient prognosis.
Furthermore, early diagnosis can reduce treatment costs. For follow-up screening, this patient will undergo annual mammogram, breast ultrasound or magnetic resonance imaging, and colonoscopy, but certainly the costs for these exams are lower than those for cancer treatment, which can be around 10,000 BRL (around 2,850 USD) per month for Herceptin (www.brasindice.com.br).
In conclusion, this case report highlights the importance of performing multigene analysis by next-generation DNA sequencing in families with cancers at multiple sites, which reinforces the need to update the ANS guideline in Brazil. Herein, the patient's needs and concerns had changed after the molecular diagnosis, since the family was concerned only about breast annual exams, and thereafter they were encouraged to be followed also by a gastroenterologist. The molecular diagnosis by deep sequencing gave the opportunity for genetic counseling and thus general medical awareness will be performed.

ACKNOWLEDGMENTS
To the psychologist Ana Élida Gonçalves and the oncologists Rodrigo Jerônimo de Araújo and Cristine Teixeira de O. Lima Gaspar of the Hospital Liga Norteriograndense Contra o Câncer, Natal, Brazil, for helping with oncogenetic counseling of the patient.